Dose Levels Research Articles

Neoadjuvant Exercise Therapy in Prostate Cancer: A Phase 1, Decentralized Nonrandomized ControlledTrial.

Observational data have shown that postdiagnosis exercise is associated with reduced risk of prostate cancer death. The feasibility and tumor biological activity of exercise therapy is not known. To identify recommended phase 2 dose of exercise therapy for patients with prostate cancer. This single-center, phase 1a dose-finding trial was conducted at a tertiary cancer center using a patientcentric, decentralized platform and included 53 inactive men with treatment-naive localized prostate cancer scheduled to undergo surgical resection between June 2019 and January 2023. Data were analyzed in June 2024. Six escalated exercise therapy dose levels ranging from 90 to 450 minutes per week of individualized, moderate-intensity treadmill walking, allocated using adaptive continual reassessment. All exercise therapy sessions were conducted remotely with real-time monitoring. Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater. Activity end points were changes in tumor cell proliferation (Ki67) and plasma prostate-specific antigen levels between pretreatment and postintervention. Safety and changes in patient physiology were also assessed. A total of 53 men were enrolled (median [IQR] age, 61 [56-66] years). All dose levels were feasible (≥75% REDI). The mean (95% CI) changes in Ki67 were 5.0% (-4.3% to 14.0%) for 90 minutes per week, 2.4% (-1.3% to 6.2%) for 150 minutes per week, -1.3% (-5.8% to 3.3%) for 225 minutes per week, -0.2% (-4.0% to 3.7%) for 300 minutes per week, -2.6% (-9.2% to 4.1%) for 375 minutes per week, and 2.2% (-0.8% to 5.1%) for 450 minutes per week. Changes in prostate-specific antigen levels were 1.0 ng/mL (-1.8 to 3.8) for 90 minutes per week, 0.2 ng/mL (-1.1 to 1.5) for 150 minutes per week, -0.5 ng/mL (-1.2 to 0.3) for 225 minutes per week, -0.2 (-1.7 to 1.3) for 300 minutes per week, -0.7 ng/mL (-1.7 to 0.4) for 375 minutes per week, and -0.9 ng/mL (-2.4 to 0.7) for 450 minutes per week. No serious adverse events were observed. Overall, 225 minutes per week (approximately 5 minutes per treatment at 5 times weekly) was selected as the recommended phase 2 dose. The results of this nonrandomized clinical trial suggest that neoadjuvant exercise therapy is feasible and safe with promising activity in localized prostate cancer. ClinicalTrials.gov Identifier: NCT03813615.

Patient dose and associated exposure parameters in pelvic x-ray examinations: dependence on radiographic system.

Technological differences between computed radiography (CR) and digital radiography (DR) systems can influence patient doses and exposure parameters in pelvic x-ray examinations. The presence of radiosensitive organs in the pelvic region underscores the need to optimize these parameters for both CR and DR systems. This prospective study aimed to compare the patient doses and exposure parameters for adult patients undergoing pelvic x-ray examinations using CR and DR systems, based on data from Sri Lanka. The study included data from 56 x-ray examinations, with 25 using CR and 31 using DR. Patient demographic characteristics and exposure parameters (kVp: kilovoltage peak, mAs: tube current-exposure time product) were recorded, and patient doses were measured in terms of the kerma-area product (PKA) using a PKA meter. Despite similar mean weight and body mass index (BMI), the CR systems showed significantly higher mean kVp (7.4%), mAs (16.4%), and PKA (29.7%) than the DR systems (CR - kVp: 73.2, mAs: 37.8, PKA: 2.29Gy cm2; DR - kVp: 67.8, mAs: 31.6, PKA: 1.61Gy cm2). The Mann-Whitney U test revealed statistically significant differences in PKA and kVp between the CR and DR systems (p < 0.05). Furthermore, even with lower patient weight and BMI, the mean mAs and PKA in this study were substantially higher than those reported in the literature for both CR and DR systems. These results suggest the need to optimize current mAs settings for the studied hospitals and introduce radiographic system-specific exposure parameters and reference dose levels for pelvic x-ray examinations in order to enhance patient protection.

