Dose Levels Research Articles

Lasmiditan ameliorates serotonergic itch in mice: Possible involvement of 5-HT1F receptors.

Previously, some allergic conditions involving pruritus have been linked to migraine, raising the possibility that migraine and itching may be governed by similar underlying mechanisms. We aimed to investigate the efficacy of Lasmiditan, a highly selective agonist of the5-hydroxytryptamine 1F (5-HT1F) receptor and a recently approved medication for the treatment of migraine headaches, in ameliorating serotonergic itching. Forty animals were employed in the present study (n = 40). Eight animals were randomly assigned to each of the following study groups (n = 8, in each group): (1) "Normal Saline": This group was given intradermal injections of normal saline (2) "5-HT": The animals were injected with intradermal 5-HT, which was used to induce itching. (3) "Lasmiditan 0.3", "Lasmiditan 1", and "Lasmiditan 3" groups: injected with 5-HT as well as intraperitoneal Lasmiditan at different dose levels (0.3, 1, and 3mg/kg, respectively). Scratching behavior was recorded for 60min, and the skin tissue of three mice was sampled at the end of the behavioral experiment to assess the levels of TLR-4, IL-31, 5-HT1F receptor, CGRP & TRPV4. In the present study, we found that Lasmiditan when administered at 1mg/kg effectively reduced serotonin-induced itching compared to the "5-HT" group (P < 0.0001). Following the administration of Lasmiditan (1mg/kg), the expression levels of the 5-HT1F receptor significantly increased (P < 0.01). Further, the levels of TLR-4, IL-31, CGRP & TRPV4 were substantially reduced upon the administration of Lasmiditan (1mg/kg). We found that Lasmiditan is effective in reducing serotonergic itch in mice through its interaction with the 5-HT1F receptor in the skin tissue of mice.

Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis.

The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5mg/kg/day and the highest risk difference for oral propranolol 2.0mg/kg/day (0.06; 95% CI -0.01 to 0.13). A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors.

Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies.This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors.Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5mg/m2/Gem 1000mg/m2) was the MTD. Accrual into DL7 (Plo 10.0mg/m2/Gem 1000mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4months occurred among 13 pts with ovarian cancer.The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5mg/m2/Gem 1000mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2)

BackgroundDavoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4...

Phase 1 study of NEDD8 activating enzyme inhibitor pevonedistat in combination with chemotherapy in pediatric patients with recurrent or refractory solid tumors (ADVL1615)

PurposeThe objective of this study was to determine the recommended Phase 2 dose (RP2D) of pevonedistat, a first in class inhibitor of NEDD8 activating enzyme, in combination with irinotecan (IRN) and temozolomide (TMZ) in children with cancer. MethodsThis Phase 1 study used a rolling 6 design to evaluate escalating doses of pevonedistat in combination with standard doses of IRN and TMZ in pediatric patients with recurrent/refractory solid or CNS tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50 mg/m2) and TMZ (orally, 100 mg/m2), on days 8–12 of a 28-day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN/TMZ on days 1–5 of a 21-day cycle. ResultsThirty patients enrolled; all were eligible and evaluable for toxicity. Six patients each enrolled on pevonedistat dose levels (DL) 1 (15 mg/m2), 2 (20 mg/m2), 3 (25 mg/m2) and 4 (35 mg/m2) as well as an expanded pharmacokinetic (PK) cohort at DL4. The maximum tolerated dose (MTD) was not exceeded. 2/12 (17 %) patients treated at the RP2D (35 mg/m2) experienced a cycle 1 dose limiting toxicity (DLT). IRN is unlikely to affect the pharmacokinetics of pevonedistat. Two patients had a partial response and 6 patients had prolonged stable disease (> 6 cycles). ConclusionsPevonedistat in combination with IRN/TMZ is well tolerated in children with solid or CNS tumors. The RP2D of pevonedistat is 35 mg/m2 on days 1, 3, 5 in combination with IRN/TMZ.

Analysis of hydrogen peroxide production in pure water: Ultrahigh versus conventional dose-rate irradiation and mechanistic insights.

