Vascular smooth muscle cells (VSMCs) are the key moderators of cerebrovascular dynamics in response to the brain’s oxygen and nutrient demands. Crucially, VSMCs may provide a sensitive biomarker for neurodegenerative pathologies where vasculature is compromised. An increasing body of research suggests that VSMCs have remarkable plasticity and their pathophysiology may play a key role in the complex process of neurodegeneration. Furthermore, extrinsic risk factors, including environmental conditions and traumatic events can impact vascular function through changes in VSMC morphology. VSMC dysfunction can be characterised at the molecular level both preclinically, and clinically ex vivo. However the identification of VSMC dysfunction in living individuals is important to understand changes in vascular function at the onset and progression of neurological disorders such as dementia, Alzheimer’s disease, and Parkinson’s disease. A promising technique to identify changes in the state of cerebral smooth muscle is cerebrovascular reactivity (CVR) which reflects the intrinsic dynamic response of blood vessels in the brain to vasoactive stimuli in order to modulate regional cerebral blood flow (CBF). In this work, we review the role of VSMCs in the most common neurodegenerative disorders and identify physiological systems that may contribute to VSMC dysfunction. The evidence collected here identifies VSMC dysfunction as a strong candidate for novel therapeutics to combat the development and progression of neurodegeneration, and highlights the need for more research on the role of VSMCs and cerebrovascular dynamics in healthy and diseased states.

/pdf/vascular-smooth-muscle-cell-dysfunction-in-neurodegeneration-3iychv6r.pdf

Vascular smooth muscle cell dysfunction in neurodegeneration

The dual orexin receptor antagonist daridorexant, studied in two phase III trials, dose-dependently improved objective and subjective sleep variables and daytime functioning in adults with insomnia. Because treatment of insomnia in older adults is challenging and has limited options, the purpose of the current analysis was to further analyse the phase III trial studying the higher doses of daridorexant, those that showed efficacy (daridorexant 50 mg, daridorexant 25 mg and placebo, nightly for 3 months), and compare the safety and efficacy of daridorexant in patients aged ≥ 65 (‘older adults’) to those aged < 65 years (‘younger adults’). Analyses by age (≥ 65 years, n = 364; < 65 years, n = 566) were performed on data from the randomised, double-blind, placebo-controlled Trial 1 in adult patients with insomnia (NCT03545191). Efficacy endpoints included a change from baseline at month 1 and month 3 in polysomnography-measured wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time (sTST) and daytime functioning assessed using the validated Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Safety endpoints included adverse events and the Visual Analog Scale for morning sleepiness. At baseline, mean [standard deviation] WASO was numerically greater (110 [39] vs 92 [38] min) in older than younger adults, while LPS was comparable (~ 65 min). Mean baseline IDSIQ total and all domain scores were numerically lower (i.e. better) in older adults. Daridorexant caused similar reductions in WASO and LPS, and similar increases in sTST, from baseline, in both age groups; improvements were numerically greater with daridorexant 50 mg than 25 mg. At month 3, daridorexant 50 mg, compared with placebo, decreased WASO by a least-squares mean of 19.6 (95% confidence interval 9.7, 29.5) in older patients versus 17.4 min (10.7, 24.0) in younger patients and decreased LPS by a least-squares mean of 14.9 (7.5, 22.3) in older patients versus 9.7 min (3.7, 15.7) in younger patients. Daridorexant 50 mg increased sTST from baseline to month 3 by a least-squares mean of 59.9 (49.6, 70.3) in older patients versus 57.1 min (48.9, 65.3) in younger patients. Daridorexant 50 mg progressively improved IDSIQ total and domain scores from week 1 onwards similarly in both groups; daridorexant 25 mg improved IDSIQ scores, but only in younger adults. In both age groups, in comparison with placebo, the overall incidence of adverse events was comparable, and there were fewer falls on daridorexant. Daridorexant improved Visual Analog Scale morning sleepiness in both groups; daridorexant 50 mg increased the mean (standard deviation) Visual Analog Scale morning sleepiness score by 15.9 (20.7) in older adults and by 14.9 (18.7) in younger adults from baseline to month 3. In older adults, there was one case of sleep paralysis, and no cases of narcolepsy, cataplexy, or complex sleep behaviour. In older patients with insomnia, as in younger patients, the efficacy of daridorexant is maximal on night-time and daytime variables at the higher dose of 50 mg. Older patients particularly require this dose to improve daytime functioning. Older patients are not at an increased risk of adverse events or residual effects the next morning after night-time administration of daridorexant, even at 50 mg. The dose of daridorexant does not need to be decreased for older patients. ClinicalTrials.gov (NCT03545191) [first posted: 4 June, 4 2018], https://clinicaltrials.gov/ct2/show/NCT03545191 . The burden of chronic insomnia (difficulty in falling/staying asleep or not getting enough sleep) increases with age yet treatment options in older patients are limited. In older patients, because of a risk of side effects, guidelines suggest caution when prescribing sleep medications and, for some drugs, recommend starting at a lower dose. Daridorexant was approved in 2022 for the treatment of insomnia in adults following positive results in two trials that showed daridorexant significantly improved night-time sleep and daytime functioning over 3 months of treatment in adults with insomnia. Approximately 40% of patients taking part in these trials were aged 65 years or older. This current analysis compared the safety and benefits of daridorexant in older adults (aged at least 65 years) and younger adults (aged less than 65 years) in the trial that administered the highest two doses of daridorexant, 25 and 50 mg. The results showed that the benefits of daridorexant were comparable in both age groups over 3 months; compared with placebo, daridorexant improved night-time sleep (reduced time awake during the night, reduced time to fall asleep and increased total sleep time) and daytime functioning—patients had less daytime sleepiness and a better mood and feeling of alertness. In older patients, the benefits, particularly for daytime functioning, were greatest at the higher 50-mg dose, without any increase in side effects. Both doses of daridorexant were equally well tolerated in the two age groups, indicating that treatment with daridorexant at 50 mg can be safely started in older patients. 

