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JMIR Research Protocols Jun 2024Cigarette smoking is a leading cause of morbidity and mortality. For adults who smoke cigarettes and cannot or will not quit smoking, smoke-free products, such as... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cigarette smoking is a leading cause of morbidity and mortality. For adults who smoke cigarettes and cannot or will not quit smoking, smoke-free products, such as nicotine pouches, have been recognized as a potential alternative to smoking combusted cigarettes to reduce harm due to cigarette smoking. The role of flavors in these smoke-free products in tobacco harm reduction has not been fully understood.
OBJECTIVE
This study evaluates the effect of flavors in on! nicotine pouch products (research products) in the reduction of cigarette smoking among adults who smoke cigarettes in their natural environment.
METHODS
This study uses a sequential, multiple assignment, randomized trial design. Approximately 400 eligible adults who smoke cigarettes will be enrolled and randomized to have access to either the Original (unflavored) on! nicotine pouch product only or a complete flavor profile (ie, Berry, Cinnamon, Citrus, Coffee, Mint, Original, and Wintergreen) of on! nicotine pouch products. After 3 weeks, participants in the Original-only arm will be randomized again, with half remaining in the Original-only arm and half having access to the complete flavor profile for another 3 weeks. Primary outcomes are expired-air carbon monoxide (CO) levels. Secondary outcomes are self-reported cigarette consumption and CO-verified cigarette abstinence.
RESULTS
Recruitment and data collection started in September 2023 and is projected to last until March 2025. We anticipate completing the data analysis in 2025. As of May 2024, we have enrolled 314 participants.
CONCLUSIONS
This study will provide empirical evidence about the effect that flavor availability in smoke-free products may have in reducing cigarette smoking.
TRIAL REGISTRATION
ClinicalTrials.gov NCT06072547; https://clinicaltrials.gov/study/NCT06072547.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/56565.
Topics: Humans; Flavoring Agents; Adult; Female; Male; Smoking Cessation; Nicotine; Middle Aged; Smoking; Tobacco Products
PubMed: 38905632
DOI: 10.2196/56565 -
Journal of Neural Transmission (Vienna,... Jun 2024Anticholinergic (AC) drugs, a medication class that acts by blocking nicotinic and muscarinic acetylcholine receptors, were first utilized for therapeutic purposes in... (Review)
Review
Anticholinergic (AC) drugs, a medication class that acts by blocking nicotinic and muscarinic acetylcholine receptors, were first utilized for therapeutic purposes in the mid-19th century. Initial applications were as symptomatic therapy for Parkinson disease (PD), a practice continuing to the present. Initially, the AC drugs used were naturally-occurring plant compounds. Synthetic AC drugs were developed in the late 1940s and predominated in neurological therapeutics. Until the advent of pharmaceuticals acting upon striatal dopaminergic motor pathways, AC drugs provided the only effective means for lessening tremors and other clinical problems of the PD patient. However, because dopaminergic compounds are so effective at meeting the needs of the typical PD patient, AC medications are far less utilized by clinicians today. In recent years, there has been only a few investigations of AC drugs as neurological treatments. This review will revisit the clinical landscape of AC pharmacology and application for movement disorders along with recent research in search of improving therapeutics with AC drugs.
PubMed: 38904792
DOI: 10.1007/s00702-024-02799-7 -
Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.Clinical Drug Investigation Jun 2024Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms... (Review)
Review
Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.
PubMed: 38904739
DOI: 10.1007/s40261-024-01377-9 -
Archives of Microbiology Jun 2024Cotinine, the primary metabolite of nicotine in the human body, is an emerging pollutant in aquatic environments. It causes environmental problems and is harmful to the...
