Years Of Trials Research Articles

Assessing nitrous oxide emissions and productivity of cropping systems for biogas production using digestate and mineral fertilisation in a coastal marsh site

Significant greenhouse gas emissions during substrate cultivation reduces the potential environmental benefits of biogas production. This study investigates the productivity of different cropping systems and their environmental impact in terms of nitrous oxide (N2O) emissions under the environmental conditions of the coastal marsh regions (Northern Germany) with heavy clay soils, in a 2-year field trial (April 2009-March 2011). Treatments included four cropping systems (perennial ryegrass (Lolium perenne, PR) ley, continuous maize (Zea mays), a rotation (CR1) of spring wheat (Triticum aestivum), Italian ryegrass (Lolium multiflorum, IR) and maize, and a rotation (CR2) of maize, winter wheat and IR; two sources of N (nitrogen) fertilizers (calcium ammonium nitrate, and biogas residue (BR)), and three levels of N fertilizer applications (control, moderate, high). Nitrous oxide emissions were determined for the unfertilized and highly fertilized cropping systems comprising PR ley, CR1 and CR2. Cumulative annual N2O emissions varied across the treatments, ranging from 0.82 to 3.4 kg N2O-N ha−1 year−1. Under high N fertilizer applications, PR ley incurred higher N2O-N losses compared to other tested cropping systems, and IR cover crop caused relatively high N2O-N emissions in a short vegetation period. The study observed wide range of yield-scaled emissions (0.00–5.60 kg N2O-N (Mg DM)−1) for different crops, emphasizing the variability in N2O emissions linked to cropping systems. The N2O-N emission factors for the three cropping systems were found to be low to moderate for all treatments, ranging from 0.03% to 0.53% compared to IPCC default Tier 1 N2O-N EFs. The lower emissions in the study were associated with prolonged high soil moisture conditions (water filled pore space >70%.), indicated by its negative correlation with N2O-N fluxes. Low dry matter and N yield of PR and of the wheat-IR sequence after BR application compared to other crops indicated a low N use efficiency. The estimation of N2O-N emissions based on N surplus was not promising specifically for the coastal study site where high groundwater level and organic matter in the soils were the predominant drivers for N2O-N emissions.

Effects of dynamic nitrogen application on rice yield and quality under straw returning conditions

Rice cultivation in Jilin Province, China, encounters challenges associated with straw management and nitrogen fertilizer usage. This study explores the effects of dynamic nitrogen fertilizer application combined with straw incorporation on soil properties, rice yield, and quality. High-quality Japonica rice varieties, “Jihong 9″ and “Jinongda 853,” were cultivated in a 3-year trial across different regions. Results showed that dynamic nitrogen fertilizer application under straw incorporation significantly improved soil properties, leading to increased yields. Over the years, the average yield in straw retuning (SR) was 10,566 kg/ha, surpassing conventional practices (CK) at 9939 kg/ha. SR exhibited higher effective tiller rates, spike numbers, and grain numbers per spike, contributing to enhanced yields. Quality analysis revealed that SR rice exhibited lower protein content, resulting in reduced chalkiness and improved taste quality, making it a more desirable option. These findings highlight the effectiveness of sustainable agricultural practices in optimizing rice production in Jilin Province.

Long-term effect of orthokeratology on choroidal thickness and choroidal contour in myopic children

PurposeTo investigate the long-term effect of orthokeratology (ortho-k) on the choroidal thickness and choroidal contour in myopic children.MethodsSubjects were from a conducted 2-year randomised clinical trial. Children (n=80) aged 8–12...

Effect of Anamorelin, a Ghrelin Receptor Agonist, on Muscle and Bone in Adults With Osteosarcopenia.

