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CMAJ Open 2022There is little evidence describing the technical aspects of medical assistance in dying (MAiD) in Canada, such as medications, dosages and complications. Our objective...
BACKGROUND
There is little evidence describing the technical aspects of medical assistance in dying (MAiD) in Canada, such as medications, dosages and complications. Our objective was to describe clinical practice in providing MAiD in Ontario and Vancouver, Canada, and explore relations between medications used, time until death and complications.
METHODS
We conducted a retrospective cohort study of a sample of adult (age ≥ 18 yr) patients who received MAiD in Ontario between 2016 and 2018, and patients who received MAiD in 1 of 3 Canadian academic hospitals (in Hamilton and Ottawa, Ontario, and Vancouver, British Colombia) between 2019 and 2020. We used de-identified data for 2016-2018 from the Office of the Chief Coroner for Ontario MAiD Database and chart review data for 2019-2020 from the 3 centres. We used multivariable parametric survival analysis to identify relations between medications, dosages and time from procedure start until death.
RESULTS
The sample included 3557 patients (1786 men [50.2%] and 1770 women [49.8%] with a mean age of 74 [standard deviation 13] yr). The majority of patients (2519 [70.8%]) had a diagnosis of cancer. The medications most often used were propofol (3504 cases [98.5%]), midazolam (3251 [91.4%]) and rocuronium (3228 [90.8%]). The median time from the first injection until death was 9 (interquartile range 6) minutes. Standard-dose lidocaine (40-60 mg) and high-dose propofol (> 1000 mg) were associated with prolonged time until death (prolonged by a median of 1 min and 3 min, respectively). Complications occurred in 41 cases (1.2%), mostly related to venous access or need for administration of a second medication.
INTERPRETATION
In a large sample of patients who died with medical assistance, certain medications were associated with small differences in time from injection to death, and complications were rare. More research is needed to identify the medication protocols that predict outcomes consistent with patient and family expectations for a medically assisted death.
Topics: Aged; Anesthetics, Intravenous; Canada; Cross-Sectional Studies; Drug Dosage Calculations; Drug Utilization; Female; Humans; Male; Neoplasms; Palliative Care; Patient Care Management; Suicide, Assisted; Time-to-Treatment
PubMed: 35042691
DOI: 10.9778/cmajo.20200268 -
Frontiers in Molecular Neuroscience 2022Shank3 is an abundant excitatory postsynaptic scaffolding protein implicated in various neurodevelopmental disorders, including autism spectrum disorder (ASD),...
Shank3 is an abundant excitatory postsynaptic scaffolding protein implicated in various neurodevelopmental disorders, including autism spectrum disorder (ASD), Phelan-McDermid syndrome, intellectual disability, and schizophrenia. -mutant mice show various molecular, synaptic, and behavioral deficits, but little is known about how transcriptomic phenotypes vary across different ages, brain regions, and gene dosages. Here, we report transcriptomic patterns in the forebrains of juvenile and adult homozygous -mutant mice that lack exons 14-16 and also the prefrontal, hippocampal, and striatal transcriptomes in adult heterozygous and homozygous -mutant mice. The juvenile and adult mutant transcriptomes show patterns opposite from and similar to those observed in ASD (termed reverse-ASD and ASD-like patterns), respectively. The juvenile transcriptomic changes accompany synaptic upregulations and ribosomal and mitochondrial downregulations, whereas the adult transcriptome show opposite changes. The prefrontal, hippocampal, and striatal transcriptomes show differential changes in ASD-related gene expressions and biological functions associated with synapse, ribosome, mitochondria, and spliceosome. These patterns also differ across heterozygous and homozygous -mutant mice. These results suggest age, brain region, and gene dosage-differential transcriptomic changes in -mutant mice.
PubMed: 36311023
DOI: 10.3389/fnmol.2022.1017512 -
Zeitschrift Fur Rheumatologie Feb 2024Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs.... (Review)
Review
Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs. Furthermore, they sometimes have a lower therapeutic index, particularly in cases of limited organ functions. The aim of this work was to establish evidence-based recommendations on the therapeutic use of DMARDs in the context of drug interactions and dosage recommendations. A systematic literature search was carried out on the issue of drug interactions and dosages in cases of patients with limited kidney function and higher age and suffering from rheumatoid arthritis. A total of 2756 scientific publications were screened and 154 selected of which 68 were scrutinized in detail. Furthermore, the respective product information was also analyzed. A multitude of possible interactions of synthetic DMARDs with different drugs were detected, which were then assessed with respect to the clinical significance and consequences. A consensus process led to making recommendations with which the interactions were classified: A: dangerous combination, B: avoid combination (if possible, pausing DMARD treatment), C: possible combination requiring increased monitoring and potential adjustments in dosage and D: pharmacological interaction without relevance in DMARD standard doses. Apart from that dosage recommendations were established for each csDMARD and tsDMARD depending on kidney function and age. There are 3 primary recommendations and 11 core recommendations on interactions and dosages of csDMARDs and tsDMARDs meant as a practical help for therapeutic decision making and to improve safety in the treatment of rheumatoid arthritis.