Ultrahigh dose-rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite. We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons ( ) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G-value (molecules/100eV) for H2O2 (G[H2O2]), because: 1, the third-order reaction between and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two-order reaction of •OH self-reaction producing H2O2; 2, has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means would dominate the competition for •OH and benefit more from the inter-track effect of UHDR. Meanwhile, we also experimentally verify the theory of long-lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies. H2O2 was measured by Amplex UltraRed assay. 430.1MeV/u carbon ions (50 and 0.1Gy/s), 9MeV electrons (600 and 0.62Gy/s), and 200kV x-ray tube (10 and 0.1Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger of , were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger of , and bubbled with N2O was irradiated by x-ray to verify the results of low-LET electron beam. UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose-rate dependency of G(H2O2). Three-spilled carbon UHDR does not have a lower G(H2O2) than one-spilled UHDR. However, the electron beam shows a lower G(H2O2) for three-spilled UHDR than for one-spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x-ray. UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x-ray beams. Both scavengers for , N2O and NaNO3, eliminate the dose-rate dependency of G(H2O2), which suggests is the reason for decreased G(H2O2) for UHDR. Three-spilled UHDR versus one-spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam.

Expression and localization of the neuropeptide Y-Y4 receptor in the chick spleen: mRNA upregulation by high ambient temperature

High ambient temperatures (HT) can increase diencephalic neuropeptide Y (NPY) expression, and central injection of NPY attenuates heat stress responses while inducing an antioxidative state in the chick spleen. However, there is a lack of knowledge about NPY receptor expression, and its regulation by HT, in the chick spleen. In the current study, male chicks were used to measure the expression of NPY receptors in the spleen and other immune organs under acute (30 vs. 40 ± 1 °C for 3 h) or chronic (30 vs. 40 ± 1 °C for 3 h/day for 3 days) exposure to HT and in response to central injection of NPY (47 pmol, 188 pmol, or 1 nmol). We found that NPY-Y4 receptor mRNA was expressed in the spleen, but not in other immune organs studied. Immunofluorescence staining revealed that NPY-Y4 receptors were localized in the splenic pulp. Furthermore, NPY-Y4 receptor mRNA increased in the chick spleen under both acute and chronic exposure to HT. Central NPY at two dose levels (47 and 188 pmol) and a higher dose (1 nmol) did not increase splenic NPY-Y4 receptor mRNA expression or splenic epinephrine under HT (35 ± 1 °C), and significantly increased 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations under HT (40 ± 1 °C). In conclusion, increased expression of NPY-Y4 receptor mRNA in the spleen under HT suggest that Y4 receptor may play physiological roles in response to HT in male chicks.

Translational pharmacokinetic/pharmacodynamic model for mRNA-0184, an investigational therapeutic for the treatment of heart failure.

Heart failure (HF) is a complex, progressive disorder that is associated with substantial morbidity and mortality on a global scale. Relaxin-2 is a naturally occurring hormone that may have potential therapeutic benefit for patients with HF. To investigate the therapeutic potential of relaxin in the treatment of patients with HF, mRNA-0184, a novel, investigational, lipid nanoparticle (LNP)-encapsulated mRNA therapy that encodes for human relaxin-2 fused to variable light chain kappa (Rel2-vlk) was developed. A translational semi-mechanistic population pharmacokinetic (PK)/pharmacodynamic (PD) model was developed using data from non-human primates at dose levels ranging from 0.15 to 1 mg/kg. The PK/PD model was able to describe the PK of Rel2-vlk mRNA and translated Rel2-vlk protein in non-human primates adequately with relatively precise estimates. The preclinical PK/PD model was then scaled allometrically to determine the human mRNA-0184 dose that would achieve therapeutic levels of Rel2-vlk protein expression in patients with stable HF with reduced ejection fraction. Model-based simulations derived from the scaled PK/PD model support the selection of 0.025 mg/kg as an appropriate starting human dose of mRNA-0184 to achieve average trough relaxin levels between 1 and 2.5 ng/mL, which is the potential exposure for cardioprotective action of relaxin.