Anamorelin, a ghrelin receptor agonist known to stimulate the pulsatile release of GH from the pituitary, has the potential to improve musculoskeletal health in adults with osteosarcopenia. To determine the effect of anamorelin treatment for 1 year on muscle mass and strength and on biochemical markers of bone turnover in adults with osteosarcopenia (OS). Randomized, placebo-controlled, 1-year anamorelin intervention trial. The Bone Metabolism Laboratory at the USDA Nutrition Center at Tufts University. 26 men and women, age 50 years and older, with OS. Muscle mass by D3-creatine dilution and lean body mass (LBM) and bone mineral density (BMD) by dual-energy X-ray absorptiometry, muscle strength, serum IGF-1, and bone turnover markers, serum procollagen 1 intact N-terminal (P1NP), and C-terminal telopeptide (CTX). Anamorelin did not have a significant effect on muscle mass or LBM; it significantly increased knee flexion torque at 240°/s by 20% (P = .013) and had a similar nonstatistically significant effect on change in knee extension; it increased bone formation (P1NP) by 75% (P = .006) and had no significant effect on bone resorption (CTX) or BMD. Serum IGF-1 increased by 50% in the anamorelin group and did not change in the placebo group (P = .0001 for group difference). In this pilot study, anamorelin did not significantly alter muscle mass; however, it may potentially improve lower extremity strength and bone formation in addition to increasing circulating IGF-1 levels in adults with OS. Further study of anamorelin in this population is warranted.

Developing Topics.

U.S. POINTER is a Phase 3, multicenter, randomized 2-year clinical trial of two multidomain lifestyle interventions in 2111 older adults who are at increased risk of cognitive decline and dementia due sedentary lifestyle, poor diet, and other factors such as family history of memory impairment and suboptimum cardiovascular health. Enrollment took place at five geographically diverse sites, beginning in 2019 and completing in early 2023. Participants are randomly assigned to one of two lifestyle intervention groups that differ in format, intensity, and accountability. Those randomized to the Self-Guided Lifestyle Intervention receive annual medical monitoring and health education information, tools, and support to encourage increased physical and cognitive activity and a healthier diet through 2-3 annual group meetings. Those randomized to the Structured Lifestyle Intervention receive frequent medical monitoring of cardiovascular health and a structured program of exercise (primarily aerobic), nutritional counseling, cognitive training and social engagement initially through weekly and then monthly group meetings. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2-year change in cognitive function measured with a global cognition composite score that permits harmonization with FINGER and other trials. Secondary and tertiary outcomes include measures of executive function and episodic memory, physical activity, diet, cognitive and physical activity, cardiometabolic disease risks, mood, quality of life, health care costs, and health care utilization. U.S. POINTER is generating a richly phenotyped cohort that will provide a rigorous comparison of two lifestyle interventions designed to preserve cognitive function. It has nurtured 4 ancillary studies to assess intervention effects on outcomes related to sleep quality, brain structure and pathology, peripheral and neurovascular function, and the microbiome. It also partners with clinical trials within the World-Wide FINGERS international network. The study is generating an archive of biospecimens and de-identified public use data. Plans for a post-intervention observational study of the U.S. POINTER cohort are underway. U.S. POINTER provides an important national resource to advance the field in understanding the role of nonpharmacological interventions in reducing risk for cognitive decline and Alzheimer's disease and related dementia.

Organic Hydromulches in Young Olive Trees in Pots: Effects on Soil and Plant Parameters

Organic hydromulches (liquid spray-on mulches) have been used traditionally in land rehabilitation, mainly to mitigate post-fire runoff and erosion. However, in recent years, a new application of these materials as an eco-friendly alternative to the widely used polyethylene mulch, both in vegetable and woody crops, has been studyied. This work analyzes the effects of six hydromulches, based on organic by-products, on different soil parameters (water content, temperature, and CO2 flux), plant–water relations (stem water potential, leaf gas exchange, and leaf temperature), and the growth (trunk diameter) of young olive trees planted in large pots in the open field over a 2-year trial. The hydromulches tested were: rice husk (RH), rice husk with linen oil (RHL), mushroom substrate (MS), wheat straw (WS), pistachio (PW), and vineyard (VW) pruning wood chips, mixed with different additives (gypsum, recycled paper paste, and Kraft fiber). A non-mulched manual weeding control (NM) was included. The results indicated that hydromulches, in comparison with NM, resulted in increased volumetric soil water content (on average, 22.9% in hydromulches and 19.5% in NM), reduced soil temperature fluctuations (4.97 °C in hydromulches and 6.13 °C in NM), and increased soil CO2 fluxes (0.80 and 0.49 g CO2 m−2 h−1, respectively). Although the differences in the soil water content did not have an obvious effect on the plant–water status, crop growth was reduced in NM (≈23% lower than PW, MS, RHL, and WS), suggesting that vegetative growth, especially in young olive trees, is extremely sensitive to water deficit. The overall study leads to considering hydromulches as a good alternative to mulching in large pots, especially PW, which would be useful for nursery crops before their final establishment in the field.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Efficacy and Safety of Secukinumab for the Treatment of Psoriasis: A Meta-Analysis of Pivotal Phase III Trials