Topics: Humans; Consensus; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Drug Interactions; Biological Products
PubMed: 37831190
DOI: 10.1007/s00393-023-01417-3 -
Dysphagia Apr 2023This study investigated how swallowing exercise dosage is recorded, and what swallowing exercise dosages are reported in a stroke rehabilitation setting. We additionally...
This study investigated how swallowing exercise dosage is recorded, and what swallowing exercise dosages are reported in a stroke rehabilitation setting. We additionally explored the relation between mean daily swallowing repetitions and likelihood of improvement in functional swallowing status and considered how swallowing exercise dosages in practice compared to evidence-based principles of neural plasticity and strength training. We audited medical records for 42 patients with post-stroke dysphagia admitted to an inpatient rehabilitation unit over 18 months. Data were collected on participant characteristics, swallowing exercises and dosages, and clinical outcomes. The relation between dosage and outcomes was investigated using logistic regression analysis. On average, patients were seen for a median of 2.4 swallowing intervention sessions per week (IQR: 1.7) over 21 days (IQR: 16) and received a median 44.5 swallowing exercise repetitions per session (IQR: 39.6). Results indicated variable reporting of swallowing exercise dosages. Frequency, intervention duration, exercise type, and number of repetitions were routinely recorded in medical records, while intensity, session length, content, and adherence to home exercise programs were not. Frequency of swallowing intervention was lower in practice compared to research studies, and swallowing exercises did not follow specificity or progressive resistance principles. Likelihood of improvement in swallowing status was partially explained by age (B = -.015, p = .007) but not by mean daily swallowing exercise repetitions. This study illustrates dosages of swallowing exercises used in clinical practice. Results highlight the need for improved consideration and reporting of dosage, and application of evidence-based principles to swallowing exercise dosages.
Topics: Humans; Stroke Rehabilitation; Deglutition Disorders; Deglutition; Stroke; Exercise Therapy
PubMed: 35951119
DOI: 10.1007/s00455-022-10500-x -
Journal of Pharmacokinetics and... Dec 2021Optimization of antibiotic administration helps minimizing cases of bacterial resistance. Dosages are often selected by trial and error using a pharmacokinetic (PK)...
Optimization of antibiotic administration helps minimizing cases of bacterial resistance. Dosages are often selected by trial and error using a pharmacokinetic (PK) model. However, this is limited to the range of tested dosages, restraining possible treatment choices, especially for the loading doses. Colistin is a last-resort antibiotic with a narrow therapeutic window; therefore, its administration should avoid subtherapeutic or toxic concentrations. This study formulates an optimal control problem for dosage selection of colistin based on a PK model, minimizing deviations of colistin concentration to a target value and allowing a specific dosage optimization for a given individual. An adjoint model was used to provide the sensitivity of concentration deviations to dose changes. A three-compartment PK model was adopted. The standard deviation between colistin plasma concentrations and a target set at 2 mg/L was minimized for some chosen treatments and sample patients. Significantly lower deviations from the target concentration are obtained for shorter administration intervals (e.g. every 8 h) compared to longer ones (e.g. every 24 h). For patients with normal or altered renal function, the optimal loading dose regimen should be divided into two or more administrations to attain the target concentration quickly, with a high first loading dose followed by much lower ones. This regimen is not easily obtained by trial and error, highlighting advantages of the method. The present method is a refined optimization of antibiotic dosage for the treatment of infections. Results for colistin suggest significant improvement in treatment avoiding subtherapeutic or toxic concentrations.
Topics: Anti-Bacterial Agents; Colistin; Humans
PubMed: 34156631
DOI: 10.1007/s10928-021-09769-6 -
Environmental Science and Pollution... May 2023Flocculants play an important role in the solid-liquid separation of tailings slurry, and its dosage directly impacts on the dewatering efficiency of tailings. Herein,...