Two dose levels of once-weekly fosravuconazole versus daily itraconazole in combination with surgery in patients with eumycetoma in Sudan: a randomised, double-blind, phase 2, proof-of-concept superiority trial

Eumycetoma is an implantation mycosis characterised by a large subcutaneous mass in the extremities commonly caused by the fungus Madurella mycetomatis. Despite the long duration of treatment, commonly a minimum of 12 months, treatment failure is frequent and can lead to amputation. We aimed to compare the efficacy of two doses of fosravuconazole, a synthetic antifungal designed for use in onychomycosis and repurposed for mycetoma, with standard-of-care itraconazole, both in combination with surgery. This phase 2, randomised, double-blind, active-controlled, superiority trial was conducted in a single centre in Sudan. Patients with eumycetoma caused by M mycetomatis, who were aged 15 years or older, with a set lesion diameter (>2 cm and ≤16 cm) requiring surgery were included. There was a limit of 20 female patients in the initial enrolment, owing to preclinical toxicity concerns. Exclusion criteria included previous surgical or medical treatment for eumycetoma; presence of loco-regional lymphatic extension; osteomyelitis, or other bone involvement; pregnancy or lactation; severe concomitant diseases; a BMI under 16 kg/m2; contraindication to use of the study drugs; pre-existing liver disease; lymphatic extension; osteomyelitis; transaminase levels more than two times the laboratory's upper limit of normal, or elevated levels of alkaline phosphatase or bilirubin; or any history of hypersensitivity to any azole antifungal drug. Patients were randomly allocated in a 1:1:1 ratio to 300 mg fosravuconazole weekly for 12 months (group 1); 200 mg fosravuconazole weekly for 12 months (group 2); or 400 mg itraconazole daily for 12 months (group 3) using a random number list with non-disclosed fixed blocks of size 12, with equal allocation to each of the three arms within a block. To ensure masking between groups, placebo pills were used to disguise the difference in dosing schedules. All groups took pills twice daily with meals. In all groups, surgery was performed at 6 months. The primary outcome was complete cure at end of treatment at the month 12 visit, as evidenced by absence of mycetoma mass, sinuses, and discharge; normal ultrasonography or MRI examination of the eumycetoma site; and, if a mass was present, negative fungal culture from the former mycetoma site. The primary outcome was assessed in the modified intention-to-treat (mITT) population (all patients who received one or more treatment dose with one or more primary efficacy assessment). Safety was assessed in all patients who received one or more doses of the study drug. This study is registered with ClinicalTrials.gov (NCT03086226) and is complete. Between May 9, 2017, and June 10, 2021, 104 patients were randomly allocated (34 in group 1 and 2, respectively, and 36 in group 3). 86 (83%) of 104 patients were male and 18 (17%) patients were female. After an unplanned second interim analysis, the study was terminated early for futility. Complete cure at 12 months in the mITT population was 17 (50%) of 34 (95% CI 32-68) for group 1, 22 (65%) of 34 (47-80) for group 2, and 27 (75%) of 36 (58-88) in group 3. Neither dose of fosravuconazole was superior to itraconazole (p=0·35 for 200 mg fosravuconazole vs p=0·030 for 300 mg fosravuconazole). 83 patients had a total of 205 treatment-emergent adverse events, and two patients had serious adverse events that led to discontinuation, neither related to treatment. Treatment with either dose of fosravuconazole was not superior to itraconazole, and the two doses had a numerically lower efficacy. However, fosravuconazole presented no new safety signals, and its lower pill burden and reduced risk of drug-drug interactions compared with the relatively expensive and inaccessible itraconazole suggests further research into effective treatments with a shorter duration and higher cure rate, without the need for surgery are warranted. Drugs for Neglected Diseases initiative.

Single Injection AAV2-FGF18 Gene Therapy Reduces Cartilage Loss and Subchondral Bone Damage in a Mechanically Induced Model of Osteoarthritis.