Cotinine, the primary metabolite of nicotine in the human body, is an emerging pollutant in aquatic environments. It causes environmental problems and is harmful to the health of humans and other mammals; however, the mechanisms of its biodegradation have been elucidated incompletely. In this study, a novel Gram-negative strain that could degrade and utilize cotinine as a sole carbon source was isolated from municipal wastewater samples, and its cotinine degradation characteristics and kinetics were determined. Pseudomonas sp. JH-2 was able to degrade 100 mg/L (0.56 mM) of cotinine with high efficiency within 5 days at 30 ℃, pH 7.0, and 1% NaCl. Two intermediates, 6-hydroxycotinine and 6-hydroxy-3-succinoylpyridine (HSP), were identified by high-performance liquid chromatography and liquid chromatograph mass spectrometer. The draft whole genome sequence of strain JH-2 was obtained and analyzed to determine genomic structure and function. No homologs of proteins predicted in Nocardioides sp. JQ2195 and reported in nicotine degradation Pyrrolidine pathway were found in strain JH-2, suggesting new enzymes that responsible for cotinine catabolism. These findings provide meaningful insights into the biodegradation of cotinine by Gram-negative bacteria.
Topics: Pseudomonas; Biodegradation, Environmental; Cotinine; Wastewater; Nicotine; Pyridines; Genome, Bacterial; Phylogeny; Succinates
PubMed: 38904699
DOI: 10.1007/s00203-024-04036-x -
Scientific Reports Jun 2024Acetylcholine (ACh) plays a pivotal role as a neurotransmitter, influencing nerve cell communication and overall nervous system health. Imbalances in ACh levels are...
Acetylcholine (ACh) plays a pivotal role as a neurotransmitter, influencing nerve cell communication and overall nervous system health. Imbalances in ACh levels are linked to neurodegenerative diseases, such as Alzheimer's and Parkinson's. This study focused on developing electrochemical sensors for ACh detection, utilizing graphene oxide (GO) and a composite of reduced graphene oxide and zinc oxide (rGO/ZnO). The synthesis involved modified Hummers' and hydrothermal methods, unveiling the formation of rGO through deoxygenation and the integration of nano-sized ZnO particles onto rGO, as demonstrated by XPS and TEM. EIS analysis also revealed the enhancement of electron transfer efficiency in rGO/ZnO. Cyclic voltammograms of the electrode, comprising the rGO/ZnO composite in ACh solutions, demonstrated prominent oxidation and reduction reactions. Notably, the composite exhibited promise for ACh detection due to its sensitivity, low detection threshold, reusability, and selectivity against interfering compounds, specifically glutamate and gamma-aminobutyric acid. The unique properties of rGO, such as high specific surface area and electron mobility, coupled with ZnO's stability and catalytic efficiency, contributed to the composite's potential in electrochemical sensor applications. This research, emphasizing the synthesis, fabrication, and characterization of the rGO/ZnO composite, established itself as a reliable platform for detecting the acetylcholine neurotransmitter.
Topics: Graphite; Zinc Oxide; Acetylcholine; Electrochemical Techniques; Oxidation-Reduction; Electrodes; Biosensing Techniques; Humans
PubMed: 38902301
DOI: 10.1038/s41598-024-64238-7 -
Clinics (Sao Paulo, Brazil) 2024To investigate how language deteriorates over the Alzheimer's Disease course. (Observational Study)
Observational Study
OBJECTIVE
To investigate how language deteriorates over the Alzheimer's Disease course.
METHODS
A cross-sectional, observational study was carried out. 35 patients diagnosed with dementia due to AD using the NINCDS-ARDRA criteria and undergoing treatment for AD with a therapeutic dose of acetylcholinesterase inhibitors were assessed by the Boston Diagnostic Aphasia Examination (BDAE). The sample comprised 15 patients with mild AD (MMSE > 23, CDR = 0 or 0.5‒1.0) and 20 patients with moderate AD (MMSE = 13‒23, CDR = 2). The results for the 2 groups on all language tasks were compared.
RESULTS
A statistically significant difference was found between the mild and moderate AD groups for total score on the BDAE (95% CI 47.10‒114.08, t = 5.0, DF = 21, p = 0.000*), as well as on several tasks involving oral and writing comprehension, language oral expression and writing.
CONCLUSION
The study results showed major changes in the moderate stage. Also, the decline in language performance correlated with the worsening of dementia syndrome, independently of sociodemographic variables.