Flocculants play an important role in the solid-liquid separation of tailings slurry, and its dosage directly impacts on the dewatering efficiency of tailings. Herein, the influence of ultrasonication on flocculant dosage in dehydration process of unclassified tailings was studied. The effects of flocculant dosage on initial settling rate (ISR), underflow concentration, and effective settling time in the process were investigated in detail. The directivity characteristics of ultrasound transducers with different frequencies in unclassified tailings slurry was simulated by MATLAB. The morphologies of underflow tailings at different flocculant dosages were detected by environmental scanning electron microscope (E-SEM). The relationship between flocculant dosage and fractal dimension (D) was quantitatively analyzed based on fractal theory. The influence mechanism of flocculant on the settling and thickening of unclassified tailings was revealed. The results show that the optimum flocculant dosage for the ultrasonically treated tailings slurry is 40 g/t, at which the ISR reach a maximum value of 0.262 cm/min and the final underflow concentration (FUC) reach a maximum value in 60 min. Compared with settling without ultrasonication, the optimum flocculant dosage is reduced by 10 g/t, the ISR increases by 10.45%, the effective settling time is reduced by 50 min, and the FUC increases by 1.65%. The fractal dimension of underflow tailings first increases and then decreases with the increase in flocculant dosage, the relationship of which is in accordance with Lorentz model.
Topics: Flocculation; Fractals
PubMed: 37022544
DOI: 10.1007/s11356-023-26676-0 -
JAMA Network Open Aug 2023Patients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Patients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not been well established.
OBJECTIVE
To evaluate the associations of pain, opioid consumption, and adverse events with different dosages of pregabalin and gabapentin in patients undergoing spine surgery.
DATA SOURCES
PubMed/MEDLINE, Embase, Web of Science, Cochrane library, and Scopus databases were searched for articles until August 7, 2021.
STUDY SELECTION
Randomized clinical trials conducted among patients who received pregabalin or gabapentin while undergoing spine surgery were included.
DATA EXTRACTION AND SYNTHESIS
Two investigators independently performed data extraction following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) reporting guideline. The network meta-analysis was conducted from August 2022 to February 2023 using a random-effects model.
MAIN OUTCOMES AND MEASURES
The primary outcome was pain intensity measured using the Visual Analog Scale (VAS), and secondary outcomes included opioid consumption and adverse events.
RESULTS
Twenty-seven randomized clinical trials with 1861 patients (median age, 45.99 years [range, 20.00-70.00 years]; 759 women [40.8%]) were included in the systematic review and network meta-analysis. Compared with placebo, the VAS pain score was lowest with gabapentin 900 mg per day, followed by gabapentin 1200 mg per day, gabapentin 600 mg per day, gabapentin 300 mg per day, pregabalin 300 mg per day, pregabalin 150 mg per day, and pregabalin 75 mg per day. Additionally, gabapentin 900 mg per day was found to be associated with the lowest opioid consumption among all dosages of gabapentin and pregabalin, with a mean difference of -22.07% (95% CI, -33.22% to -10.92%) for the surface under the cumulative ranking curve compared with placebo. There was no statistically significant difference in adverse events (nausea, vomiting, and dizziness) among all treatments. No substantial inconsistency between direct and indirect evidence was detected for all outcomes.
CONCLUSIONS AND RELEVANCE
These findings suggest that gabapentin 900 mg per day before spine surgery is associated with the lowest VAS pain score among all dosages. In addition, no differences in adverse events were noted among all treatments.
Topics: Humans; Female; Middle Aged; Gabapentin; Pregabalin; Analgesics; Analgesics, Opioid; Network Meta-Analysis; Pain, Postoperative
PubMed: 37556139
DOI: 10.1001/jamanetworkopen.2023.28121 -
Zeitschrift Fur Rheumatologie Mar 2023Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs.... (Review)
Review
Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs. Furthermore, they sometimes have a lower therapeutic index, particularly in cases of limited organ functions. The aim of this work was to establish evidence-based recommendations on the therapeutic use of DMARDs in the context of drug interactions and dosage recommendations. A systematic literature search was carried out on the issue of drug interactions and dosages in cases of patients with limited kidney function and higher age and suffering from rheumatoid arthritis. A total of 2756 scientific publications were screened and 154 selected of which 68 were scrutinized in detail. Furthermore, the respective specialist subject information was also analyzed. A multitude of possible interactions of synthetic DMARDs with different drugs were detected, which were then assessed with respect to the clinical significance and consequences. A consensus process led to making recommendations with which the interactions were classified: A: dangerous combination, B: avoid combination (if possible, pausing DMARD treatment), C: possible combination requiring increased monitoring and potential adjustments in dosage and D: pharmacological interaction without relevance in DMARD standard doses. Apart from that dosage recommendations were established for each csDMARD and tsDMARD depending on kidney function and age. There are 3 primary recommendations and 11 core recommendations on interactions and dosages of csDMARDs and tsDMARDs meant as a practical help for therapeutic decision making and to improve safety in the treatment of rheumatoid arthritis.