Background: Secukinumab, a fully humanized monoclonal antibody against IL-17A, was approved for the treatment of moderate-to-severe plaque psoriasis in the USA and European Union in 2015. Objectives: Secukinumab, a fully humanized monoclonal antibody against IL-17A, was approved for the treatment of moderate-to-severe plaque psoriasis in the USA and European Union in 2015. The aim of this study was to systematically evaluate the efficacy and safety of secukinumab for the treatment of moderate and severe plaque psoriasis and provide an evidence-based reference for clinical practice. Methods: PubMed, Google Scholar, Cochrane Library, and Clinical Trials databases were searched. Pivotal phase III clinical trials were analysed. RevMan was used for the statistical analysis of the data. Results: Seven pivotal phase III clinical trials were analysed. All trials evaluated secukinumab in moderate-to-severe plaque psoriasis and had two common primary end points: the proportion of respondents to the Psoriasis Area and Severity Index (PASI) and the proportion of respondents to the Investigator’s Global Assessment (IGA). The total response ratios of PASI and IGA respondents in the secukinumab group were 82.8 and 71.3%, respectively, compared to placebo. Secukinumab was superior to etanercept, with risk ratios of 1.7 and 2.1, respectively. Secukinumab was generally well tolerated during the 1-year trial period. However, adverse events also occurred. Conclusion: Secukinumab was found to be more effective than etanercept and had an acceptable safety profile. Since psoriasis is an autoimmune disease that requires lifelong treatment, attention should be paid to its adverse effects.

Generation of Bi-Specific Chimeric Antigen Receptor (CAR) T Cell Therapy for the Treatment of AIDS-Related B Cell Malignancies from Healthy Donors and HIV Patients

