Use Of High Doses Research Articles

Opioid use and adverse health effects in breast cancer survivors.

Little information exists on adverse effects related to opioid use in breast cancer survivors following active cancer treatment, and no studies included an age-matched comparison group. Thus, we examined opioid use and risk of falls, fractures, lung problems, and cardiovascular events in breast cancer survivors in the years following active cancer treatment along with a comparison group. We conducted a longitudinal cohort study 33989 breast cancer survivors and 157609 age-matched women without cancer. Rates of adverse events, and multivariable hazards ratios for association between opioid use and the adverse health effects were calculated. Women with breast cancer had greater opioid use (60% vs 48%); longer median opioid duration (18 vs 16 days); and were prescribed stronger opioids than the matched cohort over 5.6 median years of follow-up. In multivariable models, the risk of falls was 12% higher (HR, 95% CI, 1.12 [1.07-1.17]), and fracture risk was 56% (HR = 1.56 [1.48-1.65]) greater in women with breast cancer who used opioids vs the matched cohort unexposed to opioids. In an analysis restricted to women with breast cancer, opioid use was strongly associated with the risk of falls (HR = 1.74 [1.63-1.85]); fractures (HR = 2.10 [1.95-2.27]); lung problems (HR = 1.53 [1.43-1.64]); and cardiovascular events (HR = 1.70 [1.39-2.08]) than opioid non-use. After active cancer treatment, opioid use and high dosage use were common in breast cancer survivors, and were associated with increased risk for falls, lung problems, fractures, and cardiovascular events. Findings underscore the need for careful monitoring of opioid use in these survivors and the exploration of alternative pain management strategies.

Novel self-pretreatment of biomass by in-situ preparation of acid-assisted carbohydrate-derived DES

Deep eutectic solvents (DES) can greenly and efficiently fractionate biomass, but their utilization efficiency is severely limited by the high ratio of DES required and the wasted hemicelluloses released during the pretreatment. Herein, this work first developed a novel self-pretreatment of biomass by in-situ preparation of acid-assisted carbohydrate-derived DES with the aid of ball milling to facilitate enzymatic hydrolysis. The effect of hydrogen bond acceptor types, water content, acid content, and ball-milling time on enzymatic hydrolysis was studied systematically. Under the optimal condition (tetrabutylammonium chloride (TBAC), 1000 wt% H2O, 100 wt% acids, ball milling for 2 h), the yields of glucose and xylose produced from the pretreated substrates after enzymatic hydrolysis were >99.9 % and 88 %, respectively. Furthermore, the structural integrity of the residual lignin was well-preserved, making it suitable for positional structural characterization and ideal substrates for lignin degradation. Characterization suggested that the hemicelluloses fragments via in-situ acid hydrolysis acted as hydrogen bond donors and combined in situ with TBAC to form DES. This strategy avoided the use of high dosages of DES and the wastage of hemicelluloses, and promoted the sustainability of the entire biorefinery process.

Which dose of calcium dobesilate is more effective and safe in chronic venous insufficiency? Multicenter retrospective clinical trial

Objectives This study aimed to evaluate the effectiveness and safety of different dosages of calcium dobesilate in the management of Chronic Venous Insufficiency (CVI) among patients in CEAP classes C3–C4. Methods A comprehensive multicenter retrospective analysis was conducted, including patients aged 18-70 with CEAP class C3–C4 CVI. Participants were divided into two groups: one receiving 500 mg of calcium dobesilate twice daily and the other 1000 mg twice daily. Patient progress was monitored using the Global Index Score, CIVIC-20 Score, and precise measurements of ankle and calf circumferences over a 12-month period. Results The higher dosage group (1000 mg twice daily) showed significant improvements in both symptom relief and edema reduction. Ankle circumference reduced notably at 6 months, while calf circumference and overall quality of life, measured by the Global Index Score, showed significant improvement by 12 months compared to the lower dosage group. Conclusions Higher doses of calcium dobesilate markedly enhance the management of CVI symptoms and reduce edema more effectively than lower doses, particularly in patients with advanced CVI. These findings support the use of higher dosages for optimal treatment, though further research is needed to fully evaluate long-term safety.

Patterns of Pregabalin Users from Substance Abuse Treatment Facilities: Results from the French OPPIDUM Program from 2008 to 2022.