Comparison of Weight-Based Valproic Acid Dosing in Treatment of Mental Illness Among Obese and Nonobese Patients.

A weight-based dosing approach of 20-30 mg/kg per day of valproic acid (VPA) has been shown to achieve rapid attainment of mood symptom control. Due to interindividual pharmacokinetic variability, therapeutic drug monitoring may be a useful tool to avoid VPA toxicity. Limited research exists on the impact of patient body weight on VPA pharmacokinetic profiles. This analysis aims to explore the correlation between steady-state serum levels of VPA and weight-based dosing strategies, including total body weight (TBW), ideal body weight (IBW), and adjusted body weight (AdjBW), between obese and nonobese patients. This single-center, retrospective, observational cohort analysis evaluated weight-based dosing of VPA in obese and nonobese patients admitted to inpatient psychiatry at a large academic medical center between July 1, 2017, and July 1, 2022. This analysis included 93 obese and 93 nonobese patients. No significant difference in median VPA serum concentrations was observed between groups (P = 0.82). However, the obese group received a lower median weight-based dose (15.6 mg/kg) compared with the nonobese group (19.5 mg/kg, P < 0.001). A stronger correlation was found between VPA dose and therapeutic serum levels in the obese group compared with the nonobese group regardless of weight-based dosing strategy. Dosing with AdjBW in obese patients most closely approximated dosing with TBW in nonobese patients. In obese patients, our analysis suggests dosing VPA using AdjBW may be considered as the preferred dosing strategy over IBW or TBW to minimize toxicity risk. Further research is needed with larger sample sizes and diverse patient populations to confirm these findings.

RESPON CABAI (Capsicum annum L.) TERHADAP PENGGUNAAN PUPUK ORGANIK CAIR DAN PUPUK HAYATI MIKORIZA

Red chili (Capsicum annuum L.) is one of the commodities vegetables that have high economic value. One attempt to increase the growth and yield of chili plants by using liquid organic fertilizer and mycorrhizal biological fertilizer. This research aims to determine the best dosage of liquid organic fertilizer and mycorrhizal biological fertilizer on the yield of red chili (Capsium annum L.). The research was carried out on land of Agriculture of Palembang City, South Sumatra Province. The research period was carried out from February to June 2023. The research used a Randomized Group Factorial Design (RAKF) with 9 treatments and 3 replications. The first factor is liquid organic fertilizer from vegetable waste according to the treatment, namely O1 = 5 ml/L, O2 = 10 ml/L and O3= 15 ml/L. The second factor is the provision of Mycorrhizal biofertilizer (M) which consists of 4 treatment dose levels, namely M0 = 0 g/ta (without mycorrhiza), M1 = 2.5 g/ta, M2 = 5 g/ta, M3 = 7.5 g /ta. The observation parameters in this study were chili weight per plant (g), chili weight per plot (g) and number of productive brances (brances). The results of the research showed that treatment with a POC dose of vegetable waste of 5 ml/l of water with mycorrhizal biological fertilizer of 2.5 g/lot had the highest influence on chili plant production of 48.33 g/plot or the equivalent of 193,32 kuintal/ha.

Synthetic and Natural Vitamin C Modulation of Leaded Paint-Induced Nephrotoxicity of Automobile Painters in Ile-Ife, Nigeria.

