Dose-response Trial Research Articles

Effect of roasted purple laver (nori) on vitamin B12 nutritional status of vegetarians: a dose-response trial

PurposeTo investigate the bioavailability of vitamin B12 from nori and to evaluate the required dosage for improving vitamin B12 nutritional status in vegetarians not using supplements.MethodsThe study design is an open-label, parallel, dose-response randomized controlled trial. Thirty vegetarians were assigned to control (no nori), low-dose (5 g nori, aiming to provide 2.4 µg vitamin B12 per day), or high-dose (8 g nori, aiming to provide 4 µg vitamin B12 per day) groups. The primary outcome was changes in vitamin B12 status as measured by serum vitamin B12, holotranscobalamin (holoTC), homocysteine (Hcy), and methylmalonic acid (MMA), and a combined score of these four markers (4cB12 score) during the four-week intervention. Dietary vitamin B12 intakes were assessed at baseline and end of the trial with a 17-item food frequency questionnaire designed for vitamin B12 assessment. General linear model was used to compare least square means of changes in each biomarker of vitamin B12 status, among the three groups, while adjusting for respective baseline biomarker.ResultsAfter adjusting for baseline status, nori consumption led to significant improvement in serum vitamin B12 (among-group P-value = 0.0029), holoTC (P = 0.0127), Hcy (P = 0.0225), and 4cB12 (P = 0.0094). Changes in MMA did not differ significantly across groups, but showed within-group pre-post improvement in the low-dose group (median [p25, p75] = -339 [-461, -198] nmol/L). Vitamin B12 status appeared to plateau at low dose (5 g of nori), which compared with control group, improved serum vitamin B12 (lease square mean [95% CI] = + 59 [25, 93] pmol/L, P = 0.0014); holoTC (+ 28.2 [10.1, 46.3] pmol/L, P = 0.0035); Hcy (-3.7 [-6.8, -0.6] µmol/L, p = 0.0226); and 4cB12 score (+ 0.67 [0.24, 1.09], p = 0.0036). High-dose resulted in similar improvements. There was no significant difference between low-dose and high-dose groups in all biomarkers of vitamin B12.ConclusionsConsuming 5 g of nori per day for 4 weeks significantly improved vitamin B12 status in vegetarians. A higher dose (8 g) may not confer additional benefits.Clinical trial registrationClinicalTrials.gov Identifier: NCT05614960. Date of registration: November 14th 2022.

Randomized dose-response trial of n-3 fatty acids in hormone receptor negative breast cancer survivors- impact on breast adipose oxylipin and DNA methylation patterns.

Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative (ERPR-) breast cancer to dietary fat amount and type. Dietary n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acid profiles and downstream bioactive metabolites to counteract pro-inflammatory, pro-carcinogenic signaling in the mammary microenvironment. To determine effects of ~1 to 5 g/d EPA+DHA over 12 months on breast adipose fatty acid and oxylipin profiles in women with ERPR(-) breast cancer, a high-risk molecular subtype. We conducted a 12-month randomized controlled, double-blind clinical trial of ~5g/d vs ~1g/d DHA+EPA supplementation in women within 5 years of completing standard therapy for ERPR(-) breast cancer Stages 0-III. Blood and breast adipose tissue specimens were collected every 3 months for biomarker analyses including fatty acids by gas chromatography, oxylipins by LC-MS/MS, and DNA methylation by reduced-representation bisulfite sequencing (RRBS). A total of 51 participants completed the 12-month intervention. Study treatments were generally well-tolerated. While both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5g/d supplement was more potent (n =51, p <0.001). The 5g/d dose also reduced plasma triglycerides from baseline (p =0.008). Breast adipose oxylipins at 0, 6, and 12 months showed dose-dependent increases in unesterified and esterified DHA and EPA metabolites (n =28). Distinct DNA methylation patterns in adipose tissue after 12 months were identified, with effects unique to the 5g/d dose group (n =17). Over the course of 1 year, EPA+DHA dose-dependently increased concentrations of these fatty acids and their derivative oxylipin metabolites, producing differential DNA methylation profiles of gene promoters involved in metabolism-related pathways critical to ERPR(-) breast cancer development and progression. These data provide evidence of both metabolic and epigenetic effects of n-3 PUFAs in breast adipose tissue, elucidating novel mechanisms of action for high-dose EPA+DHA-mediated prevention of ERPR(-) breast cancer.

Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial

IntroductionSepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and...

The Median Effective Dose of Dexmedetomidine for the Inhibition of Emergence Delirium in Preschool Children Undergoing Tonsillectomy and/or Adenoidectomy: A Retrospective Dose-response Trial.

The incidence of emergence delirium (ED) is higher in preschool children undergoing tonsillectomy and/or adenoidectomy. The purpose of this study was to determine the median effective dose (ED50) of dexmedetomidine (DEX) for the inhibition of ED in preschool children by using probit regression analysis. A total of 140 anesthesia records were retrieved and divided into seven groups based on the infusion rate of DEX: .2, .25, .3, .35, .4, .45, and .5μg·kg-1·h-1. The Pediatric Anesthesia Emergence Delirium Scale (PAEDS) was used to assess ED in preschool children, and ED was defined as a PAEDS score ≥ 10. Probit regression analysis revealed that the ED50 and ED95 of DEX were .31μg·kg-1·h-1 (95% CI: .29-.35) and .48μg·kg-1·h-1 (95% CI: .44-.56), respectively. Probit(p) = -2.84 + 9.28 × ln (Dose), (χ2 = 1.925, P = .859). The PAEDS score was significantly increased in the ED group, and the rate of bradycardia was significantly decreased in the ED group compared with the without ED group (27.3% vs 54.1%, P = .02). DEX can effectively inhibit the ED in preschool children undergoing tonsillectomy and/or adenoidectomy, however, bradycardia was the main complication.

Comparison of the ED50 of prophylactic butorphanol in preventing morphine-induced pruritus with or without palonosetron: a prospective, double-blinded, randomized dose–response trial using an up-down sequential allocation method

Background Butorphanol has been used to reduce the incidence and severity of neuraxial morphine-induced pruritus. Palonosetron is a commonly used antiemetic for the prevention of postoperative nausea and vomiting. The aim of our study was to compare the effective dose in 50% of subjects (ED50) of intravenous butorphanol infusion with or without a single intravenous bolus of palonosetron for preventing pruritus induced by epidural administration of morphine. Methods A total of 120 parturients were randomly assigned to receive an intravenous bolus injection of palonosetron plus continuous infusion of butorphanol (Group P + B) or an intravenous bolus of saline plus continuous infusion of butorphanol (Group B) after epidural administration of morphine. The antipruritic effect was graded as satisfactory (numerical rating scale (NRS) of pruritus ≤3) or unsatisfactory (NRS >3) within 48 h after morphine treatment. The first patient in each group received butorphanol infusion at a rate of 4 µg/kg/h. The infusion dose for each subsequent patient in the corresponding group was increased by 0.2 µg/kg/h after an unsatisfactory response or decreased by 0.2 µg/kg/h after a satisfactory response. The ED50 was calculated for each group and compared using up-down sequential analysis. Results The ED50 (mean [95% confidence interval (CI)]) of the dose of intravenous butorphanol infusion for preventing moderate to severe pruritus was lower in Group P + B (3.29 µg/kg/min [3.25–3.34 µg/kg/min]) than in Group B (3.57 µg/kg/min [3.47–3.67 µg/kg/min]) (p < 0.05). Conclusions Under the conditions of the present study, a prophylactic use of 0.25 mg palonosetron reduced the ED50 of prophylactic infusion of butorphanol by approximately 8% to achieve a satisfactory antipruritic effect after epidural morphine for post-caesarean analgesia.

The dose-response effect of aerobic exercise on inflammation in colon cancer survivors.