In recent years, pregabalin has received growing attention due to its abuse liability. The aim of this study was to further characterize patterns of pregabalin users from substance abuse treatment facilities and detect changes in users profile over the study period. The data source was the Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse (OPPIDUM) program, an annual, repeated, cross-sectional, nationwide, multicenter survey that collects consumption data from patients with substance use disorders. First, we described the characteristics of pregabalin users and their consumption patterns. We compared these data between 2008 and 2018 (P1) and 2019 and 2022 (P2). Second, we conducted a multiple correspondence analysis to identify profiles of users. From 2008 to 2022, 291 pregabalin users (0.37% of all users) from 116 substance abuse treatment facilities were identified. The number of pregabalin users was lower than 15 per year in P1 (n = 89) and between 40 and 60 per year in P2 (n = 202). The number of users who reported pregabalin as the first substance leading to dependence increased significantly in P2 compared with P1 (p < 0.005). When comparing P2 with P1, there was a significant increase in precarity (p < 0.001), users in prison (p = 0.002), withdrawal symptoms (p < 0.001), dependence (p < 0.001), use of higher dose of pregabalin (p = 0.029), and acquisition by deal/street market (p < 0.001). The multiple correspondence analysis allowed for the identification of distinct profiles of pregabalin users: (i) a cluster with mainly users from P1, who presented a simple use of pregabalin, and were older (> 45 years), were involved in opioid agonist treatment (OAT), and obtained pregabalin legally; and (ii) a cluster with mainly users from P2, who presented pregabalin dependence, and were younger (< 26 years), reported pregabalin as the first substance leading to dependence, used doses higher than the market authorization, were in severe precarity, and were in prison. These data showed that the profile of pregabalin users has changed in the last years. Pregabalin use disorders also affect users without history of addiction.

Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

Muscle ultrasound to identify prednisone-induced muscle damage in adults with nephrotic syndrome

Steroid myopathy is a non-inflammatory toxic myopathy that primarily affects the proximal muscles of the lower limbs. Due to its non-specific symptoms, it is often overshadowed by patients’ underlying conditions. Prolonged or high-dosage use of glucocorticoids leads to a gradual decline in muscle mass. There are no tools available to identify the course of steroid myopathy before the patient displays substantial clinical symptoms. In this study, we investigated individuals with nephrotic syndrome receiving prednisone who underwent muscle ultrasound to obtain cross-sectional and longitudinal pictures of three major proximal muscles in the lower limbs: the vastus lateralis, tibialis anterior, and medial gastrocnemius muscles. Our findings revealed that grip strength was impaired in the prednisolone group, creatine kinase levels were reduced within the normal range; echo intensity of the vastus lateralis and medial gastrocnemius muscles was enhanced, the pennation angle was reduced, and the tibialis anterior muscle exhibited increased echo intensity and decreased thickness. The total dose of prednisone and the total duration of treatment impacted the degree of muscle damage. Our findings indicate that muscle ultrasound effectively monitors muscle structure changes in steroid myopathy. Combining clinical symptoms, serum creatine kinase levels, and grip strength improves the accuracy of muscle injury evaluation.

Pentavalent Antimony Associated with G-CSF in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania (Viannia) braziliensis.

This study compares the effectiveness of G-CSF associated with MA in the treatment of CL. A total of 32 patients aged between 18 and 50 years with CL confirmed for L. braziliensis were included in this study. G-CSF or placebo (0.9% saline) was applied by intralesional infiltration at four equidistant points on the edges of the largest ulcer on days 0 and 15 of treatment associated with intravenous MA. Males predominated in the G-CSF group (59%), while females predominated in the control group (53%). Injuries to the lower limbs predominated in both study groups. The cure rate in the G-CSF group was 65% and in the control group it was 47%, 90 days after initiation of therapy. Our data indicate that the association of G-CSF with MA is not superior to MA monotherapy. Although not significant, the potential benefit of this combination deserves further investigation. The use of higher doses or other routes of application of G-CSF in a greater number of patients should contribute to a definitive response.

Prescribing patterns for higher dose folic acid in pregnant women with epilepsy treated with antiseizure medication.

This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with antiseizure medication (ASM). In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country-specific time trends. Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM-treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid. Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM-treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real-world applicability.

Estimation of Mediastinal Toxicities after Radiotherapy for Hodgkin Lymphoma-A Normal Tissue Complication Analysis of the HD16/17 Trial by the German Hodgkin Study Group.

