Double Dose Research Articles

Avoiding Medication Errors Caused by Nurses in the Emergency Department in Saudi Arabia

Background: Medication errors are pervasive in healthcare, especially in emergency rooms, with diverse causes that warrant critical investigation due to the potential repercussions for both patients and healthcare providers. Aim: This research explores nurses' perspectives on medication errors in the emergency department. Methods: A descriptive cross-sectional design involved 96 nurses, using a questionnaire that covered demographic data and nurses' perceptions of error causes, reporting practices, and barriers. Results: The average age of the nurses who participated in this study was 27.7 ± 3.4 years, with 7.3 ± 1.9 years of experience. Most nurses (87.2%) were women. The majority held bachelor's degrees (88.3%) and worked fixed shifts (54.2%), and 46.8% reported medication errors in the past year, primarily occurring once (69.04%). They reported no complications in 97.5% of errors. Conclusion: Common error types included infusion rate errors, double dosing, and medication omission. Although errors are widespread, adverse consequences are infrequent, mainly occurring during prescribing or administration stages. Encouraging disclosure by nurses and fostering positive responses from hospital management are crucial for enhancing patient safety. Awareness of recovery mechanisms informs potential interventions to minimise overall safety. Key words: Medication Errors, Emergency Department, Nurses, Understanding, Perception

Evaluation of the protective efficiency of an autogenous Vibrio anguillarum vaccine in lumpfish (Cyclopterus lumpus) under controlled and field conditions in Atlantic Canada

Lumpfish (Cyclopterus lumpus) have become the predominant cleaner fish species used in North American salmon aquaculture. Vibrio anguillarum is a frequent pathogen of lumpfish in Atlantic Canada, and current vaccines against local isolates conferred low to moderate efficacy. This study evaluated the safety and efficiency of a V. anguillarum autogenous vaccine under controlled and field conditions. Two safety trials were conducted following the Canadian Food Inspection Agency (CFIA) regulations before field trial testing. The first safety trial was a common garden assay, and 250 PIT-tsgged lumpfish were used for five treatments per tank (PBS-negative control, Lab vaccine-positive control, autogenous intraperitoneal (IP) vaccine, autogenous dip vaccine, autogenous dip-IP boosted vaccine) in triplicates. Weight, gross pathology, and IgM titers were evaluated to determine the vaccine’s safety. After 10 weeks post-vaccination (wpv), lumpfish were bath-challenged with a lethal dose (1.24 x 106 CFU/mL) of V. anguillarum serotype O2. Survival rate, IgM titers, memory immune response, and cross-immune protection were evaluated. The second safety trial was conducted using a double vaccine dose in two groups, PBS and autogenous IP. The gross pathology score indicated a normal immune response without tissue damage, and no mortality nor fish health issues were observed in the immunized animals. The IP route of administration conferred the highest protection against the V. anguillarum challenge. The autogenous vaccine conferred long-term immunity but did not confer cross-protection against V. anguillarum serotype O1. To evaluate the efficiency of the autogenous vaccine under field conditions, 58,976 naïve lumpfish (8-10 g) were IP immunized with either the autogenous vaccine or the commercial Forte micro IV vaccine. After 7 wpv, the lumpfish were equally distributed into eight sea cages and co-cultivated with Atlantic salmon smolts (60,000 per cage). Lumpfish IgM titers, tissue bacterial loads, mortality, and sea lice count on salmon were monitored. The autogenous vaccine and Forte vaccine confer acceptable protection to the lumpfish in sea cages. No significant difference was observed between lumpfish vaccinated with autogenous and commercial vaccines under field conditions.

A fractional modeling approach for the transmission dynamics of measles with double-dose vaccination

Measles, a member of the Paramyxoviridae family and the Morbillivirus genus, is an infectious disease caused by the measles virus that is extremely contagious and can be prevented through vaccination. When a person with the measles coughs or sneezes, the virus is disseminated by respiratory droplets. Normally, the appearance of measles symptoms takes 10–14 d following viral exposure. Conjunctivitis, a high temperature, a cough, a runny nose, and a distinctive rash are some of the symptoms. Despite the measles vaccination being available, it is still widespread worldwide. To eradicate measles, the Reproduction Number (i.e. R 0 < 1 ) must remain less than unity. This study examines a SEIVR compartmental model in the caputo sense using a double dose of vaccine to simulate the measles outbreak. The reproduction number R 0 and model properties are both thoroughly examined. Both the local and global stabilities of the proposed model are determined for R 0 less and greater than 1. To achieve the model’s global stability, the Lyapunov function is used while the existence and uniqueness of the proposed model are demonstrated In addition to the calculated and fitted biological parameters, the forward sensitivity indices for R 0 are also obtained. Simulations of the proposed fractional order (FO) caputo model are performed in order to analyse their graphical representations and the significance of FO derivatives to illustrate how our theoretical findings have an impact. The graphical results show that the measles outbreak is reduced by increasing vaccine dosage rates.