Physical activity after surgical resection for colon cancer is associated with significantly longer disease-free survival. Inflammation is hypothesized to mediate the association between physical activity and disease-free survival in colon cancer. In this exploratory analysis of a randomized dose-response trial, 39 colon cancer survivors who completed standard therapy were stratified by cancer stage and randomized in a 1:1:1 ratio to one of three treatment groups for 24 weeks of usual-care control, 150 min/wk of moderate-intensity aerobic exercise (low-dose), or 300 min/wk of moderate-intensity aerobic exercise (high-dose). Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL6), and soluble tumor necrosis factor-alpha receptor 2 (sTNFαR2). Mixed models for repeated measures were used to test the hypothesis that exercise was associated with dose-response reductions in inflammation; exploratory analyses examined treatment effects by cancer stage. In the overall population, aerobic exercise was not associated with dose-response reductions in hs-CRP, IL6, or sTNFαR2. Cancer stage modified the association between randomized group and hs-CRP (P=0.022) and IL6 (P<0.001) but not sTNFαR2 (P=0.39). In stage I-II disease, compared to control, exercise was not associated with inflammation outcomes. In stage III disease, compared to control, low-dose exercise reduced hs-CRP: -35.4% (95% CI: -70.1, -0.7) and IL6: -29.6% (95% CI: -58.4, -0.8) but not sTNFαR2: 2.7% (95% CI: sTNFαR2: -15.7, 21.1); high-dose exercise was not associated with inflammation outcomes in stage III disease. This exploratory analysis offers preliminary data to support the hypothesis that inflammation may mediate the association between physical activity and disease-free survival in colon cancer. clinicaltrials.gov, identifier NCT02250053.

Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

Potassium (K+ ) is the main intracellular cation in the body. Elevated K+ levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K+ homeostasis and the effects of orally administered K+ binders, such as sodium zirconium cyclosilicate (SZC), on K+ redistribution and excretion in patients remain incompletely understood. We built a fit-for-purpose systems pharmacology model to describe K+ homeostasis in hyperkalemic subjects and capture serum K+ (sK+ ) dynamics in response to acute and chronic administration of SZC. The resulting model describes K+ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K+ , and K+ -SZC binding and excretion in the GI tract. The model, which was fit to time-course sK+ data for individual patients from two clinical trials, accounts for bolus delivery of K+ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose-response and inform clinical trial design in two new applications: emergency lowering of sK+ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end-stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit-for-purpose, model-informed drug development after initial approval of a drug.

Radiobiological studies on fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae)

Abstract The fall armyworm, Spodoptera frugiperda (JE Smith, 1797) is a notorious invasive pest causing significant economic damage to various crops. The extensive damage caused by this pest has created havoc in India and has become a nightmare for farmers. The management steps taken for controlling the pest have become futile. There are several instances depicting the failure of conventional management tactics, viz resistance against insecticides and transgenic maize lines paving the way for exploiting newer paradigms of pest management. Hence, a novel approach through the use of gamma irradiation against the pest was attempted. A dose-response trial encompassing doses from 50 to 200 Gy was employed to study the adverse effects of gamma irradiation on the biology of fall armyworm. The irradiated insects were crossed with their counterpart and the developmental profile of progeny was analysed. The obtained results were quite promising and showed a significant effect on the biology of the pest with progression of the irradiation dose. When females were exposed to irradiation and crossed with fertile counterparts, fecundity decreased with an increase in irradiation dose. A considerable increase in the egg, larval and pupal period was observed at 100 and 150 Gy. This decreased fecundity reduces the pest’s build-up in the field and the prolonged developmental period make the pest more prone to biotic and abiotic annihilation factors. Hence, the above-mentioned strategy has plausible applications in the near future and this tool can better be fitted into area-wide integrated pest management programmes.

Focal Onset Seizures: New Treatment Options in The Clinical Practice

This symposium took place during the 2023 Congress of the European Academy of Neurology (EAN). Mar Carreño, Director, Epilepsy Unit, Hospital Clínic and Instituto Clavel, Barcelona, Spain, presented the definition of drug-resistant epilepsy (DRE), and stressed that uncontrolled epilepsy does not necessarily indicate DRE. Before a diagnosis of DRE is made in a patient not responding to medication, questions should be asked regarding the initial epilepsy diagnosis. Carreño discussed paroxysmal events that may mimic epilepsy, and presented three cases of misdiagnosed DRE that were subsequently correctly identified as cardiac syncope, a psychogenic event, and use of inappropriate medication in a patient with generalised epilepsy. The second part of Carreño’s presentation focused on patients with confirmed DRE. They outlined the complications of DRE, including sudden unexpected death in epilepsy (SUDEP), which should be discussed with the patient. Carreño finished their lecture with a discussion of comorbid conditions, including neuropsychiatric comorbidities, which affect one in three patients with epilepsy. Bernhard J. Steinhoff, Medical Director, Kork Epilepsy Center, Kehl, Germany, then discussed the clinical approach to patients with DRE, including treatment options, the range of anti-seizure medications (ASM), and the reasons for failure of first-line treatment, noting that the probability of achieving seizure freedom decreases with each failed ASM. Steinhoff explored the options of substitution monotherapy or combination therapy after failure of the first ASM, before describing cenobamate (CNB) add-on therapy. A randomised, placebo-controlled, dose-response trial showed that adjunctive CNB reduced focal (partial)-onset seizure frequency in a dose-related fashion. Several papers have been published providing real-world evidence to show that adjunctive CNB therapy is associated with improved seizure outcomes, and that the number of concomitant ASMs could be reduced. The symposium concluded with a question and answer session.