Osteoarthritis (OA) is a highly debilitating, degenerative pathology of cartilaginous joints affecting over 500 million people worldwide. The global economic burden of OA is estimated at $260-519 billion and growing, driven by aging global population and increasing rates of obesity. To date, only the multi-injection chondroanabolic treatment regimen of Fibroblast Growth Factor 18 (FGF18) has demonstrated clinically meaningful disease-modifying efficacy in placebo-controlled human trials. Our work focuses on the development of a novel single injection disease-modifying gene therapy, based on FGF18's chondroanabolic activity. OA was induced in Sprague-Dawley rats using destabilization of the medial meniscus (DMM) (3 weeks), followed by intra-articular treatment with 3 dose levels of AAV2-FGF18, rh- FGF18 protein, and PBS. Durability, redosability, and biodistribution were measured by quantifying nLuc reporter bioluminescence. Transcriptomic analysis was performed by RNA-seq on cultured human chondrocytes and rat knee joints. Morphological analysis was performed on knee joints stained with Safranin O/Fast Green and anti-PRG antibody. Dose-dependent reductions in cartilage defect size were observed in the AAV2-FGF18- treated joints relative to the vehicle control. Total defect width was reduced by up to 76% and cartilage thickness in the thinnest zone was increased by up to 106%. Morphologically, the vehicle- treated joints exhibited pronounced degeneration, ranging from severe cartilage erosion and bone void formation, to subchondral bone remodeling and near-complete subchondral bone collapse. In contrast, AAV2-FGF18-treated joints appeared more anatomically normal, with only regional glycosaminoglycan loss and marginal cartilage erosion. While effective at reducing cartilage lesions, treatment with rhFGF18 injections resulted in significant joint swelling (19% increase in diameter), as well as a decrease in PRG4 staining uniformity and intensity. In contrast to early-timepoint in vitro RNA-seq analysis, which showed a high degree of concordance between protein- and gene therapy-treated chondrocytes, in vivo transcriptomic analysis, revealed few gene expression changes following protein treatment. On the other hand, the gene therapy treatment exhibited a high degree of durability and localization over the study period, upregulating several chondroanabolic genes while downregulating OA- and fibrocartilage-associated markers. FGF18 gene therapy treatment of OA joints can provide benefits to both cartilage and subchondral bone, with a high degree of localization and durability.

The Effect Of Casgot Fertilizer On The Growth Of Cucumber Plants

Regular use of organic fertilizer can improve soil health, reduce erosion, and increase agricultural sustainability by reducing dependence on synthetic chemicals. Kasgot fertilizer or used maggot fertilizer is a type of organic fertilizer produced from maggot droppings (larva lalat Black Soldier Fly) after they decompose organic waste. This fertilizer is rich in essential nutrients such as nitrogen, phosphorus and potassium, and contains various beneficial microorganisms that help increase soil fertility. This research aims to determine the effect of cassava fertilizer on the growth of cucumber plants (Cucumis sativus L.).This study used non-factorial RAK with 4 administration dose levels, namely: M0= 0 grams/planting hole, M1= 5 grams/planting hole, M2= 10 grams/planting hole and M3= 20 grams/planting hole. Data were analyzed using analysis of variance tests on the parameters of plant height, number of leaves and root weight. The results of the research showed that the parameters of plant height and number of leaves showed significant differences between plants aged 2 WAP and 4 WAP, while root weight did not have a significant difference between treatments and each replication. Additional doses or other organic materials are needed to increase the macro nutrients available in the soil.

Dual-Split CT to Simulate Multiple Radiation Doses From a Single Scan-Liver Lesion Detection Compared With Dose-Matched Single-Energy CT.

The aim of this study was to evaluate the potential use of simulated radiation doses from a dual-split CT scan for dose optimization by comparing their lesion detectability to dose-matched single-energy CT acquisitions at different radiation dose levels using a mathematical model observer. An anthropomorphic abdominal phantom with liver lesions (5-10 mm, both hyperattenuating and hypoattenuating) was imaged using a third-generation dual-source CT in single-energy dual-source mode at 100 kVp and 3 radiation doses (5, 2.5, 1.25 mGy). The tube current was 67% for tube A and 33% for tube B. For each dose, 5 simulated radiation doses (100%, 67%, 55%, 45%, 39%, and 33%) were generated through linear image blending. The phantom was also imaged using traditional single-source single-energy mode at equivalent doses. Each setup was repeated 10 times. Image noise texture was evaluated by the average spatial frequency (fav) of the noise power spectrum. Liver lesion detection was measured by the area under the receiver operating curve (AUC), using a channelized Hotelling model observer with 10 dense Gaussian channels. Fav decreased at lower radiation doses and differed between simulated and single-energy images (eg, 0.16 mm-1 vs 0.14 mm-1 for simulated and single-energy images at 1.25 mGy), indicating slightly blotchier noise texture for dual-split CT. For hyperattenuating lesions, the mean AUC ranged between 0.92-0.99, 0.81-0.96, and 0.68-0.89 for single-energy, and between 0.91-0.99, 0.78-0.91, and 0.70-0.85 for dual-split at 5 mGy, 2.5 mGy, and 1.25 mGy, respectively. For hypoattenuating lesions, the AUC ranged between 0.90-0.98, 0.75-0.93, and 0.69-0.86 for the single-energy, and between 0.92-0.99, 0.76-0.87, and 0.67-0.81 for dual-split at 5 mGy, 2.5 mGy, and 1.25 mGy, respectively. AUC values were similar between both modes at 5 mGy, and slightly lower, albeit not significantly, for the dual-split mode at 2.5 and 1.25 mGy. Lesion detectability was comparable between multiple simulated radiation doses from a dual-split CT scan and dose-matched single-energy CT. Noise texture was slightly blotchier in the simulated images. Simulated doses using dual-split CT can be used to assess the impact of radiation dose reduction on lesion detectability without the need for repeated patient scans.