Synchronization of ovulation (FTET) in Turcana sheep as embryo recipients

Due to the fact that the farm wants to crossbreed sheep with meat breeds, it was opted for the fastest solution to bring genetic progress, namely embryo transfer, using sheep from the Turcan breed as embryo recipients and those from the Suffolk breed as embryo donors, so that finally the batch of receivers after parturition will produce a production of Suffolk lambs. Following the selection of recipients considering the standard criteria that include: general health, functional integrity of the genital tract and cyclic activity of the ovaries, two groups were formed for the induction and synchronization of estrus. The first batch consisted of 20 sheep and the second batch of 20. The first batch was subjected to a P4-PG-PMSG protocol and the second batch to the P4-PG-GnRH protocol. The two protocols consisted of the insertion of intravaginal sponges with flugestone acetate in a concentration of 20mg, to induce the progesterone phase, for 13 days, day 0 of the protocols being represented by the day when the progesterone sponges were applied. In continuation of the protocol, Prostaglandinf2α was used on day 12 in a double dose, in the morning and in the evening at a distance of 12 hours in a dose of 0.6 ml/administration/animal. On day 13, the progesterone sponges were removed and PMSG (Folligon) was administered in the case of the first batch at a dose of 600 IU/animal, and in the second batch GnRH (Receptal) was administered at a dose of 12 μg/animal ( 3ml/animal) followed by a dose of 600 IU HCG (Chorulon) 24 hours after GnRH administration. Ovulation was accurately assessed at the time of embryo transfer through laparotomy, due to the highlighting of the ovaries and their macroscopic analysis in the operative field, after identifying the CL on the ovary, their appearance and the number of CL on the ovary. However, the assessment of the rate of entry into heat was assessed 24 hours after the end of the protocol by biostimulating the receptors with the help of detector rams, thus the ewes that entered in estrus at 12 – 24 hours, 24 – 48 of hours or over 48 hours after completing the protocol. The results obtained in the case of the first batch having the highest rate of entering in estrus between 24 - 48 hours being 40%, followed by a rate of 30% between 12 - 24 hours, the lowest rate being 20% that entered in estrus after 48 hours, the second batch with GnRH had the highest rate of entry into estrus of 60% in the first 12-24 hours and the rate at 24-48 hours, respectively those that entered heat after 48 hours was 20%. Compared between the two groups, there were differences in the timing of ovulation assessment, as in the case of the first group with PMSG, a 60% ovulation rate was assessed with well-developed CL, 10% presented CL but these were unsuitable for embryo transfer, 10% presented ovarian cysts, and 10% did not ovulate, in the case of the second batch an ovulation rate of 60% was assessed and the rate of 40% represented the animals that did not ovulate, the difference between the two batches being the fact that it is observed in the case of the first batch rate of 10% with ovarian cysts, which indicates that the PMSG-based pharmaceutical is causing ovarian cysts. In conclusion, the therapeutic protocol used in the off-season for the induction of estrus and ovulation in Turcan sheep, in this study, resulted in the detection of estrus in 90% of the ewes subjected to the protocol, and the ovulation rate was 80% (60% with CL well developed and 20% were with poorly developed CL), regarding the first batch, and regarding the second batch 100% of ewes in oestrus were detected, but 60% of them ovulated with CL well developed. These results can be largely attributed to the reproduction seasonality of the sheep.

Comparative effectiveness and cost evaluation of Risankizumab and Adalimumab in the management of psoriasis: a real-world study in Saudi Arabia