Simulated dormant peppermint (Mentha × piperita) response to mesotrione: a greenhouse study

AbstractA dose-response trial was conducted in two experimental runs at the Purdue University Horticulture Greenhouses, West Lafayette, IN, in 2021/2022 to determine the effect of mesotrione rate on simulated dormant ‘Redefined Murray Mitcham’ peppermint. Peppermint was established in 20-cm-diam polyethylene pots, it was then harvested, and pots were placed in a cooler (4 C) for 1 mo. Potted peppermint plants were removed from cold storage and treated with one of five mesotrione rates: 0 (nontreated control), 53, 105, 210, or 420 g ai ha–1. As mesotrione rate increased from 53 to 420 g ai ha–1, predicted peppermint injury increased from 35% to 80% at 2 wk after treatment (WAT), 36% to 95% at 4 WAT, 9% to 82% at 6 WAT, and 8% to 90% at 8 WAT; and peppermint height decreased from 74% to 42% of the nontreated control (7 cm) 2 WAT, 74% to 17% of the nontreated control (20 cm) 4 WAT, 81% to 15% of the nontreated control (28 cm) 6 WAT, and 88% to 19% of the nontreated control (37 cm) 8 WAT. Mesotrione rates from 53 to 420 g ai ha–1 reduced peppermint dry weight from 40% to 99%, respectively. Results from this experiment showed that mesotrione applied even at half of the recommended field use rate for corn (53 g ai ha–1) was not safe for peppermint due to a reduction in aboveground biomass.

Cocoa Consumption Decreases Oxidative Stress, Proinflammatory Mediators and Lipid Peroxidation in Healthy Subjects: A Randomized Placebo-Controlled Dose-Response Clinical Trial.

Cocoa flavonoids have been described to reduce the cardiovascular risk. Nevertheless, the involved mechanisms should be clarified and the dose-effect relation has never been evaluated. To investigate the dose-dependent effects of cocoa flavonoids on markers of endothelial and platelet activation and oxidative stress. According to a randomized, double-blind, controlled, cross-over design, 20 healthy nonsmokers were assigned to receive either five treatments with daily intake of 10g cocoa (0, 80, 200, 500 and 800mg cocoa flavonoids/day) in five periods lasting 1 week each. Compared with flavonoid-free cocoa control, cocoa reduced sICAM-1 mean values [from 1190.2 to 1123.0; 906.3; 741.7 and 625.6 pg/mL (p = 0.0198 and p = 0.0016, for 500 and 800mg respectively], sCD40L mean values [from 218.8 to 210.2; 165.5; 134.5 and 128.4 pg/mL (p = 0.023 and p = 0.013, for 500 and 800mg respectively] and 8-isoprostanes F2 mean values [from 4703.9 to 4670.7; 2000.1; 2098.4 and 2052.3 pg/mL (p = 0.025; p = 0.034 and p = 0.029, for 200, 500 and 800mg respectively)]. In our study we observed that short-term cocoa consumption improved proinflammatory mediators, lipid peroxidation and oxidative stress with a significant effect for higher dosages of flavonoids. Our findings suggest cocoa might be a valid tool for dietary intervention in prevention of atherosclerosis.

Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose–response trial

IntroductionOral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue....