Pharmacokinetics and Pharmacodynamics of Nipocalimab, a Neonatal Fc Receptor Blocker, in Healthy Japanese Volunteers.

Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab. Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo. To complement the study, genetic variation in the Fcγ receptor and transporter subunit of the neonatal Fc receptor was analyzed in Japanese and diverse populations. Nipocalimab was generally safe and well tolerated at all dose levels, with three (12.5% [3/24]) volunteers experiencing treatment-emergent adverse events across all nipocalimab doses. Mean serum immunoglobulin G levels decreased in a dose-dependent manner from baseline with nipocalimab treatment compared with placebo. Maximum serum nipocalimab concentrations demonstrated proportional increases with dose, while the area under theconcentration-time curve was dose dependent and demonstrated non-linear increases with dose. Mean observed half-life was longer as the dose increased. Analysis of genetic variation in Fcγ receptor and transporter identified no unique Japanese variants or variants that alter amino acid sequences in or near the neonatal Fc receptor immunoglobulin G binding site targeted by nipocalimab. The comparable pharmacokinetic/pharmacodynamic profiles and highly conserved neonatal Fc receptor structure among diverse populations further support the clinical development of nipocalimab for the treatment of various immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases across global sites and populations, including the Japanese population.

Effect of Chemotherapy on Gonadal Function and Sexual Function of Male Cancer Survivors: A Review Article.

The advancement of anti-cancer treatment has increased survival rates among patients, yet putting them in an increased risk for developing side-effects. In addition to early side-effects, anti-cancer treatments, in particular chemotherapeutic medications can cause long-term side-effects; fertility and sexual dysfunction included. The aim of this study was to review existing data on the effects of different chemotherapeutic agents on fertility and sexual function of male cancer survivors who received chemotherapy at different stages of life. We searched PubMed/MEDLINE, Scopus, and Google Scholar to detect studies focused on the effect of chemotherapy on the gonadal/testicular function and sexual function of male cancer survivors. We restricted our search to English language publications and manuscript published before the year 2000 were excluded. It has been well understood that chemotherapy impairs gonadal function in major number of cancer survivors and gonadal dysfunction is not protected if chemotherapeutic agents administered before puberty in males. Moreover, effect of chemotherapy on sexual function is controversial. While several articles reported the worst effect of chemotherapy on sexual function of cancer survivors, some studied reported that chemotherapy do not impair sexual function. Higher levels of chemotherapy dose seem to be associated with more gonadal and sexual dysfunction.

Development of Acceptable Quality Dose (AQD) and image quality-related diagnostic reference levels for common computed tomography investigations in a tertiary care public sector hospital of Khyber Pakhtunkhwa, Pakistan.

