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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 -
Drug and Alcohol Dependence Nov 2023Buprenorphine reduces risk of opioid overdose mortality. However, its benefits are limited by low retention, particularly in early treatment. Optimizing initial dosage...
BACKGROUND
Buprenorphine reduces risk of opioid overdose mortality. However, its benefits are limited by low retention, particularly in early treatment. Optimizing initial dosage may impact retention. However, little is known about the prescription characteristics of new buprenorphine treatment episodes.
METHODS
In a US sample of commercial and employer-sponsored pharmacy claims, we identified new buprenorphine treatment episodes (days 1-30) from individuals ≥16 years following 90 days without buprenorphine from 2010 to 2019. Outcomes included first prescription average days supplied, first prescription average daily dosage, and average dosage on days 2, 8, 15 and 30.
RESULTS
We identified 117,793 new episodes among 96,451 unique individuals. Episodes per 10,000 person-years decreased slightly over time. Stratifying by age, sex and region demonstrated decreasing episodes among individuals ≤34 years and increasing episodes among individuals ≥35 years. From 2010-2019, first prescription average days supplied and daily dosage decreased from 17.1 to 15.3 days and 13.6mg to 11.6mg, respectively. Simultaneously, the proportion of episodes without possession and with dosages <16mg increased across all days and years. By day 30, episodes without buprenorphine possession grew from 27.9% to 30.8% and episodes involving dosages of <16mg grew from 26.4% to 33.4%.
CONCLUSIONS
We found that buprenorphine dosage and days supplied for new treatment episodes decreased from 2010 to 2019 while buprenorphine possession worsened. Further investigation examining the relationship between buprenorphine dosage and retention in the early treatment period is needed.
Topics: Humans; Adult; Buprenorphine; Opioid-Related Disorders; Opiate Substitution Treatment; Opiate Overdose; Analgesics, Opioid; Retrospective Studies
PubMed: 37839942
DOI: 10.1016/j.drugalcdep.2023.110981 -
Frontiers in Veterinary Science 2022Septic peritonitis is associated with significant morbidity and mortality. As a potential therapeutic agent in the treatment of sepsis, 2-O, 3-O desulfated heparin...
OBJECTIVE
Septic peritonitis is associated with significant morbidity and mortality. As a potential therapeutic agent in the treatment of sepsis, 2-O, 3-O desulfated heparin (ODSH) reduces histones and platelet factor 4 (PF4) in mouse sepsis models. This pilot clinical trial evaluated the safety and effect of ODSH in client-owned dogs with septic peritonitis.
INTERVENTIONS
In an IACUC-approved, open-label, prospective, dose-escalation clinical trial in 6 dogs with spontaneous septic peritonitis, ODSH administration was initiated following surgical explore to achieve source control. Acute patient physiology and laboratory evaluation (APPLE and APPLE) scores on admission, source of septic peritonitis, requirement for vasopressors, the administration of blood products, and survival to discharge were recorded. Platelet count, cell free DNA (cfDNA) concentration, and platelet factor 4 (PF4) concentrations were measured at the time of each ODSH dosage. A dose of ODSH was administered every 8 hs for a total of 4 doses (maximum total dosage 75 mg/kg) based on a pre-determined escalation protocol. Patients were monitored in the ICU following administration for evidence of clinical hemorrhage.
MAIN RESULTS
The mean APPLE and APPLE scores on admission were 22 +/- 6 and 32 +/-10, respectively. Four dogs received 4 total dosages of ODSH and 2 dogs received 3 total dosages of ODSH intravenously. The mean total dosage of ODSH administered during the study period was 48.3 +/- 21.6 mg/kg. No dog required dose de-escalation or had any evidence of bleeding. Four dogs survived to discharge.
CONCLUSIONS
No adverse effects of ODSH administration were documented in dogs with septic peritonitis. A randomized controlled trial is necessary to evaluate ODSH as a novel therapeutic in the treatment of septic peritonitis.
PubMed: 35498738
DOI: 10.3389/fvets.2022.862308 -
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 -
International Journal of Molecular... Jun 2021Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural... (Review)
Review
Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.
Topics: Animals; Biological Transport; Biosynthetic Pathways; Carbohydrate Metabolism; Dietary Supplements; Gastrointestinal Absorption; Gastrointestinal Microbiome; Humans; Inositol; Kidney
PubMed: 34202683
DOI: 10.3390/ijms22136796 -
Materials (Basel, Switzerland) Apr 2023This study investigates the montmorillonite (MMT) content, rotational viscosity, and colloidal index of sodium montmorillonite (Na-MMT) as a function of the sodium agent...