/pdf/efficacy-and-safety-of-daridorexant-in-older-and-younger-3vnbrcke.pdf

Efficacy and Safety of Daridorexant in Older and Younger Adults with Insomnia Disorder: A Secondary Analysis of a Randomised Placebo-Controlled Trial

Hypertension remains a major contributor to cardiovascular disease (CVD), a leading cause of global death. One of the major insults that drive increased blood pressure is inflammation. While it is the body's defensive response against some homeostatic imbalances, inflammation, when dysregulated, can be very deleterious. In this review, we highlight and discuss the causative relationship between inflammation and hypertension. We critically discuss how the interplay between inflammation and reactive oxygen species evokes endothelial damage and dysfunction, ultimately leading to narrowing and stiffness of blood vessels. This, along with phenotypic switching of the vascular smooth muscle cells and the abnormal increase in extracellular matrix deposition further exacerbates arterial stiffness and noncompliance. We also discuss how hyperhomocysteinemia and microRNA act as links between inflammation and hypertension. The premises we discuss suggest that the blue‐sky scenarios for targeting the underlying mechanisms of hypertension necessitate further research.

Inflammation and hypertension: Underlying mechanisms and emerging understandings

Abstract In addition to their lipid-lowering functions, statins elicit additional pleiotropic effects on apoptosis, angiogenesis, inflammation, senescence, and oxidative stress. Many of these effects have been reported in cancerous and noncancerous cells like endothelial cells (ECs), endothelial progenitor cells (EPCs) and human umbilical vein cells (HUVCs). Not surprisingly, statins' effects appear to vary largely depending on the cell context, especially as pertains to modulation of cell cycle, senescence, and apoptotic processes. Perhaps the most critical reason for this discordance is the bias in selecting the applied doses in various cells. While lower (nanomolar) concentrations of statins impose anti-senescence, and antiapoptotic effects, higher concentrations (micromolar) appear to precipitate opposite effects. Indeed, most studies performed in cancer cells utilized high concentrations, where statin-induced cytotoxic and cytostatic effects were noted. Some studies report that even at low concentrations, statins induce senescence or cytostatic impacts but not cytotoxic effects. However, the literature appears to be relatively consistent that in cancer cells, statins, in both low or higher concentrations, induce apoptosis or cell cycle arrest, anti-proliferative effects, and cause senescence. However, statins’ effects on ECs depend on the concentrations; at micromolar concentrations statins cause cell senescence and apoptosis, while at nonomolar concentrations statins act reversely. 