Topics: Humans; Alzheimer Disease; Male; Female; Cross-Sectional Studies; Aged; Severity of Illness Index; Aged, 80 and over; Language Disorders; Language Tests; Disease Progression; Neuropsychological Tests; Middle Aged; Socioeconomic Factors; Cholinesterase Inhibitors
PubMed: 38901132
DOI: 10.1016/j.clinsp.2024.100412 -
Immunological Medicine Jun 2024Postural orthostatic tachycardia syndrome (POTS) is characterized by exaggerated orthostatic tachycardia in the absence of orthostatic hypotension. The pathophysiology... (Review)
Review
Postural orthostatic tachycardia syndrome (POTS) is characterized by exaggerated orthostatic tachycardia in the absence of orthostatic hypotension. The pathophysiology of POTS may involve hypovolemia, autonomic neuropathy, a hyperadrenergic state, and cardiovascular deconditioning, any of which can co-occur in the same patient. Furthermore, there is growing evidence of the role of autoimmunity in a subset of POTS cases. In recent years, investigators have described an increased rate of autoimmune comorbidities as evidenced by the finding of several types of neural receptor autoantibody and non-specific autoimmune marker in patients with POTS. In particular, the association of the disease with several types of anti-G protein-coupled receptor (GPCR) antibodies and POTS has frequently been noted. A previous study reported that autoantibodies to muscarinic AChRs may play an important role in POTS with persistent, gastrointestinal symptoms. To date, POTS is recognized as one of the sequelae of coronavirus disease 2019 (COVID-19) and its frequency and pathogenesis are still largely unknown. Multiple autoantibody types occur in COVID-related, autonomic disorders, suggesting the presence of autoimmune pathology in these disorders. Herein, we review the association of anti-GPCR autoantibodies with disorders of the autonomic nervous system, in particular POTS, and provide a new perspective for understanding POTS-related autoimmunity.
PubMed: 38900132
DOI: 10.1080/25785826.2024.2370079 -
International Journal of Oral Science Jun 2024Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal...
Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.
Topics: MicroRNAs; Oral Submucous Fibrosis; Humans; Fibroblasts; Arecoline; Epithelial Cells; Exosomes; Receptor, Transforming Growth Factor-beta Type I; Smad7 Protein; Cell Differentiation; Signal Transduction; Cell Movement; Ubiquitin-Protein Ligases; Areca
PubMed: 38897993
DOI: 10.1038/s41368-024-00302-2 -
The Cochrane Database of Systematic... Jun 2024Constipation that is prolonged and does not resolve with conventional therapeutic measures is called intractable constipation. The treatment of intractable constipation... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Constipation that is prolonged and does not resolve with conventional therapeutic measures is called intractable constipation. The treatment of intractable constipation is challenging, involving pharmacological or non-pharmacological therapies, as well as surgical approaches. Unresolved constipation can negatively impact quality of life, with additional implications for health systems. Consequently, there is an urgent need to identify treatments that are efficacious and safe.
OBJECTIVES
To evaluate the efficacy and safety of treatments used for intractable constipation in children.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, and two trials registers up to 23 June 2023. We also searched reference lists of included studies for relevant studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing any pharmacological, non-pharmacological, or surgical treatment to placebo or another active comparator, in participants aged between 0 and 18 years with functional constipation who had not responded to conventional medical therapy.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were symptom resolution, frequency of defecation, treatment success, and adverse events; secondary outcomes were stool consistency, painful defecation, quality of life, faecal incontinence frequency, abdominal pain, hospital admission for disimpaction, and school absence. We used GRADE to assess the certainty of evidence for each primary outcome.