Introduction: Lead (Pb) occupational exposure in painters has been documented to be contacted via additives in paints due to its many important properties and vitamin C has been the most widely studied when it comes to Pb- induced oxidative stress.  Aim: This study aimed at the use of freshly squeezed orange-juice due to its accessibility in investigating the modulating role of synthetic and natural vitamin-C on leaded paint-induced nephrotoxicity of automobile painters.  Study Design and Methods: Sixty (60) male automobile painters were consecutively selected and divided equally into 2 groups. Vitamin-C and orange juice were administered daily to painters for 4 weeks at dosage levels of 200 and 184 mg/day respectively. Thirty (30) male non-painters constituted the control group. Orange juice vitamin-C content was assessed by titrimetric method and synthetic vitamin-C served as the standard drug. Renal biomarkers and reduced glutathione (GSH) were done by Colorimetry. Urine aminolevulinic acid (ALA) and Pb were assessed by ELISA technique and atomic absorption spectrophotometry respectively. Phytochemical screenings (quantitative/qualitative) and proximate analysis were done using standard methods. Data were analyzed using Pearson’s correlation coefficient and One-way Analysis of Variance (ANOVA) followed by Tukey’s post-hoc test for pairwise comparison. Statistical significance was p&lt; 0.05.  Results: Baseline results at 0-week of orange juice administered group showed a significantly (P&lt;0.05) higher serum Pb, urea and creatinine compared to non- painters. Also, their urine baseline results at 0-week showed a significantly (P&lt;0.05) higher levels of ALA and GSH compared to non-painters. Orange juice administration at 4 weeks showed significant (P&lt;0.05) reductions in concentrations of lead, urea, and creatinine in serum, decreased concentrations of GSH and ALA in urine but increased urine Pb compared to baseline. However, compared with baseline, after 4 weeks of vitamin-C supplementation, serum Pb, urine GSH, and urine ALA were significantly (P&lt;0.05) reduced and urine Pb significantly (P&lt;0.05) increased. A positive correlation was observed at 2-weeks of taking orange- juice between serum lead and urine ALA (r= 0.703) and GSH (r= 0.913) but 4-week positive correlation between urea and urine GSH (r= 1.000). A negative correlation was observed at 2-week of taking vitamin-C between serum creatinine and urine lead (r= -0.857) while 4-week a negative correlation was observed between urine GSH and urine lead (r= -0.743). Presence of tannin, phenol, saponin, alkaloid, and flavonoid was detected in orange juice.  Conclusion: Orange juice administration conferred significant amelioration to renal and lead toxicity biomarkers by 4 weeks. The presence of phytochemicals suggests why orange juice may be a viable alternative in amelioration of toxic effects of leaded paint among automobile painters.

A meta-analysis of the meat physicochemical parameters of broiler chickens fed insect-based diet.

A total of 23 studies were identified in a literature search performed in the Scopus, Science Direct and Google Scholar databases for meta-analysis. The criteria used include studies that were published from 2015 to 2023 and those reporting the effects of insect meal utilisation in poultry diets. Data on live weight (LW), carcass weight (CW), moisture, meat pH, lightness (L*), redness (a*), yellowness (b*), proximate composition (protein, fat and ash content) and shear force in broilers were subjected to OpenMEE software, and data were pooled using a random-effect model. Subgroup analysis and meta-regression were performed to ascertain the influence of dietary insect meals on the response of meat aspects and the source of heterogeneity, respectively, using the following moderators (insect species, dosage level, feeding duration and age at slaughter). The results indicated that dietary insect meal did not affect LW, CW, meat L*, pH, shear force, moisture, fat and ash content. In contrast, dietary insect meal increased the a* of the meat (standardised mean differences (SMDs) = 1.03; 95% confidence intervals (CIs) = 0.484-1.578; p ≤ 0.001), b* (SMD = 1.117; 95% CI = 0.334-1.90; p = 0.005), and meat protein content (SMD = 0.365; 95% CI = 0.031-0.7; p = 0.032). The subgroup analysis showed that insect meal dosage of ≤10% and age at slaughtered ≤35 days had improved the LW, CW and meat L*. In addition, the meat a*, protein and ash content were also influenced by insect species, dosage levels and age at slaughter. In conclusion, ≤10% of either Hermetia illucens or Tenebrio molitor can be included in broiler diets without compromising the LW, CW, meat pH, colour, shear force, moisture, fat and ash content in broilers. The study therefore indicated that insect meals have a bright future as an alternative protein source in poultry diets.

Quantitative Label-Free Proteomic Analysis of Mouse Ovarian Antral Follicles Following Oral Exposure to a Human Relevant Mixture of Three Phthalates.

Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/day; PHT 32) and occupationally exposed (500 µg/kg/day; PHT 500) populations for 10 days. Antral follicles (>250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; while those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women.

Application of microalgae in cauliflower fertilisation

In a circular bioeconomy, balancing inorganic fertilisers and microalgae supplementation is important for ensuring sustainable agriculture. This study aimed to evaluate the fertilising effects of live microalgae (mostly Chlorella vulgaris and a mixture of Chlorophyceae and Trebouxiophyceae) on cauliflower (Brassica oleracea L. subsp. botrytis) plant morphology, yield, and quality of cauliflower heads. Microalgae fertilisation effects were analysed by employing an experimental factorial design with two factors: inorganic fertiliser and microalgae, each at high and low dosage levels, and the results revealed higher plant height, wider stem diameter, and lower stem slenderness in high-dose combinations than those in other combinations. In addition, an increase in nitrate, calcium, potassium, and sodium content was observed in the sap of cauliflower leaves in high-dose combinations compared to those in low-dose combinations. The high-dose combination also increased the yield, number of commercial heads, weight of the heads, and number of curds per head of cauliflower. Overall, the study demonstrates that increasing the dose of inorganic fertilisers and microalgae significantly increases nutrient concentration in the sap, which translates into a larger plant, an increase in the number of leaves and yield, and an improvement in the quality of cauliflower heads. These findings underscore the necessity for further research to ascertain the optimal combination of inorganic fertilisers and microalgae to maximise crop yield and cauliflower head quality.

Regorafenib plus FOLFIRINOX as first-line treatment for patients with RAS-mutant metastatic colorectal cancer (FOLFIRINOX-R trial): a dose-escalation study.

The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180mg/m²). Regorafenib (120 or 160mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. ClinicalTrials.gov : NCT03828799.

A multi-year heavy metal analysis of 72 dark chocolate and cocoa products in the USA

IntroductionContamination of cocoa containing products, such as dark chocolate, with heavy metals including lead, cadmium and arsenic has been reported in the US. However, a formal exploration into the significance of this contamination, nor multi-year trends in the degree or scope remain unresolved.MethodsFrom 2014 to 2022, 72 consumer cocoa-containing products were purchased and analyzed for heavy metal contamination with lead (Pb), cadmium (Cd), and arsenic (As) in 4 distinct cohorts (2014, 2016, 2019, 2022). The thresholds used to assess heavy metal contamination were set to Prop 65 maximum allowable dose levels (MADLs) of 0.5 mcg/day, 4.1 mcg/day, 10 mcg/day for Pb, Cd, and As, respectively.Results and discussionOur analysis reports that 43, 35, and 0% of the products tested exceed Prop 65 MADLs for heavy metal concentrations, respectively, of Pb, Cd, and As, while 97.2% (70 of 72) fall below US FDA IRL limits established for Pb. Median concentrations of each metal tested were lower than even the conservative Prop 65 MADLs, indicating a potentially large effect of product outliers. This indicates that heavy metal contamination—in more than half of products tested—may not pose any appreciable risk for the average person when consumed as a single serving; however, consuming some of the products tested, or more than one serving per day in combination with non-cocoa derived sources heavy metals, may add up to exposure that would exceed the Prop 65 MADLs. Notably, “organic” products were significantly more likely to demonstrate higher levels of both Cd and Pb.

THE COMPARISON OF FERTILIZING CAPACITY OF NATIVE AND NEW HAMPSHIRE MALE CHICKENS

This experiment was conducted to compare and estimate the fertilizing capacity of native with New Hampshire chicken semen. Also to study the effect. Of different levels of semen dosage on fertility percentage, duration’ of fertility and duration of fertilizing ability. In this experiment (12) native and (12) N.H. male chicken with (240) Hisex laying hens have been used. The results of the statistical analysis showed that there were no significant (P&gt;0.05) differences between the native and N.H. male chickens for the fertilizing capacity. fertilizing percentage in duration of fertility and fertility duration. The values were 90.40, 90.73%; 85.77, 85.60%; 12.11, 12.3 days for native and N.H. chickens, respectively. There were no significant (P&gt;0.05) effect of increasing semen concentration (100, 200, 300 million sperm) per single insemenation on the percentage of fertilization and duration of fertility percentage. The values for percentage of fertilization, duration of fertility percentage and fertility duration were 89.76%, 91.79, 90.14; 85.33%, 88.72, 83.01; 12.24, 11.90, 12.50 days, respectively. Using the above mentioned concentration levels, no significant interaction was found between semen concentration and male groups.