This study investigates the montmorillonite (MMT) content, rotational viscosity, and colloidal index of sodium montmorillonite (Na-MMT) as a function of the sodium agent dosage, reaction time, reaction temperature, and stirring time. Na-MMT was modified using different octadecyl trimethyl ammonium chloride (OTAC) dosages under optimal sodification conditions. The organically modified MMT products were characterized via infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopy. The results show that the Na-MMT with good properties (i.e., the maximum rotational viscosity and highest Na-MMT content with no decrease in the colloid index) was obtained at a 2.8% sodium carbonate dosage (measured based on the MMT mass), a temperature of 25 °C, and a reaction time of two hours. Upon organic modification of the optimized Na-MMT, OTAC entered the NA-MMT interlayer, and the contact angle was increased from 20.0° to 61.4°, the layer spacing was increased from 1.58 to 2.47 nm, and the thermal stability was conspicuously increased. Thus, MMT and Na-MMT were modified by the OTAC modifier.
PubMed: 37110020
DOI: 10.3390/ma16083184 -
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 -
The Journal of Pediatric Pharmacology... 2024This study aims to describe the effectiveness of low initial alprostadil dosages to maintain a patent ductus arteriosus (PDA) in infants with ductal-dependent congenital...
OBJECTIVES
This study aims to describe the effectiveness of low initial alprostadil dosages to maintain a patent ductus arteriosus (PDA) in infants with ductal-dependent congenital heart disease (DDCHD). Secondary objectives were to describe any adverse drug events, describe prescribing trends, describe ductus arteriosus diameter changes, and compare the safety and efficacy of very low and low initial alprostadil dosage regimens.
METHODS
This retrospective observational cohort study at the British Columbia's Women's and Children's Hospital neonatal intensive care unit and pediatric intensive care unit examined neonates admitted with DDCHD who received alprostadil to maintain ductal patency. Very low-dose alprostadil (less than 0.01 mcg/kg/min) versus low-dose alprostadil (equal to or greater than 0.01 mcg/kg/min) was examined. Effectiveness was defined as survival and infants not requiring a resuscitation event (cardiac arrest, cardiogenic shock, code blue, extracorporeal life support, requirement for emergent cardiac surgery, and respiratory acidosis). Adverse drug events with a Naranjo score of 3 or more were included.
RESULTS
Alprostadil was effective for 88% of patients, with no difference between the very low-dose and low-dose groups. Of the 75 patients included, 25 received very low-dose alprostadil. Adverse drug events were common (51%) with neonates in the low-dose group experiencing more apnea and pyrexia than neonates in the very low-dose group.
CONCLUSIONS
Alprostadil therapy was effective in maintaining the PDA in neonates with DDCHD with low-dosage regimens. Adverse drug events were common with both dosage regimens; however, the very low dosage appeared to have less apnea and pyrexia.
PubMed: 38332962
DOI: 10.5863/1551-6776-29.1.37 -
Neuro-ophthalmology (Aeolus Press) 2021Giant cell arteritis (GCA) is a condition that can cause irreversible visual loss if untreated. While corticosteroids remain the mainstay of treatment to prevent visual...
Giant cell arteritis (GCA) is a condition that can cause irreversible visual loss if untreated. While corticosteroids remain the mainstay of treatment to prevent visual loss, the type, dose, route, and duration of corticosteroid treatment of GCA remain controversial. Our study surveyed neuro-ophthalmologists to determine commonly prescribed dosages of corticosteroids for the treatment of GCA with or without visual loss. For patients with acute visual loss, 52% would use intravenous (IV), 46% would use IV or oral and 2% would use oral corticosteroids. Seventy-three per cent would use 500 to 1000 mg IV methylprednisolone in this group. For patients with GCA without acute visual loss, 67% would use the oral route, 30% would use IV or oral, and 3% indicated they would use IV route of treatment. Seventy-five per cent would use 1.0 to 1.5 mg/kg oral prednisone in this group. Our results suggest a majority but not a complete consensus for route and dose of corticosteroid treatment in GCA and confirm conventional recommendations for high dose IV corticosteroids for GCA with visual loss and lower dose oral regimens for GCA without visual loss.
PubMed: 33762783
DOI: 10.1080/01658107.2020.1767656