Hodgkin lymphoma is a hematologic malignancy with excellent outcomes even in advanced stages. Consequently, the importance of treatment-associated toxicity increases. However, the exact estimation of individualized rates is difficult due to different disease extents, treatment strategies and techniques. The following analysis aims at a pre-treatment estimation of relevant mediastinal toxicities. Normal tissue complication probability calculations were used to evaluate the toxicity rates for the heart, lungs and female breast of patients undergoing radiotherapy for early-stage Hodgkin lymphoma. Overall, 45 Patients of the HD16 and HD17 trials by the German Hodgkin study group were included and risks were calculated using the Lyman-Kutcher-Burman model. The median values for pericarditis, pneumonitis and fibrosis of the left or right breast were 0.0%, 0.0%, 0.7% and 0.6% in the HD16 cohort, and 0.0%, 0.1%, 1.1% and 1.0% in the HD17 cohort, respectively. Correspondingly, none of the included patients displayed any of the evaluated toxicities during clinical follow-up. The use of higher doses (30 Gy) in the HD17 cohort led to an increase in toxicity compared to the HD16 cohort (20 Gy). No significant influence of the planning target volume size or the radiation technique could be found in this study. Both the clinically observed and calculated toxicity rates corroborate the overall low-risk profile of radiotherapy for Hodgkin lymphoma. Further treatment individualization will be attempted in the future.

Different Statin Dosages and Their Effects on Osteoporosis

The aim of the study was to investigate the effect of different doses of statins on the progression of osteoporosis during a 36-month follow-up period. The study included 98 postmenopausal women diagnosed with osteoporosis and the presence of atherosclerosis of lower limb arteries. Patients were divided into 2 groups: women who received statins as part of atherosclerosis treatment (group 1, n=53) and those who did not receive statin therapy for hyperlipidemia (group 2, n=45). After 36 months of follow-up, patients were divided into two groups — with unfavorable (n=42) and favorable (n=56) course of osteoporosis. Progression of osteoporosis was considered unfavorable if during the follow-up period the patients had low traumatic fractures of large bones and/or progressive decrease in bone mineral density (BMD). Depending on the statin dose taken, patients were divided into groups: 1) those taking atorvastatin 20 mg or rosuvastatin 10 mg; 2) those taking atorvastatin 40 mg or rosuvastatin 20 mg. The results revealed a significant association between statin therapy and a favorable course of osteoporosis (OR=0.316, 95% C.I. =0.137-0.727, p=0.003). The use of higher doses of statins (atorvastatin 40 mg or rosuvastatin 20 mg) was associated with the development of low traumatic fractures of large bones and/or progressive decrease in MPC during 36 months of follow-up (OR=3.0, 95% C.I.=1.119-8.040, p=0.030). On the other hand, the use of lower doses of statins (20 mg atorvastatin or 10 mg rosuvastatin) was associated with a favorable course of osteoporosis (OR=0.047, 95% C.I.=0.010-0.212, p=0.030). The dose of statin taken was also moderately negatively correlated with IPC (r=−0.45; p=0.005). Thus, the use of statins for a long period (36 months) in low doses (atorvastatin 20 mg or rosuvastatin 10 mg) is an effective and safe method of treating cardiovascular comorbidities represented by atherosclerosis of lower limb vessels and osteoporosis in postmenopausal women and is characterized by a reduced risk of osteoporosis-related large bone fractures.

Impulse Control Disorders in Parkinson's Disease and Atypical Parkinsonian Syndromes-Is There a Difference?

Impulse control disorders (ICDs) are characterized by potentially harmful actions resulting from disturbances in the self-control of emotions and behavior. ICDs include disorders such as gambling, hypersexuality, binge eating, and compulsive buying. ICDs are known non-motor symptoms in Parkinson's disease (PD) and are associated primarily with the use of dopaminergic treatment (DRT) and especially dopamine agonists (DA). However, in atypical parkinsonism (APS), such as progressive supranuclear palsy (PSP) or multiple system atrophy (MSA), there are only single case reports of ICDs without attempts to determine the risk factors for their occurrence. Moreover, numerous reports in the literature indicate increased impulsivity in PSP. Our study aimed to determine the frequency of individual ICDs in APS compared to PD and identify potential factors for developing ICDs in APS. Our prospective study included 185 patients with PD and 35 with APS (27 patients with PSP and 9 with MSA) hospitalized between 2020 and 2023 at the Neurological Department of University Central Hospital in Katowice. Each patient was examined using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) to assess ICDs. Additionally, other scales were used to assess the advancement of the disease, the severity of depression, and cognitive impairment. Information on age, gender, age of onset, disease duration, and treatment used were collected from medical records and patient interviews. ICDs were detected in 23.39% of patients with PD (including binge eating in 11.54%, compulsive buying in 10.44%, hypersexuality in 8.79%, and pathological gambling in 4.40%), in one patient with MSA (hypersexuality and pathological gambling), and in 18.52% of patients with PSP (binge eating in 3.70%, compulsive buying in 7.41%, and hypersexuality in 11.11%). We found no differences in the frequency of ICDs between individual diseases (p = 0.4696). We confirmed that the use of higher doses of DA and L-dopa in patients with PD, as well as a longer disease duration and the presence of motor complications, were associated with a higher incidence of ICDs. However, we did not find any treatment effect on the incidence of ICDs in APS. ICDs are common and occur with a similar frequency in PD and APS. Well-described risk factors for ICDs in PD, such as the use of DRT or longer disease duration, are not fully reflected in the risk factors for ICDs in APS. This applies especially to PSP, which, unlike PD and MSA, is a tauopathy in which, in addition to the use of DRT, other mechanisms related to the disease, such as disorders in neuronal loops and neurotransmitter deficits, may influence the development of ICDs. Further prospective multicenter studies recruiting larger groups of patients are needed to fully determine the risk factors and mechanisms of ICD development in APS.