BackgroundPsoriasis, an immune-mediated chronic inflammatory disease primarily affecting skin and joints, has varying prevalence rates globally. It manifests in five types, with chronic plaque psoriasis being the most common. Treatment, which has no definitive cure, aims for complete resolution of skin symptoms and depends on disease extent, severity, and impact on patients’ lives. Biologics are an emerging treatment for psoriasis, targeting specific inflammatory pathways for potentially safer, more effective outcomes. However, these come with significant costs, necessitating more research to ensure value for money. This study aimed to compare the effectiveness of Risankizumab versus Adalimumab, the most commonly utilized biologic for managing psoriasis in Saudi Arabia.MethodsThis study retrospectively compared the effectiveness and direct medical cost of Risankizumab and Adalimumab in treating chronic plaque psoriasis in adults from two Saudi Arabian healthcare centers. The Psoriasis Area and Severity Index (PASI) and body surface area (BSA) were used to assess treatment effectiveness, with patient data sourced from electronic medical records. Multiple regression analysis was performed to examine various factors affecting treatment outcomes. An economic evaluation was conducted to examine the cost-effectiveness of the two drugs, considering four scenarios with varying dosage patterns and costs. Analysis was performed from the perspective of public healthcare payers and considered all utilized health services.ResultsThe data for 70 patients were analyzed, with comparable baseline characteristics between groups. While Risankizumab led to a greater reduction in PASI scores and BSA affected, these results were not statistically significant. The annual treatment cost for Risankizumab was higher than Adalimumab. Various scenarios were studied, considering real acquisition costs, double dosing for Adalimumab, and the use of biosimilars. A scenario assuming double dosing for Adalimumab and a 40% discount for Risankizumab demonstrated both cost and efficacy advantages in 71.25% of cases.ConclusionsThis study compared the effectiveness and cost of Risankizumab and Adalimumab for treating chronic plaque psoriasis in Saudi Arabian hospitals. Although Risankizumab showed a greater reduction in symptoms, the difference was not statistically significant. However, under certain scenarios, Risankizumab demonstrated cost and efficacy advantages. These findings may influence treatment decisions for psoriasis, but further research is needed.

176 Luteolytic efficiency of a single or double dose of cloprostenol sodium in a 5-day artificial insemination protocol in dairy cows

176 Luteolytic efficiency of a single or double dose of cloprostenol sodium in a 5-day artificial insemination protocol in dairy cows

Transmission of COVID-19 in the presence of single-dose and double-dose vaccines with hesitancy: mathematical modeling and optimal control analysis

IntroductionThe unexpected emergence of novel coronavirus identified as SAR-CoV-2 virus (severe acute respiratory syndrome corona virus 2) disrupted the world order to an extent that the human activities that are core to survival came almost to a halt. The COVID-19 pandemic created an insurmountable global health crisis that led to a united front among all nations to research on effective pharmaceutical measures that could stop COVID-19 proliferation. Consequently, different types of vaccines were discovered (single-dose and double-dose vaccines). However, the speed at which these vaccines were developed and approved to be administered created other challenges (vaccine skepticism and hesitancy).MethodThis paper therefore tracks the transmission dynamics of COVID-19 using a non-linear deterministic system that accounts for the unwillingness of both susceptible and partially vaccinated individuals to receive either single-dose or double-dose vaccines (vaccine hesitancy). Further the model is extended to incorporate three time-dependent non-pharmaceutical and pharmaceutical intervention controls, namely preventive control, control associated with screening-management of both truly asymptomatic and symptomatic infectious individuals and control associated with vaccination of susceptible individuals with a single dose vaccine. The Pontryagin's Maximum Principle is applied to establish the optimality conditions associated with the optimal controls.ResultsIf COVID-19 vaccines administered are imperfect and transient then there exist a parameter space where backward bifurcation occurs. Time profile projections depict that in a setting where vaccine hesitancy is present, administering single dose vaccines leads to a significant reduction of COVID-19 prevalence than when double dose vaccines are administered. Comparison of the impact of vaccine hesitancy against either single dose or double dose on COVID-19 prevalence reveals that vaccine hesitancy against single dose is more detrimental than vaccine hesitancy against a double dose vaccine. Optimal analysis results reveal that non-pharmaceutical time-dependent control significantly flattens the COVID-19 epidemic curve when compared with pharmaceutical controls. Cost-effectiveness assessment suggest that non-pharmaceutical control is the most cost-effective COVID-19 mitigation strategy that should be implemented in a setting where resources are limited.DiscussionPolicy makers and medical practitioners should assess the level of COVID-19 vaccine hesitancy inorder to decide on the type of vaccine (single-dose or double-dose) to administer to the population.