Introduction: Individuals with human immunodeficiency virus (HIV) face a substantially greater likelihood of developing cancers compared to the general population. The prevalence of cancer diagnosis among HIV-positive individuals ranges from 25% to 40%. Non-Hodgkin lymphoma (NHL) stands out as the most prevalent cancer type associated with people living with HIV/AIDS (PLWHA). NHL primarily manifests in two forms in PLWHA: Burkitt lymphoma, which poses an 18-fold higher risk, and diffuse large B cell lymphoma (DLBCL), accounting for 75% of cases. The advent of chimeric antigen receptor (CAR) T cell therapies, notably CD19-targeting CAR T cells, has emerged as a groundbreaking treatment for B cell NHL. Unfortunately, PLWHA has been excluded from participating in all of these clinical trials for years due to safety concerns and the challenges associated with manufacturing CAR T cell products from HIV-positive donors. Recent researches explored the feasibility of developing CD19-targeting CAR T cell products utilizing cells from HIV-positive donors with lymphoma. Although these studies have provided promising evidence that alleviates concerns regarding the safety profile and limited effectiveness of CAR T cell therapy in this particular population, they do not address the underlying HIV condition. We previously generated CAR T cells targeting either lymphoma (CD19-CAR) or HIVgp120 (N6-CAR) that show efficacy against their respective diseases in clinical and preclinical testing, respectively. We hypothesized that a dual construct capable of targeting both antigens could simultaneously target lymphoma cells and HIV-infected cells in a same individual. We report our experience developing a bi-specific N6-huCD19 CAR T cell platform that can target both antigens in a single therapeutic product. Methods: We engineered 3 bi-specific CAR candidate designs including 2 tandem and 1 loop constructs. These constructs were developed by integrating a humanized (hu) CD19 single-chain variable fragment (scFv) and an N6 scFv from an anti-HIV broadly neutralizing antibody (bNAb) into a backbone of a 2 nd-generation CAR construct. The bi-specific tandem CAR constructs consisted of N6 and huCD19 scFvs fused with a G4S linker in either huCD19-N6 or N6-huCD19 orientation. The loop-CAR was generated by fusing huCD19(VL):N6(VH):N6(VL):huCD19(VH) with a whitlow linker. All constructs included the CD4 transmembrane domain, a double-mutated IgG4 Fc spacer, 4-1BB co-stimulatory and CD3-zetta signaling domains, and EGFRt separated by a T2A ribosomal skip sequence (Fig.1). We tested the 3 bi-specific constructs in healthy donor-derived T cells using cytotoxicity co-culture assay against either Raji (CD19+) or 8E5 (gp120+) target cells. We generated N6-huCD19 CAR T cells from HIV-positive patients and confirmed the functionality of these CAR T cells against tumor cells. Results: The functional assessment of all 3 bi-specific CAR constructs revealed their efficacy against CD19 and HIVgp120 antigens. However, the N6-huCD19 tandem CAR T cells demonstrated comparable and better efficacy against both antigens. Notably, the N6-huCD19 tandem CAR T cells exhibited the capability to sequentially target either a single antigen or alternate between the 2 antigens (Fig.2). We successfully generated N6-huCD19 tandem CAR T cells using HIV-positive donors, signifying the practicality of this approach within the context of PLWHA. Remarkably these HIV donor-derived N6-huCD19 CAR T cells effectively killed tumor cells expressing CD19 or HIVgp120 antigens, thus confirming their dual functionality against these 2 antigens. Conclusion: Here we demonstrate the development of the novel N6-huCD19 bi-specific CAR T cells with functionality against both CD19 and HIVgp120 antigens. We also showed the feasibility of generating these CAR T cells from HIV-donors. This strategy could potentially provide life-saving approach tailored for treatment of HIV-patients who develop CD19+ lymphomas.

Quantitative System Pharmacology Modeling of the Effect of Recombinant ADAMTS13 on Platelets in Patients with Congenital Thrombotic Thrombocytopenic Purpura

