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TAG. Theoretical and Applied Genetics.... Aug 2021In polyploids, linkage mapping is carried out using genotyping with discrete dosage scores. Here, we use probabilistic genotypes and we validate it for the construction...
In polyploids, linkage mapping is carried out using genotyping with discrete dosage scores. Here, we use probabilistic genotypes and we validate it for the construction of polyploid linkage maps. Marker genotypes are generally called as discrete values: homozygous versus heterozygous in the case of diploids, or an integer allele dosage in the case of polyploids. Software for linkage map construction and/or QTL analysis usually relies on such discrete genotypes. However, it may not always be possible, or desirable, to assign definite values to genotype observations in the presence of uncertainty in the genotype calling. Here, we present an approach that uses probabilistic marker dosages for linkage map construction in polyploids. We compare our method to an approach based on discrete dosages, using simulated SNP array and sequence reads data with varying levels of data quality. We validate our approach using experimental data from a potato (Solanum tuberosum L.) SNP array applied to an F1 mapping population. In comparison to the approach based on discrete dosages, we mapped an additional 562 markers. All but three of these were mapped to the expected chromosome and marker position. For the remaining three markers, no physical position was known. The use of dosage probabilities is of particular relevance for map construction in polyploids using sequencing data, as these often result in a higher level of uncertainty regarding allele dosage.
Topics: Chromosome Mapping; Chromosomes, Plant; Computer Simulation; Gene Expression Regulation, Plant; Plant Proteins; Polymorphism, Single Nucleotide; Polyploidy; Quantitative Trait Loci; Solanum tuberosum
PubMed: 34032878
DOI: 10.1007/s00122-021-03834-x -
Tropical Medicine & International... Nov 2009To determine the frequency and manifestations of adverse events associated with recommended first-line anti-TB drugs in children. (Review)
Review
OBJECTIVE
To determine the frequency and manifestations of adverse events associated with recommended first-line anti-TB drugs in children.
METHOD
Literature review.
RESULTS
Overall, children tolerate anti-TB drugs very well when using currently recommended dosages. Serious adverse events are rare and even mild symptoms such as nausea or vomiting are uncommon. There are occasional case reports of severe hepatotoxicity.
CONCLUSIONS
Surveillance and reporting of adverse events will need to be improved when recommended dosages of the main first-line anti-TB therapy for children are increased. Co-morbidities such as HIV infection and severe malnutrition may affect the incidence and complicate the management of possible adverse events to anti-TB therapy.
Topics: Antitubercular Agents; Child; Child, Preschool; Female; HIV Infections; Humans; Male; Tuberculosis, Pulmonary; World Health Organization
PubMed: 19735381
DOI: 10.1111/j.1365-3156.2009.02375.x -
Malaria Journal Feb 2014Anti-malarial drugs are now mainly deployed as combination therapy (CT), primarily as a mechanism to prevent or slow the spread of resistance. This strategy is justified... (Review)
Review
Anti-malarial drugs are now mainly deployed as combination therapy (CT), primarily as a mechanism to prevent or slow the spread of resistance. This strategy is justified by mathematical arguments that generally assume that drug 'resistance' is a binary all-or-nothing genetic trait. Herein, a pharmacological, rather than a purely genetic, approach is used to investigate resistance and it is argued that this provides additional insight into the design principles of anti-malarial CTs. It is usually suggested that half-lives of constituent drugs in a CT be matched: it appears more important that their post-treatment anti-malarial activity profiles be matched and strategies identified that may achieve this. In particular, the considerable variation in pharmacological parameters noted in both human and parasites populations may compromise this matching and it is, therefore, essential to accurately quantify the population pharmacokinetics of the drugs in the CTs. Increasing drug dosages will likely follow a law of diminishing returns in efficacy, i.e. a certain increase in dose will not necessarily lead to the same percent increase in efficacy. This may allow individual drug dosages to be lowered without proportional decrease in efficacy, reducing any potential toxicity, and allowing the other drug(s) in the CT to compensate for this reduced dosage; this is a dangerous strategy which is discussed further. Finally, pharmacokinetic and pharmacodynamic drug interactions and the role of resistance mechanisms are discussed. This approach generated an idealized target product profile (TPP) for anti-malarial CTs. There is a restricted pipeline of anti-malarial drugs but awareness of pharmacological design principles during the development stages could optimize CT design pre-deployment. This may help prevent changes in drug dosages and/or regimen that have previously occurred post-deployment in most current anti-malarial drugs.