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs.

Interleukin-2 and -12 cytokines have potent anti-cancer activity, but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice, and was previously safe in pet dogs with sarcoma. Here we sought to test the efficacy of this approach with in dogs with advanced melanoma. This study examined fifteen client-owned dogs with histologically- or cytologically-confirmed malignant melanoma who received a single 9 Gray fraction of radiation therapy, followed by six cycles of combined collagen-anchored IL-2 and IL-12 therapy Q2W. Cytokine dosing followed a 3+3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. Median survival regardless of tumor stage or dose level was 256 days and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) dogs had partial responses across their combined lesions, evidence of locoregional response. Profiling by Nanostring of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

Effect of Integrated Nutrient Management in China Aster cv. Arka Poornima Under Mid Hills of Himalayas

The present investigation was conducted to investigate the effect of integrated nutrient management on vegetative parameters of China aster cv. Arka Poornima under the mid hills of Himachal Pradesh. The experiment was laid out in simple randomized design (RBD) with eighteen treatments. The experiment was conducted at the Kakhali research farm of Dr. Khem Singh Gill Akal College of Agriculture, Eternal University, Baru Sahib, Himachal Pradesh during kharif season in 2023. For integrated nutrient management eighteen treatments were constituted with three levels of recommend dose of inorganic fertilizers (50, 75 and 100 %) and three biofertilizers viz., Azotobacter, PSB and KSB along with control. The observations for the vegetative parameters plant height (cm) at maturity, numbers of leaves, number of primary branches, number of secondary branches, leaf area per plant, leaf area index and plant spread were recorded and analyzed. The plant height (91.40 cm), No. of leaves (356.13), No. of primary branches (12.40) and secondary branches (33.70) were found maximum in treatment T12 (RDF@75% + Azotobacter + PSB + KSB), while the lowest values were observed in T0 (control). The highest leaf area (27.49 cm2) was found in T8 (RDF@75% + Azotobacter), while the leaf area index (12.02) and plant spread (16.57 cm) were found in treatment T11 (RDF@75% + Azotobacter + PSB). The lowest values for leaf area (17.77 cm2), leaf area index (5.48) and plant spread (11.82 cm) were found in treatments T14 (RDF@100% + Azotobacter), T16 (RDF@100% + KSB) and T10 (RDF@75% + KSB), respectively. Therefore, it can be concluded that, application of T12 (RDF@75% + Azotobacter + PSB + KSB) is best for the getting higher production in China aster followed by T11 (RDF@75% + Azotobacter + PSB). This study will reduce the use of inorganic fertilizer without polluting the soil and environment.

Climate Change Impacts on Future Wheat (Triticum aestivum) Yield, Growth Periods and Irrigation Requirements: A SALTMED Model Simulations Analysis