Evaluation of nutritional quality for weaner piglets of a new methanotrophic microbial cell-derived protein feed

This study aimed to test the hypothesis that a new methanotrophic microbial cell protein (MCP) product, Uniprotein®, has a protein value comparable to other high-quality feeds for weaner piglets. Two experiments were conducted. Experiment 1 was a balanced 6 × 6 Latin square design experiment with six ileal cannulated castrated pigs (start weight 30.2 ± 1.4 kg). They were fed six different diets (one diet did not belong to this study) over six periods, each of one week duration. Four of the diets contained 180 g crude protein (CP)/kg as-fed with either MCP, potato protein (PP), fishmeal (FM), or soy protein concentrate as the sole N-source. The fifth diet was N-free. Experiment 2 was a dose-response trial, where piglets during the first 14 days post-weaning were fed diets including increasing amounts of MCP (0, 30.0, 60.0, or 100.0 g MCP/kg as-fed, equivalent to 0, 112, 221 and 359 g microbial-derived CP/kg diet CP) at the expense of FM and PP. Crystaline CP, Lys, Met, Thr, Trp and Val were added to minimize differences across diets, and no medicinal zinc was added to any of the diets. In experiment 1, MCP had the second highest content of essential amino acids (EAA), but the lowest coefficient of standardized ileal digestibility for all EAA except Lys (P < 0.001). However, when contents of ileal digestible EAA were expressed relative to contents of ileal digestible Lys, MCP complied with Danish nutrient recommendations for weaner piglets for 7 out of 9 EAA, and with particularly high levels of digestible Met and Trp. Microbial cell protein had a superior profile as compared to FM for digestible EAA relative to digestible Lys. In experiment 2, MCP could constitute up to 221 g CP/kg diet without any addition of medicinal zinc during the first 14 days post-weaning without any negative impacts on daily weight gain or feed efficiency (gain:feed) compared to the control diet (0 MCP). In conclusion, MCP fulfills Danish recommendations for EAA composition for most EAA and can replace other high quality protein sources to constitute up to 22% of diet CP for weaner piglets without compromising piglet performance.

The Optimum Ratio of Digestible Leucine: Lysine in Wheat-based Diets for Female Broiler Chickens From 8 – 21 Days of Age

Leucine ( Leu ) is one of the essential amino acids, and has a direct effect on protein biosynthesis in broiler skeletal muscle. So supply of sufficient amounts of Leu in young broiler is of interest. Therefore, the purpose of the current study was to estimate the optimal digestible Leu in ratio to lysine ( Lys ) of female broiler chickens from 8 – 21 days. A dose-response trial was performed, and the optimal digestible Leu was estimated applying broken-lines and quadratic regression models. A total of 540 one-week-old female broiler chickens (Cobb-500), were randomly distributed to 6 dietary treatments (6 replicate of 15 birds in each), and fed the experimental diets from 8 to 21 day of age. Dietary digestible Leu was supplied from 0.93% up to 1.18% in 0.05% increments. Wheat-soybean meal based diet was formulated to be deficient in Leu, and dietary treatments were created by gradually replacing crystalline L-glutamic acid with crystalline L-Leu in basal diet. The live performance and carcass traits were evaluated, and excretion and retention of nitrogen was measured. The results showed that weight gain ( WG ), feed intake ( FI ), carcass weight and breast weight had a quadratically response to digestible Leu: Lys from 0.93 to 1.18. Also, none of the retention and excretion of nitrogen were affected by increasing dietary digestible Leu levels. Based on the obtained data in the current study, the optimal digestible Leu: Lys of female Cobb 500 broilers fed with wheat-based diets from 8 to 21 days of age was estimated between 0.99 and 1.12 with an average of 1.06 based on quadratic broken-line model as the concluded value.

Determination of the median effective dose of sufentanil for inhibiting the laryngeal mask insertion response in geriatric patients: a prospective, double-blinded, dose–response trial