Topics: Antimalarials; Drug Combinations; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Half-Life; Humans; Malaria; Plasmodium
PubMed: 24552440
DOI: 10.1186/1475-2875-13-62 -
The American Journal of Clinical... Nov 2020Histidine is an essential amino acid with health benefits that may warrant histidine supplementation; however, the clinical safety of histidine intake above the average... (Clinical Trial)
Clinical Trial
BACKGROUND
Histidine is an essential amino acid with health benefits that may warrant histidine supplementation; however, the clinical safety of histidine intake above the average dietary intake (1.52-5.20 g/d) needs to be vetted.
OBJECTIVES
We aimed to determine the tolerance to graded dosages of histidine in a healthy adult population.
METHODS
Healthy adults aged 21-50 y completed graded dosages of histidine supplement (4, 8, and 12 g/d, Study 1) (n = 20 men and n = 20 women) and/or a 16-g/d dosage of histidine (Study 2, n = 21 men and n = 19 women); 27 participants (n = 12 men and n = 15 women) completed both studies. After study enrollment and baseline measures, participants consumed encapsulated histidine for 4 wk followed by a 3-wk recovery period. Primary outcomes included vitals, select biochemical analytes, anthropometry, serum zinc, and body composition (via DXA).
RESULTS
No changes in vitals or body composition occurred with histidine supplementation in either study. Plasma histidine (measured in subjects who completed all dosages for Studies 1 and 2) was elevated at the 12- and 16-g/d dosages (compared with 0-8 g/d, P < 0.05) and blood urea nitrogen increased with dosage (P = 0.013) and time (P < 0.001) in Study 1 and with time in Study 2 (P < 0.001). In Study 1, mean ferritin concentrations were lower in 12 g/d (46.0 ng/mL; 95% CI: 34.8, 60.9 ng/mL) than in 4 g/d (51.6 ng/mL; 95% CI: 39.0, 68.4 ng/mL; P = 0.038). In Study 2, 16 g/d increased mean aspartate aminotransferase from baseline (19 U/L; 95% CI: 17, 22 U/L) to week 4 (24 U/L; 95% CI: 21, 27 U/L; P < 0.001) and mean serum zinc decreased from baseline (0.75 μg/dL; 95% CI: 0.71, 0.80 μg/dL) to week 4 (0.70 μg/dL; 95% CI: 0.66, 0.74 μg/dL; P = 0.011).
CONCLUSIONS
Although values remained within the normal reference ranges for all analytes measured, in all dosages tested, the human no-observed adverse effect level was determined to be 8 g/d owing to changes in blood parameters at the 12-g/d dosage.This trial was registered at clinicaltrials.gov as NCT04142294.
Topics: Adult; Blood Glucose; C-Reactive Protein; Dietary Supplements; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Histidine; Humans; Male; Middle Aged; Young Adult
PubMed: 32766885
DOI: 10.1093/ajcn/nqaa210 -
Implementation Science Communications Jul 2022Initial training and ongoing post-training consultation (i.e., ongoing support following training, provided by an expert) are among the most common implementation...
How low can you go? Examining the effects of brief online training and post-training consultation dose on implementation mechanisms and outcomes for measurement-based care.
BACKGROUND
Initial training and ongoing post-training consultation (i.e., ongoing support following training, provided by an expert) are among the most common implementation strategies used to change clinician practice. However, extant research has not experimentally investigated the optimal dosages of consultation necessary to produce desired outcomes. Moreover, the degree to which training and consultation engage theoretical implementation mechanisms-such as provider knowledge, skills, and attitudes-is not well understood. This study examined the effects of a brief online training and varying dosages of post-training consultation (BOLT+PTC) on implementation mechanisms and outcomes for measurement-based care (MBC) practices delivered in the context of education sector mental health services.