Climate change poses emerging threats to wheat growth in coming future. These threats need to be explored to ensure sustainable wheat production. To do this, the SALTMED model was calibrated using data from experiments conducted on different levels of irrigation and nitrogen doses. The performance of the SALTMED model was assessed based on values of the root mean square error (RMSE), normalized root mean square error (NRMSE), coefficient of determination (R2) and coefficient of residual mass (CRM) that ranged from 0.23–1.82, 0.09–0.17, 0.91–0.93 and −0.01–0.02, respectively for calibration and 0.31–1.89, 0.11–0.31, 0.87–0.90 and −0.02–0.01, respectively for validation. Projections for future climate scenarios for wheat growth indicated that by the end of the century, sowing dates advanced by nine days under the RCP4.5 scenario and eleven days under the RCP8.5 scenario, while harvesting dates shifted earlier by twenty-four days under RCP4.5 and twenty-eight days under RCP8.5. Consequently, the overall crop duration was shortened by fifteen days under RCP4.5 and eighteen days under RCP8.5. Further simulations revealed that the wheat yield was reduced by 14.2% under RCP4.5 and 21.0% under RCP8.5; the dry matter was reduced by 14.9% under RCP4.5 and 23.3% under RCP8.5; the irrigation amount was expected to increase by 14.9% under RCP4.5 and 18.0% under RCP8.5; and water productivity was expected to be reduced by 25.3% under RCP4.5 and 33.0% under RCP8.5 until the end of century. The hypothetical scenarios showed that adding an extra 20–40% more nitrogen can enhance wheat yield and dry matter by 10.2–23.0% and 11.5–24.6%, respectively, under RCP4.5, and by 12.0–23.4% and 12.9–29.6%, respectively, under RCP8.5. This study offers valuable insights into the effects of climate change on future wheat production so that effective contingency plans could be made by policymakers and adopted by stakeholders for higher wheat productivity.

Climate Change Impacts on Future Wheat (Triticum aestivum) Yield, Growth Periods and Irrigation Requirements: A SALTMED Model Simulations Analysis

Climate change poses emerging threats to wheat growth in coming future. These threats need to be explored to ensure sustainable wheat production. To do this, the SALTMED model was calibrated using data from experiments conducted on different levels of irrigation and nitrogen doses. The performance of the SALTMED model was assessed based on values of the root mean square error (RMSE), normalized root mean square error (NRMSE), coefficient of determination (R2) and coefficient of residual mass (CRM) that ranged from 0.23–1.82, 0.09–0.17, 0.91–0.93 and −0.01–0.02, respectively for calibration and 0.31–1.89, 0.11–0.31, 0.87–0.90 and −0.02–0.01, respectively for validation. Projections for future climate scenarios for wheat growth indicated that by the end of the century, sowing dates advanced by nine days under the RCP4.5 scenario and eleven days under the RCP8.5 scenario, while harvesting dates shifted earlier by twenty-four days under RCP4.5 and twenty-eight days under RCP8.5. Consequently, the overall crop duration was shortened by fifteen days under RCP4.5 and eighteen days under RCP8.5. Further simulations revealed that the wheat yield was reduced by 14.2% under RCP4.5 and 21.0% under RCP8.5; the dry matter was reduced by 14.9% under RCP4.5 and 23.3% under RCP8.5; the irrigation amount was expected to increase by 14.9% under RCP4.5 and 18.0% under RCP8.5; and water productivity was expected to be reduced by 25.3% under RCP4.5 and 33.0% under RCP8.5 until the end of century. The hypothetical scenarios showed that adding an extra 20–40% more nitrogen can enhance wheat yield and dry matter by 10.2–23.0% and 11.5–24.6%, respectively, under RCP4.5, and by 12.0–23.4% and 12.9–29.6%, respectively, under RCP8.5. This study offers valuable insights into the effects of climate change on future wheat production so that effective contingency plans could be made by policymakers and adopted by stakeholders for higher wheat productivity.

Identifying SCS Trial Responders Immediately After Postoperative Programming with ECAP Dose-Controlled Closed-Loop Therapy.

