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Frontiers in Microbiology 2023In Taiwan, the pesticides dimethomorph and imidacloprid are recommended for pest control in vineyards. Therefore, tank-mixing of these two pesticides is usually a...
In Taiwan, the pesticides dimethomorph and imidacloprid are recommended for pest control in vineyards. Therefore, tank-mixing of these two pesticides is usually a routine practice before application. This study analyzed the influence of vineyard soil microbial flora under the recommended and high dosages (100 times the recommended dosage) of dimethomorph and imidacloprid. Individual and combined applications of pesticides were also tested through batches of soil incubation experiments. Four treatments-control (C), dimethomorph (DT), imidacloprid (IM), and mixed application of dimethomorph and imidacloprid (ID)-were used in the experimental design. From the soil metabolism, no significant reaction was observed after 2 months in the recommended dosage group, regardless of whether the pesticides were being applied individually or combined. For the high dosage, imidacloprid showed a higher effect than the co-exposure treatments, showing a possible prolonged effect after its repetitive application. From PCoA analysis, pesticide treatments altered the soil ecology after 2 months, and the effect of imidacloprid can be explicitly observed at high dosages. At the phylum level, can indicate pesticide application around the recommended dosage. It was inhibited by ID on day 7 and was augmented by all pesticides on day 63. The effect of the recommended dosage of pesticide mixtures after 2 months of incubation was revealed in the minor families and , while the high dosage treatments affected both the core and the minor families. Our findings verified the changes in the composition of microbial communities upon pesticide application, which would affect carbon, nitrogen, sulfur, phosphorous cycles, and contaminant removal ability within the vineyard.
PubMed: 38029114
DOI: 10.3389/fmicb.2023.1249167 -
Musculoskeletal Science & Practice Apr 2024Evidence supporting type and dosage of joint mobilizations and rationale for selecting joint mobilization dosage for patients with rotator cuff-related shoulder pain are... (Review)
Review
BACKGROUND
Evidence supporting type and dosage of joint mobilizations and rationale for selecting joint mobilization dosage for patients with rotator cuff-related shoulder pain are limited.
OBJECTIVES
This scoping review aimed to systematically map the type and dosage of joint mobilizations used in previous trials for managing patients with rotator cuff-related shoulder pain; and summarize the rationale for adopting a specific joint mobilization dosage.
METHODS
We searched six databases. We included randomised controlled trials using joint mobilization for patients with rotator cuff-related shoulder pain. We extracted data regarding technique, treatment joint mobilization dosages and rationale for a specific dosage.
RESULTS
We included 32 studies. Most studies did not or partially report technique (67%) and within-session dosage (64%) of passive joint mobilization. Overall treatment was fully reported in 95% of studies. The dosage used for passive joint mobilization was heterogeneous (ranging from grade I to grade V). Most studies (85%) did not or partially report technique of mobilization with movement (MWM), whereas within-session and overall treatment dosages were fully reported in more than 85% of studies. Three sets of 10 repetitions were commonly used within-session dosage for MWM. We found very limited information on the rationale for selecting dosage of joint mobilization.
CONCLUSION
We found limited information about the dosage or the rationale for selecting joint mobilization, with a heterogeneous dosage being tested across trials. Our findings highlight the importance of detailed reporting for dosage and rationale for selecting a specific dosage of joint mobilization.
Topics: Humans; Rotator Cuff; Shoulder Pain; Physical Therapy Modalities; Rotator Cuff Injuries
PubMed: 38412572
DOI: 10.1016/j.msksp.2023.102903 -
BioRxiv : the Preprint Server For... Aug 2023Genetic study of late-onset Alzheimer's disease (AD) reveals that a rare Arginine-to-Histamine mutation at amino acid residue 47 (R47H) in Triggering Receptor Expressed...
BACKGROUND
Genetic study of late-onset Alzheimer's disease (AD) reveals that a rare Arginine-to-Histamine mutation at amino acid residue 47 (R47H) in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) results in increased disease risk. TREM2 plays critical roles in regulating microglial response to amyloid plaques in AD, leading to their clustering and activation surrounding the plaques. We previously showed that increasing human gene dosage exerts neuroprotective effects against AD-related deficits in amyloid depositing mouse models of AD. However, the effects of the R47H mutation on human TREM2-mediated microglial reprogramming and neuroprotection remains poorly understood.
METHOD
Here we created a BAC transgenic mouse model expressing human TREM2 with the R47H mutation in its cognate genomic context (BAC-TREM2-R47H). Importantly, the BAC used in this study was engineered to delete critical exons of other TREM-like genes on the BAC to prevent confounding effects of overexpressing multiple TREM-like genes. We crossed BAC-TREM2- R47H mice with 5xFAD [1], an amyloid depositing mouse model of AD, to evaluate amyloid pathologies and microglial phenotypes, transcriptomics and expression of key -dosage dependent genes. We also compared the key findings in 5xFAD/BAC-TREM2-R47H to those observed in 5xFAD/BAC-TREM2 mice.