METHODS
A national sample of 75 clinicians who provide mental health interventions to children and adolescents in schools were randomly assigned to BOLT+PTC or control (services as usual). Those in BOLT+PTC were further randomized to 2-, 4-, or 8-week consultation conditions. Self-reported MBC knowledge, skills, attitudes, and use (including standardized assessment, individualized assessment, and assessment-informed treatment modification) were collected for 32 weeks. Multilevel models were used to examine main effects of BOLT+PTC versus control on MBC use at the end of consultation and over time, as well as comparisons among PTC dosage conditions and theorized mechanisms (skills, attitudes, knowledge).
RESULTS
There was a significant linear effect of BOLT+PTC over time on standardized assessment use (b = .02, p < .01), and a significant quadratic effect of BOLT+PTC over time on individualized assessment use (b = .04, p < .001), but no significant effect on treatment modification. BOLT + any level of PTC resulted in higher MBC knowledge and larger growth in MBC skill over the intervention period as compared to control. PTC dosage levels were inconsistently predictive of outcomes, providing no clear evidence for added benefit of higher PTC dosage.
CONCLUSIONS
Online training and consultation in MBC had effects on standardized and individualized assessment use among clinicians as compared to services as usual with no consistent benefit detected for increased consultation dosage. Continued research investigating optimal dosages and mechanisms of these established implementation strategies is needed to ensure training and consultation resources are deployed efficiently to impact clinician practices.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05041517 . Retrospectively registered on 10 September 2021.
PubMed: 35869500
DOI: 10.1186/s43058-022-00325-y -
American Journal of Veterinary Research Nov 2010To determine the pharmacokinetics of DL-α-lipoic acid in dogs when administered at 3 dosages via 3 methods of delivery.
OBJECTIVE
To determine the pharmacokinetics of DL-α-lipoic acid in dogs when administered at 3 dosages via 3 methods of delivery.
ANIMALS
27 clinically normal Beagles.
PROCEDURES
In a 3 × 3 factorial Latin square design, 3 dosages (2.5, 12.5, and 25 mg/kg) of DL-α-lipoic acid were administered orally in a capsule form and provided without a meal, in a capsule form and provided with a meal, and as an ingredient included in an extruded dog food. Food was withheld for 12 hours prior to DL-α-lipoic acid administration. Blood samples were collected before (0 minutes) and at 15, 30, 45, 60, and 120 minutes after administration. Plasma concentrations of DL-α-lipoic acid were determined via high-performance liquid chromatography. A generalized linear models procedure was used to evaluate the effects of method of delivery and dosage. Noncompartmental analysis was used to determine pharmacokinetic parameters of DL-α-lipoic acid. Nonparametric tests were used to detect significant differences between pharmacokinetic parameters among treatment groups.
RESULTS
A significant effect of dosage was observed regardless of delivery method. Method of delivery also significantly affected plasma concentrations of DL-α-lipoic acid, with extruded foods resulting in lowest concentration for each dosage administered. Maximum plasma concentration was significantly affected by method of delivery at each dosage administered. Other significant changes in pharmacokinetic parameters were variable and dependent on dosage and method of delivery.
CONCLUSIONS AND CLINICAL RELEVANCE
Values for pharmacokinetic parameters of orally administered DL-α-lipoic acid may differ significantly when there are changes in dosage, method of administration, and fed status.
Topics: Administration, Oral; Animal Feed; Animals; Capsules; Chromatography, High Pressure Liquid; Coenzymes; Dogs; Dose-Response Relationship, Drug; Feeding Methods; Female; Male; Orchiectomy; Ovariectomy; Thioctic Acid
PubMed: 21034330
DOI: 10.2460/ajvr.71.11.1377 -
Nonlinear Changes in Botulinum Toxin Treatment of Task-Specific Dystonia during Long-Term Treatment.Toxins May 2021Botulinum toxin (BoTX) is the standard treatment for task-specific dystonias (TSDs) such as musician's dystonia (MD). Our aim was to assess the long-term changes in BoTX...