MAIN RESULTS
This review included 10 RCTs with 1278 children who had intractable constipation. We assessed one study as at low risk of bias across all domains. There were serious concerns about risk of bias in six studies. One study compared the injection of 160 units botulinum toxin A (n = 44) to unspecified oral stool softeners (n = 44). We are very uncertain whether botulinum toxin A injection improves treatment success (risk ratio (RR) 37.00, 95% confidence interval (CI) 5.31 to 257.94; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Frequency of defecation was reported only for the botulinum toxin A injection group (mean interval of 2.6 days). The study reported no data for the other primary outcomes. One study compared erythromycin estolate (n = 6) to placebo (n = 8). The only primary outcome reported was adverse events, which were 0 in both groups. The evidence is of very low certainty due to concerns with risk of bias and serious imprecision. One study compared 12 or 24 μg oral lubiprostone (n = 404) twice a day to placebo (n = 202) over 12 weeks. There may be little to no difference in treatment success (RR 1.29, 95% CI 0.87 to 1.92; low certainty evidence). We also found that lubiprostone probably results in little to no difference in adverse events (RR 1.05, 95% CI 0.91 to 1.21; moderate certainty evidence). The study reported no data for the other primary outcomes. One study compared three-weekly rectal sodium dioctyl sulfosuccinate and sorbitol enemas (n = 51) to 0.5 g/kg/day polyethylene glycol laxatives (n = 51) over a 52-week period. We are very uncertain whether rectal sodium dioctyl sulfosuccinate and sorbitol enemas improve treatment success (RR 1.33, 95% CI 0.83 to 2.14; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Results of defecation frequency per week was reported only as modelled means using a linear mixed model. The study reported no data for the other primary outcomes. One study compared biofeedback therapy (n = 12) to no intervention (n = 12). We are very uncertain whether biofeedback therapy improves symptom resolution (RR 2.50, 95% CI 1.08 to 5.79; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). The study reported no data for the other primary outcomes. One study compared 20 minutes of intrarectal electromotive botulinum toxin A using 2800 Hz frequency and botulinum toxin A dose 10 international units/kg (n = 30) to 10 international units/kg botulinum toxin A injection (n = 30). We are very uncertain whether intrarectal electromotive botulinum toxin A improves symptom resolution (RR 0.96, 95% CI 0.76 to 1.22; very low certainty evidence) or if it increases the frequency of defecation (mean difference (MD) 0.00, 95% CI -1.87 to 1.87; very low certainty evidence). We are also very uncertain whether intrarectal electromotive botulinum toxin A has an improved safety profile (RR 0.20, 95% CI 0.01 to 4.00; very low certainty evidence). The evidence for these results is of very low certainty due to serious concerns with risk of bias and imprecision. The study did not report data on treatment success. One study compared the injection of 60 units botulinum toxin A (n = 21) to myectomy of the internal anal sphincter (n = 21). We are very uncertain whether botulinum toxin A injection improves treatment success (RR 1.00, 95% CI 0.75 to 1.34; very low certainty evidence). No adverse events were recorded. The study reported no data for the other primary outcomes. One study compared 0.04 mg/kg oral prucalopride (n = 107) once daily to placebo (n = 108) over eight weeks. Oral prucalopride probably results in little or no difference in defecation frequency (MD 0.50, 95% CI -0.06 to 1.06; moderate certainty evidence); treatment success (RR 0.96, 95% CI 0.53 to 1.72; moderate certainty evidence); and adverse events (RR 1.15, 95% CI 0.94 to 1.39; moderate certainty evidence). The study did not report data on symptom resolution. One study compared transcutaneous electrical stimulation to sham stimulation, and another study compared dietitian-prescribed Mediterranean diet with written instructions versus written instructions. These studies did not report any of our predefined primary outcomes.
AUTHORS' CONCLUSIONS
We identified low to moderate certainty evidence that oral lubiprostone may result in little to no difference in treatment success and adverse events compared to placebo. Based on moderate certainty evidence, there is probably little or no difference between oral prucalopride and placebo in defecation frequency, treatment success, or adverse events. For all other comparisons, the certainty of the evidence for our predefined primary outcomes is very low due to serious concerns with study limitations and imprecision. Consequently, no robust conclusions could be drawn.
Topics: Humans; Constipation; Child; Randomized Controlled Trials as Topic; Child, Preschool; Adolescent; Defecation; Botulinum Toxins, Type A; Quality of Life; Laxatives; Infant; Bias; Lubiprostone
PubMed: 38895907
DOI: 10.1002/14651858.CD014580.pub2 -
BioRxiv : the Preprint Server For... Jun 2024Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving...
Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.
PubMed: 38895393
DOI: 10.1101/2024.06.04.597341