Impact of aminopenicillin administration routes on antimicrobial effects of platelet-rich fibrin: An in-vitro investigation

IntroductionThe aim of the study was to investigate the impact of different aminopenicillin administration routes on the antimicrobial effects of platelet-rich fibrin (PRF). MethodsWe enrolled patients undergoing treatment with amoxicillin/clavulanic acid (AMC) orally or ampicillin/sulbactam (SAM) intravenously. AMC was applied in a single oral dose (875/125 mg), or in a double oral dose (1750/250 mg), and SAM in a dose of 2000/1000 mg. Blood was obtained one hour after the intake of AMC or 15 min after the infusion of SAM ended. Antimicrobial effects were investigated in agar diffusion tests with fresh PRF, PRF stored for 24, and PRF stored for 48 h. Agar diffusion tests were performed with Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Porphyromonas gingivalis. Inhibition zones (IZs) around a 6 mm PRF disc were measured after 24 h. ResultsIZs for fresh PRF and the single oral dose of AMC were 0.0, 4.7, 15.2, 2.3, and 0.9 mm (E. coli, S. aureus, S. pneumoniae, H. influenzae, and P. gingivalis, respectively). For the double oral dose, these values were 0.0, 11.4, 20.0, 8.1, and 7.4 mm. IZs for SAM were 11.9, 18.2, 24.7, 20.3, and 22.1 mm. Differences between parenteral and oral application as well as between different oral doses were significant (p<0.0001, one-way ANOVA). DiscussionThe results of our study demonstrate that oral administration is a suitable route to load PRF with these drugs. This could expand the scope of PRF application to prevent infections at the surgical site, especially in an outpatient setting in which drugs are normally applied orally.

Multidrug resistance in Haemonchus contortus in sheep - can it be overcome?

Gastrointestinal nematodes pose a threat to animal health and affect farmers by negatively impacting farm management. The study was conducted on a sheep farm with suspected reductions in the efficacies of anthelmintics. Efficacy was determined using in vivo faecal egg count reduction, in vitro egg hatch (EHT) and larval development (LDT) tests. In the first phase, 60 sheep were equally split into six groups. Group 1 received the recommended dose of albendazole (ALB), group 2 received the same after fasting for 24 h, group 3 received the dose divided into two halves at 6 h intervals, group 4 received a double dose of ALB, and group 5 received the recommended dose of ivermectin (IVM). Group 6 served as a control. The second phase of the experiment had two groups: one treated with levamisole (LEV) and a control group. Faecal samples were collected from all sheep. No reduction of egg output was observed in the groups treated with single, double, or divided doses of ALB, but one of 13.7-16.9% was noted in the fasting group. Efficacy in the IVM group ranged from 31.50 to 39.97%. The mean concentrations sufficient to prevent 50% of the eggs from hatching in the in vitro EHT and the mean concentrations in which the development of larvae to the L3 stage was inhibited by 50% in the LDT exceeded established thresholds for benzimidazoles and IVM. Haemonchus contortus was the only species identified after treatment. The LDT did not indicate the presence of resistance to LEV. All animals treated with LEV were negative for eggs 10 d after treatment. Resistance to ALB and IVM in Haemonchus contortus was confirmed. Alternative approaches to improve the efficacies of benzimidazole did not sufficiently increase the efficacy, but LEV was an efficient anthelmintic treatment.

Long-term effects of biochar on soil chemistry, biochemistry, and microbiota: Results from a 10-year field vineyard experiment

Application of biochar to soil has been recommended as a carbon sequestration approach that can also improve soil physical and chemical properties. The addition of biochar to soil can change the physicochemical properties of the soil, leading to a subsequent modification of the microbial community. However, the long-term implications of these changes remain insufficiently elucidated. Here, we examined soil chemical and biochemical properties of the bulk soil and employed next-generation sequencing techniques to analyze the microbiological properties of both bulk and rhizosphere soils after 10 years of biochar application. Specifically, we compared these properties between soil treated with two doses of biochar, i.e., SB and DB, and untreated soil, i.e., CK. After 10 years, biochar application increased the soil organic carbon from 12.7 g.kg−1 in CK to 17.3 and 23.1 g.kg−1, in SB and DB, respectively. Moreover, biochar application led to a slight decrease in soil bulk density, and increased the soil pH value 6.33 in CK to 7.07 in DB. Moreover, our findings revealed a distinct taxonomic signature within bacteria; however, this signature was not observed in terms of diversity. Specifically, we observed an increase in the abundance of oligotrophic bacteria compared to copiotrophic bacteria. The double dose of biochar increased the fungal species richness in the rhizosphere, particularly of Basidiomycota yeasts, from a relative abundance of 9.4 % in the CK soil to 17.0 % in the SB soil and 24.8 % in the DB soil and reduced putative plant pathogens like Phaeoacremonium and Aspergillus. Biochar amendment can significantly improve soil physical, chemical, and biological fertility on the long-term even under intensive viticulture management, with no detectable detrimental effects on microbial diversity and soil functions, and potential of soil organic carbon storage.