BackgroundLaryngeal mask airway(LMA) have been widely used in clinical practice. Irritation to the patient during the insertion of a laryngeal mask can cause hemodynamic fluctuations, which is particularly unsafe for geriatric patients. We used probit regression analysis to determine the median effective dose of sufentanil to inhibit the response to LMA insertion in geriatric patients.MethodsA total of 90 patients were selected for the study using the following inclusion criteria: age ≥ 65 years old, ASA grade I–III, and scheduled to undergo intravenous general anesthesia with LMA insertion. Each patient received a dose of sufentanil for anesthesia induction in one of six levels: 0.05, 0.1, 0.15, 0.2, 0.25, or 0.3 μg kg−1. LMA insertion was scored with a 3-point, 6-category scale, with scores ≥ 16 indicating effective LMA insertion, and < 16 indicating ineffective LMA insertion. Mean arterial blood pressure (MAP), heart rate (HR), and bispectral index (BIS) were recorded 1 min before induction (T1), 1 min after induction (T2), 1 min after LMA insertion (T3), and 5 min after LMA insertion (T4) in each group. In addition, the plasma norepinephrine (NE) levels and adverse reactions were measured at T2 and T3 in each dosage group.ResultsProbit regression analysis showed that the ED50 of sufentanil inhibiting the response to LMA insertion in geriatric patients was 0.18 μg kg−1 (95% CI: 0.16–0.21 μg kg−1), and the ED95 was 0.31 μg kg−1 (95% CI: 0.27–0.38 μg kg−1), and the probit(p) = -2.34 + 12.90 × ln(Dose)(chi^{2} = 0.725, p = 0.948). Among all the patients, the number of effective LMA insertions was 57 (group A), and the number of ineffective LMA insertions was 33 (group B). The MAP, HR, and NE in group B were significantly higher than in group A at T3.ConclusionsSufentanil can effectively inhibit the patient’s response to LMA insertion, with stable hemodynamics and small stress response. The ED50 and ED95 were 0.18 μg kg−1 (95% CI: 0.16–0.21 μg kg−1) and 0.31 μg kg−1(95% CI: 0.27–0.38 μg kg−1), respectively.Trial registrationThis study was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2100051827) on October 6, 2021.

Knee-extensor strength, symptoms, and need for surgery after two, four, or six exercise sessions/week using a home-based one-exercise program: a randomized dose–response trial of knee-extensor resistance exercise in patients eligible for knee replacement (the QUADX-1 trial)

To investigate firstly the efficacy of three different dosages of one home-based, knee-extensor resistance exercise on knee-extensor strength in patients eligible for knee replacement, and secondly, the influence of exercise on symptoms, physical function and decision on surgery. One-hundred and forty patients eligible for knee replacement were randomized to three groups: 2, 4 or 6 home-based knee-extensor resistance exercise-sessions per week (group 2, 4 and 6 respectively) for 12 weeks. isometric knee-extensor strength. Oxford Knee Score, Knee injury and Osteoarthritis Outcome Score, average knee pain last week (0-10 numeric rating scale), 6-min walk test, stair climbing test, exercise adherence and "need for surgery". Primary analysis: Intention-to-treat analysis of 140 patients did not find statistically significant differences between the groups from baseline to after 12 weeks of exercise in isometric knee-extensor strength: Group 2 vs 4 (0.003 Nm/kg (0.2%) [95% CI -0.15 to 0.15], P=0.965) and group 4 vs 6 (-0.04 Nm/kg (-2.7%) [95% CI -0.15 to 0.12], P=0.628). Secondary analysis: Intention-to-treat analyses showed statistically significant differences between the two and six sessions/week groups in favor of the two sessions/week group for Oxford Knee Score: 4.8 OKS points (15.2%) [1.3 to 8.3], P=0.008) and avg. knee pain last week (NRS 0-10):-1.3 NRS points (-19.5%) [-2.3 to-0.2], P=0.018. After the 12-week exercise intervention, data were available for 117 patients (N=39/group): 38 (32.5%) patients wanted surgery and 79 (67.5%) postponed surgery. This was independent of exercise dosage. In patients eligible for knee-replacement we found no between-group differences in isometric knee extensor strength after 2, 4 and 6 knee-extensor resistance exercise sessions per week. We saw no indication of an exercise dose-response relationship for isometric knee-extensor strength and only clinically irrelevant within group changes. For some secondary outcome (e.g., KOOS subscales) we found clinically relevant within group changes, which could help explain why only one in three patients decided to have surgery after the simple home-based exercise intervention. ClinicalTrials.gov identifier: NCT02931058. Preprint: https://doi.org/10.1101/2021.04.07.21254965.