/pdf/paradoxical-effects-of-statins-on-endothelial-and-cancer-3bd7cujx.pdf

Paradoxical effects of statins on endothelial and cancer cells: the impact of concentrations

Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced neointima (NI) and vascular fibrosis through mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through the inactivation of Yes-associated protein (YAP). The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, VSMC proliferation, and ECM degradation remodeling through the inhibition of transforming growth factor (TGF)-beta/NF-κB pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced IH in response to endothelial damage. Therefore, this study suggests a promising strategy for treating coronary artery disease through localized drug delivery of customized drug combinations. 

Effect of sequential release of sirolimus and rosuvastatin using silk fibroin microneedle to prevent intimal hyperplasia.

STUDY OBJECTIVES
Significant variability exists in patient populations and diagnostic capabilities among hospital-based emergency departments (HBEDs) and freestanding emergency departments (FSEDs). While high sensitivity cardiac troponin (hs-cTn) research has focused on HBEDs, its application in FSEDs remains unexplored. This study assesses the comparative, real-world effectiveness of a 0/1-h accelerated protocol (AP) using hs-cTn between HBEDs and FSEDs.


METHODS
We conducted a pre-planned, secondary analysis of a stepped-wedge cluster randomized trial involving nine EDs within an integrated health system, from July 2020 to March 2021, comprised of five HBEDs and four FSEDs. The trial implemented a 0/1-h AP utilizing hs-cTnI to evaluate acute myocardial infarction (AMI). Adult ED patients with an ECG and cardiac troponin ordered were eligible, excluding those with STEMI, hs-cTnI > 18 ng/L, or trauma-related symptoms. The primary outcome was safe ED discharge, defined as discharge without death or AMI within 30 days.


RESULTS
The trial included 32,609 patients, 26,957 in HBEDs and 5652 in FSEDs. Safe discharge from HBED occurred 53.7% (5935/11,062) of the time in the standard care arm and 50.3% (7991/15895) under the AP (aOR 1.04, 95% CI 0.94-1.15, p = 0.50). Safe discharge from a FSED occurred 86.0% (2102/2443) of the time in the standard care arm and increased to 95.0% (3049/3209) under the AP (aOR 1.48, 95% CI 1.03-2.13, p = 0.033). Overall, the observed association between the AP and safe discharge was stronger in FSEDs than in HBEDs ( Δ $$ \Delta $$ log(aOdds) 1.05, 95% CI (0.82, 1.29), p < 0.001).


CONCLUSION
Implementing a 0/1-h AP using hs-cTnI to evaluate for AMI was associated with higher rates of safe discharge in FSEDs compared to HBEDs.

Comparing Outcomes of a Rapid High-Sensitivity Troponin Protocol Between Hospital-Based and Freestanding Emergency Departments.

Accuracy and Actionability of TikTok Content on Cosmetic Limb Lengthening: A Comparison between Healthcare Professional and Non-professional Sources

Role of RhoA and Rho-associated kinase in phenotypic switching of vascular smooth muscle cells: Implications for vascular function.

This study aims to examine the sleep pattern and predictors of daily vs. as-needed use of hypnotics in middle-aged and older adults with insomnia.Patients aged 50-75 who use hypnotics for insomnia were identified via electronic medical records and were recruited. Data about sociodemographics, mood and cognitive screening measures, and questions related to sleep patterns were collected through an interview conducted over the phone.A sample of 66 participants was recruited, of which 69.7% were females. Three quarters (49/66, 74.2%) used hypnotics daily, with 43% (21/49) of daily hypnotics users sleeping more than 8 h per night. Two-fifths (26/66, 39.4%) of participants still had clinically significant insomnia even after taking hypnotics. After adjusting for age, years of hypnotics use, sleeping hours per night, PHQ-2 score, and frequency of pain at night, the logistic regression model showed that younger age (p = 0.023) and longer sleeping hours per night (p = 0.025) were significantly associated with daily hypnotics use when compared to as needed hypnotics use.Many hypnotic users still have clinically significant insomnia and poor quality of sleep as reflected by perceived longer sleep duration and more daytime napping which could be related to drug-related residual sedation. Hypnotic use may not be the best solution for insomnia treatment in an older population, and physicians should regularly reassess the use of hypnotics. 

/pdf/sleep-pattern-and-predictors-of-daily-versus-as-needed-3omklzki.pdf

Sleep pattern and predictors of daily versus as-needed hypnotics use in middle-aged and older adults with insomnia

Contemporary Approach to Acute Pancreatitis in Emergency Medicine

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Munir Sidani

Author Tools

Chat about Author