Topics: Humans; Consensus; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Drug Interactions; Biological Products
PubMed: 36633662
DOI: 10.1007/s00393-022-01308-z -
Ecotoxicology and Environmental Safety Feb 2021Fluoride, widely presented in drinking water and tea, may be detrimental or beneficial to the human health, depending on its dosages ingested. However, the relationship...
Fluoride, widely presented in drinking water and tea, may be detrimental or beneficial to the human health, depending on its dosages ingested. However, the relationship of different dosages of fluoride and gut microbiota is still unclear. In this work, the fermentation model using fecal samples provided by four volunteers was used to evaluate the effects of different dosages of fluoride (1, 2, 10 and 15 mg/L) on the gut microbiota in vitro. The result showed low dosages of fluoride (1 and 2 mg/L) had limited effect on the structure and functional Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of gut microbiota. Furthermore, the low dosage of fluoride could promote the growth of beneficial gut microbiota, including Faecalibacterium and Lactobacillus. Whereas, the high dosage of fluoride (10 and 15 mg/L) significantly changed the composition and functional KEGG pathway of gut microbiota. Moreover, the high dosage of fluoride could also reduce the beneficial gut microbiota, including Faecalibacterium and Phascolarctobacterium, and increase the harmful bacterium including Proteobacteria and Enterobacteriaceae. Both low and high dosages of fluoride showed limited effect on the productions of short-chain fatty acids (SCFAs). Thus, the beneficial or detrimental fluoride to gut microbiota depends on its dosages. The fluoride is expected to serve as a food additive in suitable dosage to improve human health through modulation of the gut microbiota. Moreover, more attention should be paid to toxicity of fluoride with high dosage to gut microbiota.
Topics: Bacteria; Fatty Acids, Volatile; Feces; Fermentation; Fluorides; Gastrointestinal Microbiome; Humans; Lactobacillus; Water Pollutants, Chemical
PubMed: 33373928
DOI: 10.1016/j.ecoenv.2020.111732 -
Contraception Jun 2022To investigate the effect of different oral dosages of levonorgestrel (LNG) on ovarian activity and to identify the lowest dosage at which no ovulation occurred....
OBJECTIVES
To investigate the effect of different oral dosages of levonorgestrel (LNG) on ovarian activity and to identify the lowest dosage at which no ovulation occurred. Secondary objectives were to assess return of ovulation after stopping treatment, bleeding pattern, pharmacokinetic (PK) parameters and safety and tolerability.
STUDY DESIGN
A parallel-group study with adaptive design was performed in 90 healthy women with proven ovulatory cycles. Investigated dosages were LNG 0.095, 0.115 and 0.135 mg per day. Measurements of follicular growth and estradiol (E) and progesterone concentrations were performed every 3 (±1) days during a 56-day treatment and a post-treatment period. Follicle-stimulating hormone and luteinizing hormone concentrations and multiple-dose PK parameters were determined during treatment.
RESULTS
Two normal ovulations occurred in the LNG 0.095 mg group, none in the higher dose groups. Most subjects had active follicle-like structures without ovulation (Hoogland-Skouby scores 4). Ovarian activity was more suppressed in the highest dose group than in the other groups. Mean E concentrations were 241, 219 and 180 pmol/L during treatment with 0.095, 0.115 and 0.135 mg per day, respectively. PK results showed dose-proportionality. Most subjects ovulated during the post-treatment period.
CONCLUSION
LNG 0.115 mg per day was the lowest effective dosage for consistent ovulation inhibition. All investigated dosages were safe and well-tolerated, and mean E concentrations were sufficient for prevention of hypoestrogenic side effects.
IMPLICATIONS
Marketed progestogen-only pills (POP) containing 0.03 mg LNG do not consistently inhibit ovulation. Increasing the dosage to 0.115 mg or 0.135 mg per day, resulting in consistent ovulation inhibition, may improve the contraceptive efficacy of the LNG-POP.
Topics: Estradiol; Female; Follicle Stimulating Hormone; Humans; Levonorgestrel; Luteinizing Hormone; Ovary; Ovulation; Ovulation Inhibition; Progesterone
PubMed: 35123981
DOI: 10.1016/j.contraception.2022.01.018