(074) Safety and Efficacy Varying Doses of Prednisone Post Vasectomy Reversal: Results from a Randomized, Controlled Trials

Abstract Introduction There has been significant ongoing debate on the role and utility of prednisone post-vasectomy reversal to improve sperm counts and long-term patency. However, there are relatively limited data available on the efficacy, with essentially no data available on pregnancy outcomes. Objective To report outcomes of randomized, clinical trial evaluating varying protocols for prednisone administration post vasectomy reversal. Methods A randomized, controlled trial was performed (NCT04788823) with an anticipated 100 men randomized to one of four prednisone protocols post vasectomy reversal: no treatment (Control), prednisone 20 mg taper over 1 month beginning the first month post-op and then every other month x 6 months (High Dose), prednisone 20 mg taper over 1 month if declining sperm counts or a 0 count were identified (PRN), and prednisone 5 mg daily x 1 week, followed by no treatment x 1 week, continued for 6 months (Low Dose). Randomization tables were created a priori to ensure an equal representation of differing durations of time since the original vasectomy as well as an equal distribution of VV/VV vs VV/EV vs EV/EV procedures. All men had semen analyses obtained monthly for a first 12 months. Surveys were sent periodically to follow-up on subsequent pregnancies. Inclusion criteria included having a female partner &amp;lt;36 years of age with no known fertility factors. Results A total of 75 men were ultimately enrolled due to interim findings suggesting inferiority of the High Dose and PRN treatment arms and decision to close those arms before completing full enrollment. Final enrollment included: Control (n=25), High Dose (n=14), PRN (n=11), and Low Dose (n=25). The mean patient age was 38.5 years, mean partner age 29.6, and mean time since vasectomy 6.3 years (SD 5.0). 82% of men underwent VV/VV, while 15% VV/EV, and 3% EV/EV. All men underwent successful anastomosis bilaterally with no cases of one-sided or no anastomosis performed. At a mean follow-up of 16.5 months (range 7.6 to 25.1), an overall patency (sperm observed on sample) rate of 93% was noted (Control 96%, High Dose 93%, PRN 100%, Low Dose 88%, p=0.41). The mean sperm concentration post-op was 34.4 million/ml (Control 24.0, High Dose 38.4, PRN 21.0, Low Dose 49.8, p=0.33). Patency rates at 6- and 12-months were: 6-months (Control 88%, High Dose 80%, PRN 83%, Low Dose 94%, p=0.75); 12-months (Control 75%, High Dose 71%, PRN 75%, Low Dose 91%). Mean sperm concentrations at 6- and 12-months were: 6-months (Control 15.7, High Dose 21.5, PRN 6.9, Low Dose 25.7, p=0.50); 12-months (Control 12.6 million/ml, High Dose 17.1, PRN 36.1, Low Dose 50.4, p=0.64) At the 6-month post-op time point, the overall rate of pregnancy was 47%, with notable differences between cohorts: Control 57%, High Dose 10%, PRN 38%, and Low Dose 67%, p=0.02. No patients discontinued prednisone due to side effects. Conclusions Prednisone taper protocols appear to reduce the likelihood for pregnancy following vasectomy reversal. Use of low-dose prednisone results in non-statistically higher rates of patency at 6- and 12-months, mean sperm concentration at 6- and 12-months, and pregnancy at 6-months. Overall results suggest superiority of either no prednisone post-vasectomy reversal or a low dose protocol but argue against the use of higher dosages at any time due to its negative impacts on pregnancy rates despite maintained sperm counts. Disclosure No.

Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real-world efficacy from the EoE CONNECT registry.

Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses. To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice. Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations. Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4mg/day provided no benefit over 2mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p<0.001); use of higher doses (OR 4.3, p=0.03) and lower symptom scores (OR 0.9, p=0.01) were also determinants of effectiveness. Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness.

Normal saline infiltration as a treatment of steroid injection induced tissue atrophy: A clinical study

Introduction and Aim: Intramuscular steroid injection is a technique often used by unqualified village practitioners to control symptoms of a variety of disease processes. Such injudicious use of high dosages of steroids results in local side effects. Such side effects include occurrence of tissue atrophy at the site of injection. The treatment of such tissue atrophy includes filling up the gap with injection of autologous fat and other materials. However, these are expensive and require specialised set up. Normal saline infiltration into the atrophic area at varying intervals has been successfully tried by several authors in the past. The aim of the study was to find the efficiency and side effects of normal saline infiltration into acquired lipoatrophy areas as a method of treatment. Material and Methods: After informed consent, normal saline was infiltrated into the defect till sufficient tumescence was obtained. Results: Nine children were treated. Most of them had received steroid injections for exacerbation of childhood asthma. The defect had appeared shortly (2 to 4 months) after the last injection was received. The site of the defect was rounded and located on the deltoid region in the majority. Our success rate was 66%. The determination of the success rate of this technique and the factors contributing to the success of the technique requires more studies in this field. Conclusion: Normal saline infiltration is a safe and effective way for treating steroid injection induced skin and tissue atrophy.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Nutrition Value of Baked Meat Products Fortified with Lyophilized Dragon Fruit (Hylocereus undatus).

This study evaluates the nutritional value of a baked pork meat product containing lyophilized dragon fruit pulp. The selected nutritional properties of a baked pork meat product fortified with lyophilized Hylocereus undatus pulp in doses of 0.5%, 1.5%, 2.5%, and 4% were evaluated. For this assessment, changes in the basic chemical composition of the products, the content of calcium, magnesium, potassium, iron, and phosphorus, and the profile of fatty acids were considered. Additionally, characteristics typical for meat products, such as pH, water activity, oxidation-reduction potential or thiobarbituric acid reactive substances, and antioxidant properties of the product during 21 days of refrigerated storage, were assessed. The findings indicate that the use of higher doses of lyophilizate, i.e., in the amounts of 2.5% and 4%, significantly (p < 0.05) increases the nutritional value of meat products, leading to an increase in the concentration of essential minerals important for the proper functioning of the human body (calcium, magnesium, potassium, and iron). These changes occurred without affecting the basic chemical composition (except for an increase in the content of fat and carbohydrates in the sample with the addition of 4% lyophilizate). The introduction of the fortification treatment improved the fatty acid profile, resulting in an increase in the content of C14:0, C16:0, C20:0, and C20:5n3. In addition, in the variant with a 4% dosage, there was an increased content of C8:0, C10:0, C16:1n7, C18:0, C18:1n9C + C18:1n9t, and C18:2n6C + C18:2n6t, C18:3n3 (alpha), C20:1n15, and C20:1n9. In this particular variant, an increase in saturated-, monounsaturated-, and polyunsaturated fatty acids was also observed, which was associated with an increased level of TBARS in meat products. However, the increase in the dose of lyophilizate caused an increase in the antiradical effect of meat extracts. Based on the results obtained, it seems reasonable to use a plant additive in the form of lyophilized dragon fruit pulp in the amount of 4.0% in the production of pork meat products.

A study on the appropriate dose of rocuronium for intraoperative neuromonitoring in Da Vinci robot thyroid surgery: a randomized, double-blind, controlled trial.