RESULT
Both BAC-TREM2 and BAC-TREM2-R47H showed proper expression of three splicing isoforms of that are normally found in human. In 5xFAD background, elevated TREM2-R47H gene dosages significantly reduced the plaque burden, especially the filamentous type. The results were consistent with enhanced phagocytosis and altered NLRP3 inflammasome activation in BAC- TREM2-R47H microglia in vitro. However, unlike TREM2 overexpression, elevated TREM2- R47H in 5xFAD failed to ameliorate cognitive and transcriptomic deficits. analysis of key -dosage dependent genes and microglial morphology uncovered that TREM2-R47H showed a loss-of-function phenotype in reprogramming of plaque-associated microglial reactivity and gene expression in 5xFAD.
CONCLUSION
Our study demonstrated that the AD-risk variant has a previously unknown, mixture of partial and full loss of TREM2 functions in modulating microglial response in AD mouse brains. Together, our new BAC-TREM2-R47H model and prior BAC-TREM2 mice are invaluable resource to facilitate the therapeutic discovery that target human TREM2 and its R47H variant to ameliorate AD and other neurodegenerative disorders.
PubMed: 37577582
DOI: 10.1101/2023.08.03.551881 -
Journal of Trace Elements in Medicine... May 2024The effectiveness of selenium (Se) supplementation on glycemic control is disparate.
BACKGROUND
The effectiveness of selenium (Se) supplementation on glycemic control is disparate.
OBJECTIVE
This study aims to evaluate the effects of different dosages of Se diets on the blood glucose in type 2 diabetes mellitus (T2DM, db/db) and normal (db/m) mice.
METHODS
The db/db and db/m mice were fed with different dosages of Se supplemented diets (0, 0.1, 0.3, 0.9, 2.7 mg/kg) for 12 weeks, respectively. Se concentrations of tissues, physical and biochemical characteristics, oxidative stress indexes and gene expression related to glucose, lipid metabolism and Se transporters of liver were detected.
RESULTS
The Se concentrations in tissues were related to the dosages of Se supplementation in db/db (blood: slope=11.69, r = 0.924; skeletal muscle: slope=0.36, r = 0.505; liver: slope=22.12, r = 0.828; kidney: slope=11.81, r = 0.736) and db/m mice (blood: slope=19.89, r = 0.876; skeletal muscle: slope=2.80, r = 0.883; liver: slope=44.75, r = 0.717; kidney: slope=60.15, r = 0.960). Compared with Se2.7 group, the fasting blood glucose (FBG) levels of Se0.1 and Se0.3 group were decreased at week3 in db/db mice. Compared with control (Se0) group, the FBG levels of Se2.7 group were increased from week6 to week12 in db/m mice. The oral glucose tolerance test (OGTT) showed that the area under the curve (AUC) of Se0.3 group was lower than that of Se0.9 and Se2.7 group in db/m mice. Furthermore, compared with control group, the malondialdehyde (MDA) level in skeletal muscle of Se0.1 group was decreased, while that of Se2.7 group was increased in db/db mice; the glutathione peroxidase (GPx) activity in skeletal muscle of Se0.3, Se0.9 and Se2.7 group was increased both in db/db and db/m mice. For db/db mice, glucose-6-phosphatase catalytic (G6pc) expression of other groups were lower and fatty acid synthase (Fasn) expression of Se0.9 group were lower compared with Se0.3 group. For db/m mice, compared with Se0.3 group, (peroxisome proliferative activated receptor gamma coactivator 1 alpha) Pgc-1α expression of control and Se0.9 group were higher; (phosphoenolpyruvate carboxykinase 1) Pck1 expression of Se0.1, Se0.9, and Se2.7 group were higher.
CONCLUSION
Low dosages (0.1 and 0.3 mg/kg) of Se supplementation exerted beneficial effects on FBG levels and glucose tolerance through regulating hepatic glycolysis and gluconeogenesis and inhibit the oxidative stress while high dosages of Se (0.9 and 2.7 mg/kg) supplementation enhanced FBG levels, impaired glucose tolerance and aggravate oxidative stress.
Topics: Mice; Animals; Selenium; Diabetes Mellitus, Type 2; Blood Glucose; Antioxidants; Oxidative Stress; Mice, Inbred Strains; Dietary Supplements; Liver; Mice, Inbred C57BL; Glucose
PubMed: 38377660
DOI: 10.1016/j.jtemb.2024.127410 -
Tidsskrift For Den Norske Laegeforening... May 2024A woman in her seventies presented to the accident and emergency department (A&E) with shortness of breath that had increased over a period of three weeks. She had a...