The Therapeutic Efficacy and Blood Drug Concentration of Posaconazole Enteric-Coated Tablets in Preventing Pulmonary Invasive Fungal Disease after HSCT

Introduction The risk of fungal infection in patients after HSCT is high. Prophylactic use of antifungal drugs can significantly reduce the occurrence of invasive fungal disease (IFD) and potential IFD-related mortality. Posaconazole oral suspension shows good preventive effects for patients with neutropenia and severe GVHD . However, there is still a lack of prospective research confirming the effectiveness of posaconazole enteric-coated tablets in preventing fungal infections in HSCT patients. Methods This study is a prospective, non-randomized, single-arm study. 143 patients who received hematopoietic stem cell transplantation at the Transplantation Center of Blood Diseases Hospital, the Chinese Academy of Medical Sciences from December, 2020 to May, 2022 were included. Posaconazole enteric-coated tablets were administered orally at a dose of 300mg QD (double dose for the first day) for the prevention of pulmonary invasive fungal disease from the first day to the 90th day after transplantation. The study collected baseline data, serum posaconazole concentrations, UGT1A4*3 genotype of the involved patients and observed whether pulmonary invasive fungal disease occurred. Retrospective data on the use of other antifungal drugs for the prevention of pulmonary invasive fungal disease at the center were collected as a control group for comparison. After applying propensity score matching at a ratio of 1:2, a comparative analysis was conducted on 140 cases in the posaconazole enteric-coated tablets group and 280 cases in the non-posaconazole group. Results Among the 143 patients who were included in the clinical trial and treated with posaconazole enteric-coated tablets alone for the prevention of fungal infection from day 1 to day 90 after hematopoietic stem cell transplantation, 4 cases developed invasive pulmonary fungal infection, including 1 case of mold and 3 cases of undefined pathogens, with a breakthrough rate of 2.80%, significantly lower than the historical control group breakthrough rate of 7.86% in the non-posaconazole group (P=0.014). In the 90 days after transplantation, a total of 246 measurements of posaconazole blood concentration were performed in the 143 patients in the clinical trial group. The average blood drug concentrations on the 4th, 8th, 15th, 22nd, and 30th day were 930.97 ng/ml, 1143.97 ng/ml, 1569.8 ng/ml, 1652.57 ng/ml, and 1644.75 ng/ml respectively. The blood drug concentration of posaconazole enteric-coated tablets tended to stabilize since the 15th day after treatment. In the 37 patients who tested the UGT1A4*3 genotype, there was no significant correlation between UGT1A4*3 gene polymorphism and posaconazole blood drug concentration. In terms of adverse reactions, the incidence of liver adverse events in this clinical study was 1.4%. Except for a slight increase in ALT after the 14-day medication (18.29 U/L vs. 26.22 U/L, P&amp;lt;0.001), there were no differences in other liver and kidney function laboratory test before and after treatment. Conclusion Posaconazole enteric-coated tablets is a highly safe prophylactic drug for invasive pulmonary fungal infections after HSCT, and its efficacy is superior to other antifungal prophylaxis regimens. Posaconazole enteric-coated tablet blood drug concentration in transplant patients gradually rose over time and tended to stabilize after 15 days of medication. The UGT1A4*3 gene polymorphism has no effect on the blood drug concentration of posaconazole enteric-coated tablets. Keywords Posaconazole enteric-coated tablets, hematopoietic stem cell transplantation, pulmonary invasive fungal disease

Yield and energy efficiency in winter wheat agrocenosis under different fertilization systems in the conditions of the northern part of the Forest-Steppe

The influence of different types of fertilizers on the yield and energy efficiency of winter wheat cultivation was evaluated. It was found that the highest productivity was obtained under the organic-mineral fertilizer system, which involves the combined use of 12 t/ha of cattle bedding manure and mineral fertilizers in a dose of N100Р60К100, applied against the background of two-time fertilization with complex chelated fertilizers at a dose of 2 l/ha, where the yield was 5.67 t/ha, and when applying a double mineral dose (N100Р60К100) and a triple dose (N150Р90К150) – 5.76 and 6.00 t/ha respectively, which in terms of yield growth was lower than the NIR05 values. The combined use of litter manure and mineral fertilizers resulted in a synergistic effect, as winter wheat grain yields were 15–20 % lower when mineral and organic fertilizers were applied separately than when they were applied together. Increasing NPK doses by 1.5 times to N150P90K150 compared to N100P60K100 did not compensate for the lack of manure. Under the organic fertilizer system, the grain yield was the highest when OMBF was applied at a dose of 2 t/ha against a background of pea straw 3 t/ha, which amounted to 5.18 t/ha with an increase of 41 %, compared to the control (straw). The highest levels of energy efficiency were determined for the application of organic-mineral fertilizer of the organic brand in doses of 1 and 2 t/ha (5.4 and 5.3) and OMBF brand 4-4-4 in a dose of 1 t/ha (5.2). Under the organic-mineral system of fertilizing application of N50P30K50 and N100P60K100 at the background of 12 t/ha of manure established the index of energy efficiency at the level of 3.4 and 3.7 units, respectively. Application of cattle manure at a dose of 12 t/ha did not provide a significant difference in crop energy, compared to the variant 6 t/ ha – 75755 and 73305 MJ/ha respectively, but due to increased energy inputs in production and application of more manure Kee was 3.9 and 4.6 respectively. Key words: cattle manure, fertilizers, OMBF, yield, mineral fertilizers, by-products, fertilizer system, energy efficiency.