To describe the first experience of patient dose optimization in developing AQD, SSDE and image quality-related DRLs for common CT examinations in the adult age group using the concept of AQD. The recent published IQSC from 0 to 4 were used by radiologists for the assessment of image quality. The entire data were collected for five types (brain CT, chest CT, chest HRCT, abdomen KUB CT and abdomen + pelvic CT) CT investigations based on anatomic region (head, chest and abdomen + pelvic). The entire datasets of 264 patients were categorized into three groups based on their weights: group-1 (41-60kg), group-2 (61-80kg) and group-3 (81-100kg). Only score-3 images were considered to assess median and 75th percentile values of CTDIvol and DLP to obtain AQDs and DRLs, respectively. Following the practical training of four radiologists on image quality scoring criteria for CT images, 264 (92%) out of 288 patient images were clinically acceptable as per IQSC for the study. The AQD (median) values in terms of CTDIvol for the mentioned weight groups were 25.8, 2.7, and 30.6mGy, while the median DLP values for these groups were 496, 510 and 557 mGycm, respectively, for brain CT. The 75th percentile values in terms of CTDIvol were 30.2, 35.3 and 36.2mGy, while in terms of DLP, they were 583, 619 and 781 mGycm for brain CT, respectively. Similar results are presented for the above-mentioned procedures, as well as in terms of SSDE. The first ever experience in obtaining AQD, SSDE and DRLs values for specific CT procedures couples image quality with dose indices, showing comparable values with other relevant studies. Hence, it will provide a baseline for comparison within the facility for future studies and facilitate dose optimization for other facilities aiming for improvement.

Evaluating the impact of variability in the source of waste polyethylene on the design of plastic modified asphalt mixtures

Use of waste plastics in asphalt mixtures suffers from a serious problem of significant variability with global sources; preventing proper guidelines for field applications. The aim of this study is to address the variability in source of waste plastic and its impact on asphalt mixture design. Polyethylene (PE) obtained from 5 different sources was used as a replacement for asphalt binder through dry mixing at dosage levels of 3 %, 6 %, and 9 % by weight of binder. Two mixing temperatures (151°C, 165°C) with respective compaction temperatures (140°C, 156°C) were utilized during mix production to account for the increase in binder stiffness due to plastic modification. The changes in asphalt mixture volumetrics were correlated to plastic properties such as density(ρ), viscosity (η), melting point (Tm), and Degree of Crystallinity (Xc), apart from plastic source. Construction Densification Index (CDI) and Traffic Densification Index (TDI) values were also calculated for further understanding the workability of PE modified asphalt mixtures. Even though five plastics irrespective of sources could be categorized as PE, the Xc (<65 %) and η (<5594 Pa.sec at 165°C) played a prominent role in ensuring mixtures met volumetric requirements; after increasing the mixing and compaction temperatures. PE with Xc value (> 65 %) and η value (>5594 Pa.sec at 165°C) resulted in reduced workability with increased tendency of PE to behave as a filler. The study further recommends addressing PE in terms of core properties such as Xc and η rather than source or supplier to reduce variability and better understand its suitability in asphalt mixtures.

JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase 2 trial results

AbstractOur phase 1 graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib (PAC; recommended phase 2 dose: 100 mg orally twice a day on day 0 to +70) plus sirolimus and tacrolimus (SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits interleukin 6 (IL-6) receptor activity and pathogenic T helper cell 1 (Th1)/Th17 differentiation in preclinical models and the phase 1 trial. Herein, we report on our completed phase 2 trial of PAC/SIR/TAC after 8/8 human leukocyte antigen matched alloHCT. This single-arm phase 2 trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed percentage phosphorylated STAT3 (pSTAT3)+ CD4+ T cells at day +21 (primary end point: percentage pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II to IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T-cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n = 28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary end point, reducing percentage pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of Tregs to Th1 and Th17 cells with PAC/SIR/TAC at recommended phase 2 dose PAC compared with dose level 1 PAC. The cumulative incidence of grade II to IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46% vs 43%). Although PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.

Toxicological evaluation of primary particulate matter emitted from combustion of aviation fuel