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, thrombotic microangiopathy due to an inherited deficiency of the von Willebrand factor (VWF)-cleaving protease, ADAMTS13.Accumulation of ultra-large VWF multimers increases blood clot formation in small blood vessels, leading to a low platelet count (thrombocytopenia). Treatment of cTTP consists of ADAMTS13 replacement with infusions of plasma-based therapies (PBT). Recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) is in development for patients with cTTP.The ultra-rare nature of cTTP limits the sample size for a formally powered study to assess the impact of ADAMTS13 supplementation on efficacy outcome. This study was a proof-of-principle that model-based clinical trial simulations can be used to supplement clinical trial data in ultra-rare indications. Aims: To calibrate and validate a quantitative system pharmacology (QSP) model describing a mechanistic relationship between ADAMTS13, VWF and platelet numbers in patients with cTTP who received long-term prophylaxis with rADAMTS13 or PBT (fresh frozen or solvent/detergent treated plasma). In addition, to evaluate the treatment benefits of rADAMTS13 versus PBT using clinical trial simulations in virtual patients with cTTP as a supplement to the cTTP phase 3 study (NCT03393975) data. Methods: A QSP model was built using i) in vitro enzyme kinetic data and preclinical experimental data following administration of recombinant VWF and rADAMTS13 in ADAMTS13 knockout (KO) mice, and ii) data from the literature including platelet count and VWF activity from healthy human and untreated patients with cTTP. These data were used to calibrate the parameters corresponding to interactions between ADAMTS13 activity, VWF activity, and platelets. The model was validated against literature data from patients with cTTP treated with PBT and with data from a phase 2 study of patients with immune-mediated TTP treated with rADAMTS13 (NCT03922308). The model was then calibrated to longitudinal platelet data from the cTTP phase 3 study, in which patients with cTTP received prophylaxis for 6 months with PBT (exposure equivalent to ~10 IU/kg ADAMTS13 in the form of 10-20 mL/kg doses) and rADAMTS13 (40 IU/kg) either once every week (Q1W) or once every 2 weeks (Q2W) dosing intervals . The model was used to provide 1-year clinical trial simulations of isolated thrombocytopenia occurrences in a population of 1,000 virtual patients, phenotype-matched to patients in the cTTP phase 3 study. Results:Virtual clinical trial simulations using the QSP model suggested that rADAMTS13 administered over 1 year with a Q1W or Q2W schedule results in significantly fewer patients experiencing occurrences of thrombocytopenia (platelet count threshold of <150 x 10 9/L) compared to patients treated with PBT (hazard ratio [HR] relative to Q2W PBT: Q1W PBT, HR = 0.62; Q2W rADAMTS13, HR = 0.47; Q1W rADAMTS13, HR = 0.18). The treatment difference between rADAMTS13 and PBT was even more pronounced when a thrombocytopenia threshold of <100 x 10 9/L was used (Figure and Table). Simulations also predicted a prophylactic carry-over effect on platelets, with approximately 20 days taken to reach 90% of the long-term average platelet count when switching from rADAMTS13 to PBT or from PBT to rADAMTS13. A correlation analysis for a Q2W dosing of rADAMTS13 demonstrated that ADAMTS13 trough activity (C trough, Spearman ρ = 0.96) and time with ADAMTS13 activity above 10% (Spearman ρ = 0.93) showed stronger correlations with increased platelet count than the maximum plasma ADAMTS13 activity level (C max, Spearman ρ = 0.68). A correlation analysis for a Q1W dosing frequency produced similar results.Mean time above 10% ADAMTS13 activity was higher following rADAMTS13 versus PBT administration (5.2 vs 1.7 days). Conclusions: This model-based virtual clinical trial simulation predicts that dosing with rADAMTS13 would provide >50% reduction in the HR of thrombocytopenia occurrences over PBT. Patients may also have a higher level of protection for 2-3 weeks when switching from rADAMTS13 to PBT. These findings supplement the assessment of clinical benefit of rADAMTS13 in the cTTP phase 3 study and show that increased ADAMTS13 activity following rADAMTS13 administration is likely to reduce occurrences of thrombocytopenia in cTTP.

Seedling emergence and biomass production of soybean cultivars under wheat-soybean relay cropping.

Diversification and intensification of cropping systems can ensure farm profitability while reducing negative environmental impacts of agriculture. Wheat-soybean relay cropping (RC), which consists in planting soybean into standing wheat prior to its harvest, may have this potential although it is poorly adopted by French and European farmers. One of the reasons underlying this lack of adoption could be poor emergence rates and biomass production of soybean, due to a severe competition from the already established primary crop for water, light and nutrients during the co-growth or intercrop phase. All these constraints during the early plant growth could finally affect soybean grain yield and thus farm profitability. Here, we performed a laboratory experiment followed by a 2-year field trial (2021-2022) to investigate potential differences among seven soybean cultivars belonging to different maturity groups (from very early to late) in terms of early growth traits viz. seed germination, seedling emergence vigor and final rates, and early biomass production in wheat-soybean RC. A reference soybean variety belonging to late maturity group (cv. ES Pallador) was also sown under conventional cropping system as control treatment (hereafter referred to as CC). Under laboratory conditions, the base water potential for germination ranged from -0.65 to -0.45 MPa with significant differences (p<0.001) among the tested cultivars indicating their differential tolerance to water stress. Under field conditions, seedling emergence vigor, an index explaining the speed of emergence, ranged from 0.23 to 0.41 and from 0.24 to 0.33 while final emergence rates ranged from 69% to 93% and from 65 to 90% in 2021 and 2022, respectively. We found significant effect of cultivar, year and cultivar x year interaction on emergence vigor (p<0.001) and final emergence rates (p<0.01, p<0.05 and p<0.01, respectively) of soybean cultivars. Significantly higher emergence vigor of the referent cv. ES Pallador was observed in RC compared to CC cropping system in 2021 (0.40 and 0.34, respectively) but not in 2022 (0.29 and 0.31, respectively). Water stress in the seedbed was higher in RC compared to the CC and was the main cause affecting seed germination and seedling emergence vigor especially in 2022. We found a positive correlation between seedling emergence vigor and seedling final emergence rates indicating that a lower speed of seedling emergence, due to seedbed stress factors, affects final emergence rates of soybean. Post-emergence losses due to pigeons were significantly higher (p<0.001) in CC compared to RC (30% and 2% in 2021, and 29% and 2% in 2022 in CC and RC, respectively). Significantly higher biomass production was observed in CC compared to that in RC both in 2021 (162 vs 33 g/m2 of dry matter; p<0.001) and 2022 (252 vs 60 g/m2 of dry matter; p<0.001). Overall, pre-/post-emergence water stress in the seedbed and post-emergence damage due to pigeons are the most important factors affecting a uniform and robust soybean establishment under RC and CC, respectively under southern French conditions.