Efficacy of flukicides against Fasciola hepatica and first report of triclabendazole resistance on German sheep farms

Fasciola hepatica infections lead to severe health problems and production losses in sheep farming, if not treated effectively. Triclabendazole has been used extensively over decades due to its unique efficacy range against all definitive hostfluke stages but published data about the susceptibility of F. hepatica to anthelmintics in Germany are lacking. This study aimed to identify current F. hepatica infections in German sheep flocks by coproscopic examinations and to evaluate the efficacy of anthelmintics with a focus on triclabendazole in a field study conducted from 2020 to 2022. Initial screening included 71 sheep farms, many of them with known history of fasciolosis. In this highly biased sample set, the frequency of F. hepatica infection at individual sheep and farm level were 12.8% and 35.2%, respectively. Additionally, eggs of Paramphistominae were found at frequencies of 4.8% and 15.5% at individual sheep and farm level, respectively. Due to low egg shedding intensity, faecal egg count reduction (FECR) tests could only be conducted on a few farms. The efficacy of triclabendazole was tested on 11 farms and albendazole on one farm, including 3–53 sheep/farm. Individual faecal samples were collected before and two weeks after treatment to evaluate the FECR using the sedimentation or FLUKEFINDER® or a modified FLUKEFINDER® method. On all farms a coproantigen reduction test was conducted in parallel. Lacking efficacy of triclabendazole even at double dosage was shown on one farm associated with a high number of animal losses due to acute fasciolosis. On this farm, the Fasciola miracidium development test was additionally performed, revealing a high in vitro ovicidal activity of albendazole while closantel was effective in vivo. On all other farms, sufficient efficacy of triclabendazole was observed. In conclusion, triclabendazole resistance appears not to be widespread on German sheep farms but, when present, can have serious effects on animal health.

Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir With Rifampicin.

Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia. Twice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target. NCT04121195. Registered on 09 October 2019, https://clinicaltrials.gov/ct2/show/NCT04121195.

Ex-vivo rectal tissue infection with HIV-1 to assess time to protection following oral preexposure prophylaxis with tenofovir disoproxil/emtricitabine.

We wished to assess time to protection from HIV-1 infection following oral tenofovir disoproxil and emtricitabine (TDF/FTC) as preexposure prophylaxis (PrEP), using ex-vivo rectal tissue infections and drug concentration measures in blood and rectal tissue. Participants from the ANRS PREVENIR study (NCT03113123) were offered this sub-study after a 14-day wash-out. We used an ex-vivo model to evaluate rectal tissue HIV-1 susceptibility before and after PrEP, 2 h after two pills or 7 days of a daily pill of TDF/FTC. PrEP efficacy was expressed by the difference (after-before) of 14-day cumulative p24 antigen levels. TFV-DP and FTC-TP levels were measured in rectal tissue and PBMCs and correlated with HIV-1 infection. Twelve and 11 men were analyzed in the 2 h-double dose and 7 days-single dose groups, respectively. Cumulative p24 differences after-before PrEP were -144 pg/ml/mg (IQR[-259;-108]) for the 2 h-double dose group ( P = 0.0005) and -179 pg/ml/mg (IQR [-253;-86]) for the 7 days-single dose group ( P = 0.001), with no differences between groups ( P = 0.93). Rectal TFV-DP was below quantification after a double dose, but FTC-TP levels were similar to levels at 7 days. There was a significant correlation between rectal FTC-TP levels and p24 changes after a double dose ( R = -0.84; P = 0.0001). Oral TDF/FTC provided similar protection against HIV-1 infection of rectal tissue 2 h after a double dose or 7 days of a daily dose. At 2 h, this protection seems driven by high FTC-TP concentrations in rectal tissue. This confirms the importance of combining TDF and FTC to achieve early protection.