Drawbacks of fixed-output spinal cord stimulation (SCS) screening trials may lead to compromised trial outcomes and poor predictability of long-term success. Evoked compound action potential (ECAP) dose-controlled closed-loop (CL) SCS allows objective confirmation of therapeutic neural activation and pulse-to-pulse stimulation adjustment. We report on the immediate patient-reported and neurophysiologic treatment response post-physiologic CL-SCS and feasibility of early SCS trial responder prediction. Patient-reported pain relief, functional improvement, and willingness to proceed to permanent implant were compared between the day of the trial procedure (Day 0) and end of trial (EOT) for 132 participants in the ECAP Study undergoing a trial stimulation period. ECAP-based neurophysiologic measurements from Day 0 and EOT were compared between responder groups. A high positive predictive value (PPV) was achieved with 98.4% (60/61) of patients successful on the Day 0 evaluation also responding at EOT. The false-positive rate (FPR) was 5.6% (1/18). ECAP-based neurophysiologic measures were not different between patients who passed all Day 0 success criteria ("Day 0 successes") and those who did not ("needed longer to evaluate the therapy"). However, at EOT, responders had higher therapeutic usage and dose levels compared to non-responders. The high PPV and low FPR of the Day 0 evaluation provide confidence in predicting trial outcomes as early as the day of the procedure. Day 0 trials may be beneficial for reducing patient burden and complication rates associated with extended trials. ECAP dose-controlled CL-SCS therapy may provide objective data and rapid-onset pain relief to improve prognostic ability of SCS trials in predicting outcomes. The ECAP Study is registered with ClinicalTrials.gov (NCT04319887).

Aggregation behaviour of radiolytically degraded diglycolamide based solvent system

AbstractThe 0.1 M TODGA + 0.2 M DOHyA/n-DD phase was irradiated to various absorbed dose levels and the extraction behaviour of nitric acid and Nd(III) in the irradiated organic phases were studied. The organic phase was then subjected to dynamic light scattering studies to understand the aggregation behaviour in the organic phase. The results showed that the polar degradation products formed in the organic phase decreased the aggregation, while the higher homologue of n-DD enhanced aggregation.

Toxicological Assessment of Pesticide Exposure in Wistar Rats: An Acute and Sub-Acute Inhalation Study

Background: Pesticide ubiquity and extensive applications have attendant public health implications. This study examines the immediate and prolonged inhalation toxicity of various commonly used insecticides in male Wistar rats. Methods: 192 male Wistar rats were utilized and kept in regular housing. The study was carried out in three stages: a preliminary test, an acute test, and a sub-acute. Wistar rats, housed in an improvised chamber, were exposed to varying doses of insecticides in each phase to assess their toxicities to insecticides. For comparativeness, we withdrew 57 of the rats from exposure to ascertain possible recovery. The study included monitoring behavioral changes, recording mortality rates, and conducting necropsies to evaluate organ pathology. Dose-response relationships were analyzed to determine lethal doses (LD50) and potential sublethal effects. Results: Overall, we found a dose-related increase in the severity of the response, which potentially indicates an alteration of a specific biochemical process. The range-finding test assessed the effects of DD Force, Sniper, Industrial Camphor, Edible Camphor, Kerosene, and combined pesticides. It revealed significant physiological impacts followed by mortalities at specific dosage levels. Subsequent acute toxicity testing determined LC50 values for each insecticide. Rats showed a dose-dependent health deterioration following sub-acute exposure, particularly in the combined pesticide group, indicating synergistic toxicity. Conclusion: Exposure to the combined pesticide at high doses was associated with severe toxicities in the tested rats. This evidence suggests that commonly used pesticides could potentiate adverse health outcomes when results are extrapolated in humans.

A pharmacokinetic-pharmacodynamic analysis of l-glutamine for the treatment of sickle cell disease: Implications for understanding the mechanism of action and evaluating response to therapy.

The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use.

Ophthalmic Nanoemulsion Fingolimod Formulation for Topical Application.

Purpose: Fingolimod (FTY720; FT), a structural analog of sphingosine, has potential ocular applications. The goal of this study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. Methods: FT-NE formulations were prepared using homogenization followed by the probe sonication method. The lead FT-NE formulations (0.15% and 0.3% w/v loading), comprising soybean oil as oil and Tween® 80 and Poloxamer 188 as surfactants, were further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. Ocular bioavailability following topical application of FT-NE (0.3%) was examined in Sprague-Dawley rats. Results: The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature postfiltration through a polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release over 24 h, compared with the control FT solution (FT-S). In vivo studies revealed that effective concentrations of FT were achieved in the vitreous humor and retina following topical application of FT-NE. Conclusions: The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route.