The effects of high-intensity functional training on cardiometabolic risk factors and exercise enjoyment in men and women with metabolic syndrome: study protocol for a randomized, 12-week, dose-response trial

BackgroundIndividuals with metabolic syndrome (MetS) are at a greater risk for developing atherosclerotic cardiovascular disease (ASCVD) than those without MetS, due to underlying endothelial dysfunction, dyslipidemia, and insulin resistance. Exercise is an effective primary and secondary prevention strategy for MetS; however, less than 25% of adults meet the minimum stated public recommendations. Barriers often identified are lack of enjoyment and lack of time. High-intensity functional training (HIFT), a time-efficient modality of exercise, has shown some potential to elicit positive affectivity and elicit increased fitness and improved glucose metabolism. However, the effects of HIFT on dyslipidemia and endothelial dysfunction have not been explored nor have the effects been explored in a population with MetS. Additionally, no studies have investigated the minimal dose of HIFT per week to see clinically meaningful changes in cardiometabolic health. The purpose of this study is to (1) determine the dose-response effect of HIFT on blood lipids, insulin resistance, and endothelial function and (2) determine the dose-response effect of HIFT on body composition, fitness, and perceived enjoyment and intention to continue the exercise.Methods/designIn this randomized, dose-response trial, participants will undergo a 12-week HIFT intervention of either 1 day/week, 2 days/week, or 3 days/week of supervised, progressive exercise. Outcomes assessed at baseline and post-intervention will be multiple cardiometabolic markers, and fitness. Additionally, the participant’s affective response will be measured after the intervention.DiscussionThe findings of this research will provide evidence on the minimal dose of HIFT per week to see clinically meaningful improvements in the risk factors of MetS, as well as whether this modality is likely to mitigate the barriers to exercise. If an effective dose of HIFT per week is determined and if this modality is perceived positively, it may provide exercise specialists and health care providers a tool to prevent and treat MetS.Trial registrationClinicalTrials.gov NCT05001126. August 11, 2021.

O-109 A first dose-response trial investigating the effects of adding choriogonadotropin beta to follitropin delta in women undergoing ovarian stimulation in a long GnRH agonist protocol

Abstract Study question Does addition of choriogonadotropin beta (CG beta) to follitropin delta increase the number of good-quality blastocysts following ovarian stimulation in a long GnRH agonist protocol? Summary answer At the doses investigated, the addition of CG beta reduced the number of intermediate follicles and decreased the number of oocytes and blastocysts. What is known already CG beta is a new recombinant hCG (rhCG) molecule expressed by a human cell line (PER.C6â) with a different glycosylation profile compared to urinary hCG or rhCG derived from a Chinese Hamster Ovary (CHO) cell-line. In the first-in-human trial, the CG beta pharmacokinetics were similar between men and women. In women, the area under the curve (AUC) and the peak serum concentration (Cmax) increased dose proportionally following single and multiple daily doses. In men, a single dose of CG beta provided higher exposure with a longer half-life and proportionately higher testosterone production than rhCG derived from a CHO cell line. Study design, size, duration Placebo-controlled, double-blind, randomised trial (RAINBOW) to explore the efficacy and safety of CG beta as add-on treatment to follitropin delta in women undergoing COS in a long GnRH agonist protocol. The primary endpoint was the number of good-quality blastocysts (grade 3 BB or higher, Gardner and Schoolcraft, 1999). Subjects were randomised to receive either placebo or 1, 2, 4, 8, or 12 µg CG beta added to the daily individualised follitropin delta dose during COS. Participants/materials, setting, methods In total 619 women (30-42 years) with AMH levels between 5 and 35 pmol/L were randomized in equal proportions to the six treatment groups. All subjects were treated with an individualised dose of follitropin delta determined based on AMH (Elecsys AMH Plus Immunoassay) and body weight. Triggering was performed when 3 follicles were ≥17 mm but no more than 25 follicles ≥12 mm were reached Main results and the role of chance The incidence of cycle cancellation (range 0%-2.9%), total follitropin delta dose (mean 112 µg) and duration of stimulation (mean 10 days) were similar across the groups. A reduced number of intermediate follicles (12 to 17 mm) and fewer oocytes (mean range 9.7 to 11.2) were observed for all doses of CG beta compared to the follitropin delta only group (mean 12.5). The mean number of goodquality blastocysts was 3.3 in the follitropin delta group and ranged between 2.1 and 3.0 across the CG beta groups. The incidence of transfer cancellation was higher in the 4, 8 and 12 µg group, mostly as no blastocyst was available for transfer. In the group receiving only follitropin delta, the ongoing pregnancy rate (10-11 weeks after transfer) was high i.e. 43% per started cycle vs 28-39% in CG beta groups and 49% per transfer vs 38-50% in the CG beta groups. In line with the number of collected oocytes, the OHSS incidence was overall lower following follitropin delta with CG beta than following follitropin delta only treatment. Regardless of the dose, CG beta was safe and well-tolerated with low risk of immunogenicity. Limitations, reasons for caution The effect of the unique glycosylation of CG beta and the associated potency implications in women were not known prior to this trial. Further studies will be needed to evaluate potentially lower doses of CG beta for this and/or different indications. Wider implications of the findings The high ongoing pregnancy rate in the follitropin delta group supports the use of individualised follitropin delta dosing in a long GnRH agonist protocol. The differential potency of CG beta may have impaired the growth of intermediate follicles with the investigated doses without affecting the ongoing pregnancy rates per transfer. Trial registration number NCT03564509