Palmatine treats urticaria by reducing inflammation and increasing autophagy.

Chronic spontaneous urticaria (CSU) is mainly manifested as wheals and erythema on the skin accompanied by itching, which will cause emotional anxiety and seriously affect the quality of life in patients. Palmatine (PAL) is a main chemical component of Yajieshaba, which has been found to effectively alleviate the symptoms of food allergy. However, its role and mechanism in CSU remain unclear. The present study aimed to investigate the protective effect of PAL on CSU rats. We replicated the CSU rat model by intraperitoneal injection of ovalbumin (OVA) in rats on days 0, 2, 4, and 14, with a double dose given on the last challenge. PAL, loratadine and saline were given by gavage from day 5 to day 14. We observed the skin pathologic changes, mast cell degranulation, immune factor levels, inflammatory response and autophagy-related protein expression in CSU rats. We found PAL treatment to be effective in alleviating CSU-like skin lesions and reducing itching and mast cell degranulation in rats. Compared with the OVA group, the levels of immune and inflammatory factors were significantly reduced, neutrophil recruitment was alleviated, suggesting a reduced inflammatory response. The autophagy results showed that PAL further increased the expression of LC3, Beclin-1 and p-LKB1, p-AMPK, Atg5, Atg12 and Atg5-Atg12, while P62 and p-p70S6K1 expression decreased. They collectively suggested that autophagic flux was activated after PAL treatment. However, there was an increase in the expression of LC3I, probably due to the fact that PAL induced its accumulation in order to provide substrate for the generation of more LC3II. Overall, PAL had a protective effect on CSU in normal rats, activated the expression of autophagy and improved the inflammatory response.

Biochar of Prosopis juliflora for Improving Crops Germination and Growth on Sandy–Loam Soil

Prosopis juliflora (Sw.) DC. is an invasive alien species (IAS) damaging agricultural and natural ecosystems that threat biodiversity in Ethiopia. This IAS can be managed by utilizing it as a resource in agricultural production. This study analyzed the role of P. juliflora biochar on germination and growth performance of maize and wheat under field conditions in Wollo, Ethiopia. A randomized complete block design (RCBD) was used to test the effect of biochar on sandy–loam soil with and without fertilizer. In this experiment, biochar from P. juliflora was applied on the above two crops at 5, 10, and 20 t/ha with and without N–P fertilizers. From the result, a 100% germination and high growth of test crops were observed from 10 t/ha biochar with fertilizer mixed treatments. The shoot dry weight of both maize and wheat showed significant differences among treatments. While a single dosage (10 t/ha) increased maize dry weight by 21% without fertilizer, but it reduced dry weight by 10% when used with fertilizer. In the case of wheat, single and double dose biochar with NPS treatments increased shoot dry weight by 22.2% and 30%, respectively. This showed that application of biochar up to 20 t/ha in combination with fertilizers can significantly improve crop growth. Thus, it can be concluded that the application of biochar of P. juliflora is a good soil amendment option and, thus, this IAS can be managed by utilization.

Comparative evaluation of dose dependent efficacy of vitamin C, in relation to oxidative stress level in subjects with Oral Submucus Fibrosis

Background Oral submucus fibrosis (OSMF) has a 0.2-0.5 prevalence rate in India. The malignancy rate of OSMF was found to be 7.6%. The focus of pathogenesis is currently on reactive oxygen species levels which can rise to extremely high levels, exceeding the human body’s antioxidant defense system and causing oxidative stress that goes beyond physiological limitations. Since oxidative stress plays such a significant part in carcinogenesis and other degenerative diseases, it is fair to believe that antioxidants will help to reduce or even stop these processes. Vitamin C is known for its antioxidant properties which act as a lipid-soluble free radical scavenger in cell membranes. But in some of studies a paradoxical effect of antioxidant doses was found. Thus, the present study will be conducted to evaluate the dose dependent efficacy of Vitamin C level in relation to oxidative stress level in subjects of OSMF. Methods After informed consent, the patient’s examination will be conducted. For each individual, 5ml of the blood sample will be withdrawn under all the aseptic precautions and oxidative stress level will be assessed depending on MDA &amp; SOD level in a central research laboratory. Depending on oxidative stress level patients will be divided into two groups. Group I - Moderate oxidative stress in OSMF SI less than 240 but more than 192 Group II - High Oxidative Stress in OSMF SI more than 240 Single and double doses of Vitamin C will be given to patients accordingly and the MDA &amp; SOD levels will be calculated on day 30,90 days and on 180th day Conclusions Positive results of the study will give direction for choosing the correct dose of the antioxidant Vitamin C for OSMF depending on oxidative stress level.