BACKGROUND
A woman in her seventies presented to the accident and emergency department (A&E) with shortness of breath that had increased over a period of three weeks. She had a history of COPD, hypertension and polymyalgia rheumatica. A medication error involving methotrexate, used for autoimmune diseases, was discovered during her medical history review.
CASE PRESENTATION
The patient arrived with stable vital signs, including 94 % oxygen saturation and a respiratory rate of 20 breaths/min. She had been taking 2.5 mg of methotrexate daily for the past three weeks instead of the prescribed weekly dose of 15 mg. Other examinations revealed no alarming findings, except for a slightly elevated D-dimer level.
INTERPRETATION
Considering her medical history and exclusion of other differential diagnoses, methotrexate toxicity was suspected. The patient was admitted to the hospital and intravenous folinic acid was initiated as an antidote treatment. Five days later, the patient was discharged with an improvement in the shortness of breath. This case underscores the importance of effective communication in health care, particularly in complex cases like this, where understanding dosages and administration is crucial. Medical history, clinical examinations and medication reviews, often involving clinical pharmacists, are vital in the A&E to reveal medication errors.
Topics: Humans; Medication Errors; Female; Methotrexate; Aged; Dyspnea; Leucovorin; Antidotes; Antirheumatic Agents
PubMed: 38747669
DOI: 10.4045/tidsskr.23.0657 -
The American Journal of Clinical... Mar 2024The optimal dosage range for B-vitamin supplementation for stroke prevention has not received sufficient attention. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The optimal dosage range for B-vitamin supplementation for stroke prevention has not received sufficient attention.
OBJECTIVE
Our aim was to determine the optimal dosage range of a combination of folic acid, vitamin B12, and vitamin B6 supplementation in stroke prevention.
METHODS
We searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase database for randomized controlled trials published between January 1966 and April 2023, whose participants received B-vitamin supplementation and that reported the number of stroke cases. Relative risk (RR) was used to measure the effect of combined supplementation on risk of stroke using a fixed-effects model. Risk of bias was assessed with the Cochrane risk-of-bias algorithm.
RESULTS
The search identified 14 randomized controlled trials of folic acid combined with vitamin B12 and vitamin B6 supplementation for stroke prevention that included 76,664 participants with 2720 stroke cases. In areas without and with partial folic acid fortification, combined B-vitamin supplementation significantly reduced the risk of stroke by 34% [RR: 0.66; 95% confidence interval (CI): 0.50, 0.86] and 11% (RR: 0.89; 95% CI: 0.79, 1.00), respectively. Further analysis showed that a dosage of folic acid ≤0.8 mg/d and vitamin B12 ≤0.4 mg/d was best for stroke prevention (RR: 0.65; 95% CI: 0.48, 0.86) in these areas. In contrast, no benefit of combined supplementation was found in fortified areas (RR: 1.04; 95% CI: 0.94, 1.16).
CONCLUSIONS
Our meta-analysis found that the folic acid combined with vitamin B12 and vitamin B6 supplementation strategy significantly reduced the risk of stroke in areas without and with partial folic acid fortification. Combined dosages not exceeding 0.8 mg/d for folic acid and 0.4 mg/d for vitamin B12 supplementation may be more effective for populations within these areas. This trial was registered at PROSPERO asCRD42022355077.
Topics: Humans; Vitamins; Vitamin B 12; Folic Acid; Vitamin B 6; Stroke; Dietary Supplements
PubMed: 38432716
DOI: 10.1016/j.ajcnut.2023.12.021 -
The Journal of Pain May 2024Opioid use and dosage following knee arthroplasty (KA) has not been reported for subgroups with persistent moderate pain versus rapidly improving mild pain, externally... (Randomized Controlled Trial)
Randomized Controlled Trial
Perioperative Opioid Use and Dosage Trajectories Vary Depending on Pain Outcome Classification and Bodily Pain in Patients who Catastrophize About Their Pain: A Secondary Analysis of a Randomized Trial in Knee Arthroplasty.