Recently, Sustainable Aviation Fuel (SAF) blends and novel combustion technologies have been introduced to reduce aircraft engine emissions. However, there is limited knowledge about the impact of combustion technology and fuel composition on toxicity of primary Particulate Matter (PM) emissions, comparable to regulated non-volatile PM (nvPM).In this study, primary PM was collected on filters using a standardised approach, from both a Rich-Quench-Lean (RQL) combustion rig and a bespoke liquid fuelled Combustion Aerosol Standard (CAST) Generator burning 12 aviation fuels including conventional Jet-A, SAFs, and blends thereof. The fuels varied in aromatics (0–25.2%), sulphur (0–3000 ppm) and hydrogen (13.43–15.31%) contents. Toxicity of the collected primary PM was studied in vitro utilising Air-Liquid Interface (ALI) exposure of lung epithelial cells (Calu-3) in monoculture and co-culture with macrophages (differentiated THP-1 cells). Cells were exposed to PM extracted from filters and nebulised from suspensions using a cloud-based ALI exposure system. Toxicity readout parameters were analysed 24 h after exposure.Results showed presence of genotoxicity and changes in gene expression at dose levels which did not induce cytotoxicity. DNA damage was detected through Comet assay in cells exposed to CAST generated samples. Real-Time PCR performed to investigate the expression profile of genes involved in oxidative stress and DNA repair pathways showed different behaviours after exposure to the various PM samples. No differences were found in pro-inflammatory interleukin-8 secretion. This study indicates that primary PM toxicity is driven by wider factors than fuel composition, highlighting that further work is needed to substantiate the full toxicity of aircraft exhaust PM inclusive of secondary PM emanating from numerous engine technologies across the power range burning conventional Jet-A and SAF.

Selective and low transfer of pyrrolizidine alkaloids from Jacobaea vulgaris Gaertn. into muscle and liver of dairy cattle, goat and sheep

1,2-unsaturated pyrrolizidine alkaloids and their N-oxides (PA/PANO) are plant toxins that are produced by several hundreds of plant species. Due to the pronounced liver toxicity and carcinogenicity of certain PAs, their presence in food and feed has raised concern. However, since PA-producing weeds cannot generally be prevented on grassland and Senecio species often occur in high densities, the transfer of PAs into muscle and liver of dairy cattle, goat and sheep was determined. In 28-day feeding studies extracts of tansy ragwort (Jacobaea vulgaris Gaertn.) were administered orally in three dose levels per animal species. Of the administered Senecio PAs only jacobine, jaconine and jacoline could be detected in relevant quantities by LC-MS/MS in the muscle and liver tissues of the three animal species. The calculated transfer parameters show a low transfer of total PAs into muscle (transfer factors: 0.0004–0.0009) and liver (transfer factors: 0.0008–0.0030), which is lower than reported for other typical contaminants and residues in the literature. This selective transfer can be explained by the rumen passage, during which the other Senecio PAs are largely and rapidly transformed to fully saturated metabolites. These ruminal metabolites were not detected in muscle and liver. No evidence of bioaccumulation of PAs in muscle and liver was observed.

Cannabidiol Increases Psychotropic Effects and Plasma Concentrations of Δ9-Tetrahydrocannabinol Without Improving Its Analgesic Properties.

Cannabidiol (CBD), the main non-intoxicating compound in cannabis, has been hypothesized to reduce the adverse effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive and analgesic component of cannabis. This clinical trial investigated the hypothesis that CBD counteracts the adverse effects of THC and thereby potentially improves the tolerability of cannabis as an analgesic. A randomized, double-blind, placebo-controlled, five-way cross-over trial was performed in 37 healthy volunteers. On each visit, a double-placebo, THC 9 mg with placebo CBD, or THC 9 mg with 10, 30, or 450 mg CBD was administered orally. Psychoactive and analgesic effects were quantified using standardized test batteries. Pharmacokinetic sampling was performed. Data were analyzed using mixed-effects model. Co-administration of 450 mg CBD did not reduce, but instead significantly increased subjective, psychomotor, cognitive, and autonomous effects of THC (e.g., VAS "Feeling High" by 60.5% (95% CI: 12.7%, 128.5%, P < 0.01)), whereas THC effects with 10 and 30 mg CBD were not significantly different from THC alone. CBD did not significantly enhance THC analgesia at any dose level. Administration of 450 mg CBD significantly increased AUClast of THC (AUClast ratio: 2.18, 95% CI: 1.54, 3.08, P < 0.0001) and 11-OH-THC (AUClast ratio: 6.24, 95% CI: 4.27, 9.12, P < 0.0001) compared with THC alone, and 30 mg CBD significantly increased AUClast of 11-OH-THC (AUClast ratio: 1.89, 95% CI: 1.30, 2.77, P = 0.0013), and of THC (AUClast ratio: 1.44, 95% CI: 1.01, 2.04, P = 0.0446). Present findings do not support the use of CBD to reduce adverse effects of oral THC or enhance THC analgesia.