Botulinum toxin (BoTX) is the standard treatment for task-specific dystonias (TSDs) such as musician's dystonia (MD). Our aim was to assess the long-term changes in BoTX treatment in a highly homogeneous and, to our knowledge, largest group of MD patients with respect to the following parameters: (1) absolute and (2) relative BoTX dosage, (3) number of treated muscles, and (4) inter-injection interval. We retrospectively assessed a treatment period of 20 years in 233 patients, who had received a cumulative dose of 68,540 MU of BoTX in 1819 treatment sessions, performed by two neurologists. Nonlinear correlation was used to analyze changes in the parameters over the course of repeated treatments. Post-hoc we applied a median-split to classify two subgroups (high-BoTX, low-BoTX) depending on the total amount of BoTX needed during treatment. Across all patients, we found a decrease of dosage for the first approximately 25 treatments with an increase afterwards. The number of muscles and inter-injection intervals increased with time with a discrete decrease of inter-injection intervals after about 35 treatments. Subgroup differences were observed in the amount of BoTX and inter-injection intervals, with continuously increasing inter-injection intervals and decreasing BoTX dosage in the low-BTX group. Both groups showed a continuously increasing number of injected muscles. In summary, we found nonlinear changes of BoTX dosage and inter-injection intervals and a continuously increasing number of injected muscles with treatment duration in TSD-patients. Furthermore, we, for the first time, identified two subgroups with distinct differences. Increasing inter-injection intervals and decreasing BoTX dosages in the low-BoTX group indicated improvement of symptoms with continued treatment. Continually increasing BoTX dosages with unchanged inter-injection intervals in the high-BoTX group indicated deterioration.
Topics: Adult; Aged; Botulinum Toxins; Dystonic Disorders; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Retrospective Studies
PubMed: 34067306
DOI: 10.3390/toxins13060371 -
Toxicology Mar 1991Cyclophosphamide (CP) is a known immunomodulating agent. When presented to either late stage chick embryos (e.g. 18 days of incubation (DI] or neonatal chicks. CP...
Cyclophosphamide (CP) is a known immunomodulating agent. When presented to either late stage chick embryos (e.g. 18 days of incubation (DI] or neonatal chicks. CP induces selective B cell damage resulting in humoral immunosuppression in chickens. The present study was undertaken in order to provide further insights into CP's selective immunotoxic effects. We investigated the influences of age, CP-dose, and drug distribution on CP-induced cytotoxicity in the B and T cell compartments of the developing chick. In this test system, differential immunotoxicity was strongly dosage-dependent; at all ages tested, B cell depletion predominated at low CP dosages (50 and 100 mg/kg) whereas equally extensive lymphocyte toxicity was observed in both thymus and bursa at 200 mg/kg drug levels. Furthermore, while immunotoxicity profiles were similar at the two later developmental timepoints (18 DI and 1 day post-hatch), significantly higher CP dosages were required to induce lymphoid damage at 12 DI. Pharmacokinetic studies with radiolabeled CP revealed that approximately two-fold higher levels of CP and its metabolites are taken up in bursal tissue as compared to the thymus. Experiments concerning the possible inherent differences in susceptibility to CP-induced mitotic inhibition and cell killing mediating selective toxicity towards B cells versus T cells showed that B cell mitosis was inhibited at CP dosages as low as 5 mg/kg. No such inhibition of T cell mitosis was observed at this same low dosage. However, mitosis was completely arrested in both B and T cells at 50 mg/kg CP. Observations of cellularity in immune organs shortly after CP exposure revealed that the bursa is at least ten times more sensitive than the thymus to CP-induced mitotic inhibition and killing of resident lymphocytes. These studies reveal that multiple factors are involved in modulating CP selective immunotoxicity in the developing embryo. These include the dosage level, preferential distribution of the drug to the bursa, and a much greater sensitivity of B cells to CP-mediated mitotic inhibition and cell killing.