Opioid use and dosage following knee arthroplasty (KA) has not been reported for subgroups with persistent moderate pain versus rapidly improving mild pain, externally validated from prior work. We determined if opioid use and dosage varied for persons classified into these externally validated subgroups. A secondary purpose determined if bodily pain scores are associated with the outcome subgroup. This was a secondary analysis of a prospective no-effect randomized clinical trial conducted on 384 participants with pain catastrophizing and scheduled for KA. Data were collected preoperatively and at 2-, 6-, and 12-month following surgery. Two-piece latent class growth curve analyses applied previously validated pain outcomes to determine subgroup outcome trajectories for the proportion of opioid users and oral morphine equivalent (OME) dosages. Substantial trajectory separation was found for opioid use and OME. Specifically, the average OME dosage for the persistent moderate pain subgroup was more than double that for the other outcome subgroup. The average preoperative opioid daily OME dosage for 170 patients reporting opioid use was 24.94 (95% [confidence interval] CI = 20.52, 29.38). Bodily pain was consistently higher for the persistent moderate pain subgroup compared to the other subgroup. Outcome subgroups in patients with pain catastrophizing demonstrated substantial differences in opioid use and dosage and were predicted by high pain catastrophizing, more bodily pain, and changes in bodily pain over time. The persistent moderate pain subgroup is at greater risk of opioid use and greater opioid dosages and should be targeted for preoperative screening and interventions to reduce opioid use and potential opioid misuse. PERSPECTIVE: More frequent and higher opioid dosage following KA was found for the persistent moderate pain subgroup compared to the other subgroup. Patients with persistent pain had worse catastrophizing, contralateral and ipsilateral lower extremity pain, low back pain, and whole body pain compared to the rapidly improving mild pain subgroup.
Topics: Humans; Arthroplasty, Replacement, Knee; Analgesics, Opioid; Catastrophization; Male; Female; Pain, Postoperative; Middle Aged; Aged; Pain Measurement; Prospective Studies
PubMed: 38007035
DOI: 10.1016/j.jpain.2023.11.017 -
EClinicalMedicine Apr 2024Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA)...
Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials.
BACKGROUND
Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area.
METHODS
We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130).
FINDINGS
A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400 mg/d was top-ranked, followed by RTG 1200 mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100 mg/d leading, followed by CNB 400 mg/d. Regarding tolerability, LCM 600 mg/d had the lowest ranking, followed by CNB 400 mg/d. For the safety outcome of AEs, ESL 1200 mg/d was ranked lowest, followed by CNB 400 mg/d. Regarding SAEs, LCM 400 mg/d was ranked lowest, followed by RTG 1200 mg/d.
INTERPRETATION
ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS.
FUNDING
None.
PubMed: 38449838
DOI: 10.1016/j.eclinm.2024.102513 -
Harm Reduction Journal May 2024Naloxone is an effective FDA-approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public and can be administered through intramuscular... (Review)
Review
Naloxone is an effective FDA-approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review investigates the adequacy of two doses of standard IM or IN naloxone in reversing fentanyl overdoses compared to newer high-dose naloxone formulations. Moreover, our initiative incorporates the experiences of people who use drugs, enabling a more practical and contextually-grounded analysis. The evidence indicates that the vast majority of fentanyl overdoses can be successfully reversed using two standard IM or IN dosages. Exceptions include cases of carfentanil overdose, which necessitates ≥ 3 doses for reversal. Multiple studies documented the risk of precipitated withdrawal using ≥ 2 doses of naloxone, notably including the possibility of recurring overdose symptoms after resuscitation, contingent upon the half-life of the specific opioid involved. We recommend distributing multiple doses of standard IM or IN naloxone to bystanders and educating individuals on the adequacy of two doses in reversing fentanyl overdoses. Individuals should continue administration until the recipient is revived, ensuring appropriate intervals between each dose along with rescue breaths, and calling emergency medical services if the individual is unresponsive after two doses. We do not recommend high-dose naloxone formulations as a substitute for four doses of IM or IN naloxone due to the higher cost, risk of precipitated withdrawal, and limited evidence compared to standard doses. Future research must take into consideration lived and living experience, scientific evidence, conflicts of interest, and the bodily autonomy of people who use drugs.
Topics: Humans; Naloxone; Narcotic Antagonists; Drug Overdose; Fentanyl; Opiate Overdose; Analgesics, Opioid; Administration, Intranasal
PubMed: 38741224
DOI: 10.1186/s12954-024-00994-z -
BioRxiv : the Preprint Server For... Mar 2024A longstanding challenge in gene therapy is expressing a dosage-sensitive gene within a tight therapeutic window. For example, loss of function causes Rett syndrome,...
A longstanding challenge in gene therapy is expressing a dosage-sensitive gene within a tight therapeutic window. For example, loss of function causes Rett syndrome, while its duplication causes duplication syndrome. Viral gene delivery methods generate variable numbers of gene copies in individual cells, creating a need for gene dosage-invariant expression systems. Here, we introduce a compact miRNA-based, incoherent feed-forward loop circuit that achieves precise control of expression in cells and brains, and improves outcomes in an AAV-based mouse model of Rett syndrome gene therapy. Single molecule analysis of endogenous and ectopic mRNA revealed precise, sustained expression across a broad range of gene dosages. Delivered systemically in a brain-targeting AAV capsid, the circuit strongly suppressed Rett behavioral symptoms for over 24 weeks, outperforming an unregulated gene therapy. These results demonstrate that synthetic miRNA-based regulatory circuits can enable precise in vivo expression to improve the safety and efficacy of gene therapy.
PubMed: 38559034
DOI: 10.1101/2024.03.13.584179