Longitudinal resting-state EEG in amyloid-positive patients along the Alzheimer’s disease continuum: considerations for clinical trials

BackgroundTo enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer’s disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD.MethodsResting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration.ResultsWhole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures’ rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power.ConclusionsResting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.

Clinical Evaluation of MyoCare in Europe (CEME): study protocol for a prospective, multicenter, randomized, double-blinded, and controlled clinical trial

BackgroundMyopia prevalence has been increasing in the last decades, and its pathological consequences, including myopic maculopathy and high myopia-associated optic neuropathy, are now one of the most common causes of visual impairment. It is estimated that by 2050, more than 50% of Europeans and Americans will be myopes, which is alarming due to the high morbidity of myopes over − 6.00D. Once myopia has appeared, there are different options with scientific evidence to try to slow the axial length growth. Ophthalmic lenses are the less invasive treatment to control myopia, and there is evidence about the efficacy of different designs, mainly in the Asiatic population. However, new designs have been launched, and it is not known if efficacy is the same between Asiatic and European subjects. Thus, we have set up a randomized, controlled, double-blind, and multicenter trial to investigate the efficacy of a new design of ophthalmic lenses for myopia control in European children.MethodsA 2-year prospective, multicenter, randomized controlled, and double-blind clinical trial is used to investigate the efficacy of a new design of ophthalmic lenses to slow the progression of myopia. Three hundred children aged from 6 to 13 years old will be recruited and randomly assigned to a study or control group. The study group will be composed of 150 children wearing MyoCare while the control group will be composed of 150 children wearing Clearview. The inclusion criteria will be myopia with a spherical equivalent between − 0.75D and − 5.00D, astigmatism < 1.50D, and anisometropia < 1.00D and having a historical evolution of at least − 0.50 The primary outcome is to compare the mean annual progression of the spherical equivalent between both groups. The secondary outcomes are axial length, choroidal thickness, phorias, and accommodative status of both groups.DiscussionThis study will be the first randomized and controlled clinical trial in European children with spectacle lenses based on simultaneous competing defocus. The results will shed light on the clinical evidence of spectacle lenses relying on this new design for the management of myopia with results of efficacy in the non-Asiatic population.Trial registrationEU Clinical Trials Register (EudraCT) 2022–001696. Registered on 27 April 2022. ClinicalTrials.gov NCT05919654. Registered on 26 June 2023.