Escitalopram population pharmacokinetics and remedial strategies based on CYP2C19 phenotype

Background and purposeCYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy. MethodsNonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window. ResultsResults showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects. LimitationAll samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age. ConclusionThe study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.

Double Step-up Dosing (2SUD) Regimen Mitigates Severe Icans and CRS While Maintaining High Efficacy in Subjects with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL) Treated with AZD0486, a Novel CD19xCD3 T-Cell Engager (TCE): Updated Safety and Efficacy Data from the Ongoing First-in-Human (FIH) Phase 1 Trial

Background: AZD0486 (formerly TNB-486) is a novel, IgG4 fully human CD19xCD3 bispecific TCE incorporating a unique low affinity anti-CD3 moiety designed to reduce cytokine release while retaining potent T-cell mediated cytotoxicity of malignant B cells. A silenced Fc prevents nonspecific binding, antibody-dependent cellular cytotoxicity, and confers a long half-life suitable for intermittent administration. Preliminary clinical activity in Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) was reported [ Hou et al, Blood 2022; Jacobs et al, HemaSphere 2023] following fixed and single step-up dosing (1SUD). We now present focused updated safety data following implementation of 2SUD in the ongoing FIH phase 1 study (NCT04594642). Methods: Patients with R/R CD19+ B-NHL failing ≥2 prior lines of therapy, including prior CD19 CART and/or CD20 TCE, were enrolled. AZD0486 was administered in escalating doses in either no SUD (Day (D)1, D15 0.03-2.4mg), 1SUD (D1 0.27-1 mg, D15 2.4-10 mg), or 2SUD (D1 0.27 mg, D8 1 mg, D15 2.4-7.2 mg, FL/DLBCL only) schedules. AZD0486 was given IV every 2 weeks in 28D Cycles (C) up to 2 years. Monthly dosing was considered for patients in complete response (CR) at C6. Responses were assessed by RECIL 2017 by Central Imaging Review, AEs by CTCAE v5.0, and CRS/ICANS by 2019 ASTCT criteria. Results: As of 03 July 2023, 62 patients (27 DLBCL, 25 FL, 5 mantle cell lymphoma, 4 marginal zone lymphoma, 1 other) received AZD0486 and were evaluable for safety. Median age was 68 (range 22-86), with 58% male, 81% stage III/IV. Median prior lines of therapy was 3 (range 2-16) including 23 (37%) failing CART and 3 (4.8%) failing CD20 TCE. Fifteen (24%) were CD20 negative at study entry. The complete response (CR) rate was 91% (10/11) in patients with FL treated in 2.4 mg dose cohorts and for all FL efficacy evaluable subjects dosed at 2.4mg or above, CR was achieved in 14/17 (83%) with an overall response rate (ORR) of 88%. Median duration of response (DOR) has not beenreached. With the implementation of 2SUD regimen, no Grade 3+ CRS or ICANS events were observed (Table 1). Grade 1-2 CRS events decreased from 62.5% to 22.2% (fixed/1SUD, 15/24 and 2SUD, 4/18). Grade 1-2 ICANS events decreased from 20% (5/24) to 5.6% (1/18), presented mainly as confusion, and typically resolved in 1-2 days. The most common AEs (occurring in &amp;gt;20%) of any grade and regardless of drug causality were CRS (48%), anemia (34%), neutropenia (32%), lymphopenia (29%), ICANS (27%) and decreased WBC (20.9%). Treatment-related events of Grade ≥3 included lymphopenia (24%), neutropenia (15%), ICANS (9.7%) and anemia (3.2%). No treatment related deaths were reported (1 death due to COVID19, unrelated) and no treatment-related AEs lead to discontinuation (1 patient discontinued due to COVID-19, unrelated). Preliminary analysis (TNF-a, IL-6, IL-8, IL-10) suggests a decrease in cytokine levels after target dose with 2 SUD compared to fixed dosing and 1SUD, regardless of target dose. Conclusions: AZD0486 (formerly TNB-486) is an active treatment in patients with advanced R/R B-NHL and has a predictable safety profile characterized by mainly low-grade AEs and fully transient and reversible CRS/ICANS events. The 2 SUD schedule reduced the overall rate of low grade CRS and ICANS (Grade 1-2) and abrogated Grade 3 events further improving the risk/benefit profile of AZD0486. Dose escalation is ongoing to identify the RP2D.