This study was to explore the effect of different doses of rocuronium bromide on neuromonitoring during Da Vinci robot thyroid surgery. This was a prospective, randomized, double-blind, controlled trial that included 189 patients who underwent Da Vinci robot thyroidectomy with intraoperative neuromonitoring(IONM). Patients were randomly divided into three groups and given three different doses of rocuronium (0.3mg/kg, 0.6mg/kg, 0.9mg/kg). Outcome measurements included IONM evoked potential, postoperative Voice Handicap Index-30(VHI-30), intraoperative body movement incidence rate, Cooper score, and hemodynamic changes during anesthesia induction.Results: The difference in IONM evoked potentials at various time points between the three groups was not statistically significant (P>0.05). The difference in Cooper scores and intraoperative body movement incidence rate between 0.6 and 0.9mg/kg groups was statistically significant compared with the 0.3mg/kg group (both P<0.001). There was no statistically significant difference in VHI-30 score and hemodynamic changes during anesthesia induction among the three groups (both P>0.05). For patients undergoing Da Vinci robot thyroidectomy, a single dose of rocuronium at 0.6 and 0.9mg/kg during anesthesia induction can provide stable IONM evoked potential. Additionally, compared to 0.3 mg/kg, it can offer better tracheal intubation conditions and lower incidence of body movements during surgery. It is worth noting that the use of higher doses of rocuronium should be adjusted based on the duration of IONM and local practices.

Toxicological influence of decis pesticide on soil and human health

The Decis preparation is part of the group of phytosanitary products with low impact on environmental components. On the soil, its action is achieved through the impact on the vital activity of its microbiome, the suppression of the basic fermentation systems and the metabolic processes involved in pedogenesis and plant nutrition. The toxic action of the Decis preparation on the soil microbiome intensifies against the background of treatments with preparations from the group of those with a strong (Nurela-D, Zolon) and moderate (Delan) impact. The impact of the Decis preparation on the human sympathoadrenal system depends on the administered doses. Its action in a dose of 1.2 mg/kg on the level of catecholamines leads to an imbalance of amines, and its use in higher doses (2.0 and 2.4 mg/kg) leads to a sudden increase in the level of adrenaline and noradrenaline in the tissues of the studied or gans.

Prescribing Practices for Agitation Medication in Obese Patients Admitted to the Emergency Department.

Weight is a factor that influences the dosages of many medications, although no clinical studies have evaluated this factor in the use of agitation medications in the obese population. The objectives of this study were to assess the need for weight considerations in dosing antipsychotics and benzodiazepines for patients with agitation and to assess prescribing patterns in agitated patients. This retrospective cohort study compared outcomes between obese and nonobese adult patients who received at least one parenteral administration of an antipsychotic or benzodiazepine for agitation in the emergency department. The primary outcomes were total antipsychotic and benzodiazepine doses within 24 hours (in chlorpromazine equivalents and lorazepam equivalents, respectively). Key secondary outcomes included antipsychotic and benzodiazepine doses used for first administration, incidence of repeat emergency medication administration within 24 hours, time to next administration, and number of repeat administrations within 24 hours. The study examined 115 patient encounters in each cohort of patients in the study. The baseline characteristics of the 2 study cohorts were similar. Both groups had similar mean 24-hour antipsychotic usage [272.7 chlorpromazine equivalents (nonobese cohort), 313.5 chlorpromazine equivalents (obese cohort); P=0.157] and mean 24-hour benzodiazepine usage [0.9 lorazepam equivalents (both cohorts); P=0.750]. Differences between the study cohorts on all of the secondary outcomes were also not statistically significant (P>0.05). This study did not find the use of higher dosages of agitation medication in the obese compared with the nonobese population. Future prospective trials, with possible emphasis on individual medications, specific etiologies of agitation, or morbid obesity, are required to confirm this finding or to elucidate potential differences in optimal medication dosages for the obese population.

Influence of Bio-Fertilizer Type and Amount Jointly on Microbial Community Composition, Crop Production and Soil Health

To ensure long-term food production in a changing world, it is critical to identify field management practices that increase crop yields and maintain soil health. Additionally, sustainable agriculture needs to provide experimental evidence to support the use of traditional agricultural practices. In this study, a 20-year investigation of the effects of different combinations of fertilizer types (control, chemical fertilizer, organic fertilizer, and bio-fertilizer) and fertilization amount (conventional dosages and high dosages) on wheat yield and soil health, including soil enzyme activity and microbial biomass, soil microbial diversity, and crop yield. Our long-term study indicates that the use of high dosages of bio-fertilizer can increase the fertilizer yield contribution rate by a minimum of 76.7% compared to other management combinations. Furthermore, this practice can improve soil biological quality, including the concentration of soil microbial biomass carbon, promote bacterial biodiversity, and enhance the soil health index. The effect of high dosages fertilizer was greater than that of conventional dosages fertilizer. The highest soil health index was 0.88 in high dosage bio-fertilizer, and the lowest was 0.12 in chemical fertilizer. In summary, these results suggested that the use of bio-fertilizer can help maintain soil health and crop productivity in the long term.