Ameliorating hydroxychloroquine induced retinal toxicity through cerium oxide nanoparticle treatments.

The present study investigated the potential protective effects of cerium oxide nanoparticles (CNP) on human retinal pigment epithelium (ARPE-19) cells damaged by hydroxychloroquine (HCQ). Toxicity of HCQ on the ARPE-19 cells was explored with a dose response trial. CNP rescue both a pre-treatment protocol, where CNP were applied 24 hours prior to HCQ application and a simultaneous treatment protocol where both CNP and HCQ were applied together, were used. In the dose response trial, 250 µM HCQ showed 51.84% cell viability after 24 hours and 32.75% after 48 hours time period. This was selected as model HCQ dose for rescue trials. The simultaneous treatment trials did not show a significant increase in viability compared to model toxic dose. The CNP pre-treatment trials showed a significant increase in cellular viability compared to model toxic dose with 68.03% ± 3.27 viability (p = 4.56E-05) at 24 hours and 51.85% ± 4.96 (p = 1.18E-05) at 48 hours time period. CNP pre-treatment showed significant protection of cells from HCQ induced toxicity. The difference in efficacy of simultaneous and pre-treatment is hypothesized to lie in the cellular localization of CNP. Furthermore, including the reactive oxygen species (ROS) scavenging properties of CNP seems to be responsible for protection, the effect of CNP on autophagosome and lysosome colocalization are also hypothesized to play a significant role.

Determination of the Median Effective Dose of Dexmedetomidine for the Prevention of Emergence Agitation in Geriatric Patients Undergoing Major Open Surgery With General Anesthesia: A Prospective, Double-Blinded, Dose-Response Trial.

Dexmedetomidine can effectively decrease the incidences of emergence agitation (EA) in adult patients, but there are major side effects related to increased dose of dexmedetomidine. The purpose of this study was to determine the median effective dose of dexmedetomidine in the prevention of EA among geriatric patients undergoing major open surgery with general anesthesia. A total of 50 geriatric patients were enrolled in this study. Dexmedetomidine 0.5 μg·kg−1·h−1 continuous intravenous infusion was administered to the first patient. The next dose was increased or decreased by .05 depending on the response of the previous patient, according to the Dixon up-and-down method. An “effective” or “ineffective” response was determined based on the Riker sedation-agitation score (RSAS), we defined “effective” as RSAS<5, and “ineffective” as RSAS≥5. The ED50 of dexmedetomidine in prevention of EA was .30 μg·kg−1·h−1 (95% CI, .27–.33) and the predicted ED95 was .42 μg·kg−1·h−1 (95% CI, .38–.51). The incidence of bradycardia was significantly increased in the group without EA compared to the group with EA (57.1% vs 13.6%, P = .002). The ED50 of dexmedetomidine in prevention of EA was .30 μg·kg−1·h−1 (95% CI, .27–.33) and the predicted ED95 was .42 μg·kg−1·h−1 (95% CI, .38–.51). Bradycardia was the main complication.