Topics: Animals; B-Lymphocytes; Body Weight; Bursa of Fabricius; Chick Embryo; Chickens; Cyclophosphamide; Dose-Response Relationship, Drug; Mitotic Index; T-Lymphocytes; Thymus Gland; Tissue Distribution
PubMed: 2011850
DOI: 10.1016/0300-483x(91)90196-8 -
BMC Emergency Medicine Sep 2020Amidst the ongoing opioid crisis there are debates regarding the optimal route of administration and dosages of naloxone. This applies both for lay people administration... (Observational Study)
Observational Study
BACKGROUND
Amidst the ongoing opioid crisis there are debates regarding the optimal route of administration and dosages of naloxone. This applies both for lay people administration and emergency medical services, and in the development of new naloxone products. We examined the characteristics of naloxone administration, including predictors of dosages and multiple doses during patient treatment by emergency medical service staff in order to enlighten this debate.
METHODS
This was a prospective observational study of patients administered naloxone by the Oslo City Center emergency medical service, Norway (2014-2018). Cases were linked to The National Cause of Death Registry. We investigated the route of administration and dosage of naloxone, clinical and demographic variables relating to initial naloxone dose and use of multiple naloxone doses and one-week mortality.
RESULTS
Overall, 2215 cases were included, and the majority (91.9%) were administered intramuscular naloxone. Initial doses were 0.4 or 0.8 mg, and 15% of patients received multiple dosages. Unconscious patients or those in respiratory arrest were more likely to be treated with 0.8 mg naloxone and to receive multiple doses. The one-week mortality from drug-related deaths was 4.1 per 1000 episodes, with no deaths due to rebound opioid toxicity.
CONCLUSIONS
Intramuscular naloxone doses of 0.4 and 0.8 mg were effective and safe in the treatment of opioid overdose in the prehospital setting. Emergency medical staff appear to titrate naloxone based on clinical presentation.
Topics: Adult; Decision Making; Drug Overdose; Emergency Medical Services; Female; Humans; Male; Naloxone; Narcotic Antagonists; Norway; Prospective Studies
PubMed: 32891142
DOI: 10.1186/s12873-020-00366-3 -
Tidsskrift For Den Norske Laegeforening... Mar 2006Traditional medical treatment of acute heart failure has remained unchanged for many years. It has been based on oxygen supplementation and mechanical ventilatory... (Review)
Review
BACKGROUND
Traditional medical treatment of acute heart failure has remained unchanged for many years. It has been based on oxygen supplementation and mechanical ventilatory support as well as the administration of morphine, diuretics, nitrates and inotropic agents. In 2005 the European Society of Cardiology published new guidelines on diagnosis and treatment. Also, new therapies have been introduced recently, giving rise to changes in therapeutic concepts.
MATERIAL AND METHOD
The article is based on these new guidelines and recent studies selected from the literature.
RESULTS
Mechanical ventilatory support reduces the number of patients who require endotracheal intubation. Nitrates in higher dosages than employed today appear to be beneficial to patients with pulmonary congestion, probably because of the pronounced afterload reducing effect. Nesiritide has shown better haemodynamic effects than common nitrate dosages in patients with congestive heart failure. Tezosentan was tested in the biggest trial ever which, however, was terminated prematurely, because of futility with regard to the endpoints dyspnoea and death. Dobutamine and milrinone are associated with increased mortality in patients with pronounced chronic and acute congestive heart failure. Levosimendan has shown lower mortality compared to dobutamine in patients with acute congestive heart failure.
INTERPRETATION
New concepts have finally emerged, including the application of old drugs such as nitrates in new (i.e., higher) dosages, as well as the novel compound levosimendan, and hypoperfused organs without severe hypotension. The new European Society of Cardiology classification provides a valuable and long-awaited guideline to diagnosis and treatment.
Topics: Acute Disease; Adrenergic beta-Agonists; Cardiotonic Agents; Continuous Positive Airway Pressure; Diuretics; Dobutamine; Furosemide; Heart Failure; Humans; Hydrazones; Isosorbide Dinitrate; Natriuretic Agents; Natriuretic Peptide, Brain; Nitric Oxide Donors; Oxygen Inhalation Therapy; Practice Guidelines as Topic; Pyridazines; Simendan; Vasodilator Agents
PubMed: 16541166
DOI: No ID Found