Cost-effectiveness of left atrial appendage closure with Watchman for non-valvular atrial fibrillation patients in Japan

AimsLeft atrial appendage closure (LAAC) has been demonstrated to be cost-saving relative to oral anticoagulants for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) in the United States and Europe. This study assessed the cost-effectiveness of LAAC with the Watchman device relative to warfarin and direct oral anticoagulants (DOACs) for stroke risk reduction in NVAF from a Japanese public healthcare payer perspective.MethodsA Markov model was developed with 70-year-old patients using a lifetime time horizon. LAAC clinical inputs were from pooled, 5-year PROTECT AF and PREVAIL trials; warfarin and DOAC inputs were from published meta-analyses. Baseline stroke and bleeding risks were from the SALUTE trial on LAAC. Cost inputs were from the Japanese Medical Data Vision database. Probabilistic and one-way sensitivity analyses were performed.ResultsOver the lifetime time horizon, LAAC was less costly than warfarin (savings of JPY 1,878,335, equivalent to US $17,600) and DOACs (savings of JPY 1,198,096, equivalent to US $11,226). LAAC also provided 1.500 more incremental quality-adjusted life years (QALYs) than warfarin and 0.996 more than DOACs. In probabilistic sensitivity analysis, LAAC was cost-effective relative to warfarin and DOACs in 99.98% and 99.73% of simulations, respectively. LAAC dominated (had higher cumulative QALYs and was less costly than) warfarin and DOACs in 89.94% and 83.35% of simulations, respectively.ConclusionsOver a lifetime time horizon, LAAC is cost-saving relative to warfarin and DOACs for stroke risk reduction in NVAF patients in Japan and is associated with improved quality-of-life.

Guselkumab-Treated Patients with Plaque Psoriasis Who Achieved Complete Skin Clearance for ≥156 Consecutive Weeks: A Post-Hoc Analysis From the VOYAGE 1 Clinical Trial.

Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. This post-hoc analysis of the 5-year VOYAGE1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥156 consecutive weeks (PASI=0 group) with those that never achieve PASI=0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4-156. Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥156consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p<0.05) associated with the PASI = 0 group. A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. NCT02207231.

Subjective versus objective, polymer bur-based selective carious tissue removal: 2-year randomized clinical trial

ObjectivesWe aimed to compare subjective (S) selective carious tissue removal using hand instruments versus objective (O) removal using a self-limiting polymer bur in a single-blind cluster-randomized controlled superiority trial. Methods115 children (aged 7–8 years) with ≥1 vital primary molar with a deep dentin lesion (>1/2 dentin depth) were included and randomized (60 S/55 O); all eligible molars in a child were treated identically (91 S/86 O). Cavities were prepared and carious tissue on pulpal walls selectively removed using hand instruments (S) or a self-limiting polymer bur (Polybur P1, Komet), followed by restoration using a glass hybrid material (Equia Forte, GC). Treatment time and satisfaction data have been reported in a 1-year-interim report. We here report on 2 year survival (tooth retained with or without further retreatments being needed, or tooth exfoliated), analyzed using multi-level Cox-regression analysis, as well as success (ART criteria 0/1, no pulpal complications, no re-intervention needed, or tooth extraction). Results71 restorations in S and 65 in O were examined after a mean (SD, range) of 22 (11; 3–31) months, of which 50 S and 48 O restorations were successful and 70 S and 65 O survived. The majority of failures were restorative, not pulpal, and distribution of ART codes was not significant different between groups. Risk of failure was not significantly associated with the removal protocol (HR; 95 % CI: 0.95; 0.51–1.78), and also not age, sex or dental arch, while single surfaced restorations showed significantly lower hazard (0.14; 0.06–0.37). ConclusionThere was no significant difference in success or survival between objective and subjective carious tissue removal. Clinical significanceIn primary teeth, subjective selective excavation had no disadvantage compared with objective excavation, which required a separate instrument (polymer-based bur) for carious tissue removal. Polymer-based burs may be particularly useful when standardized excavation is needed.

Inferring bovine tuberculosis transmission between cattle and badgers via the environment and risk mapping.

Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is one of the most challenging and persistent health issues in many countries worldwide. In several countries, bTB control is complicated due to the presence of wildlife reservoirs of infection, i.e. European badger (Meles meles) in Ireland and the UK, which can transmit infection to cattle. However, a quantitative understanding of the role of cattle and badgers in bTB transmission is elusive, especially where there is spatial variation in relative density between badgers and cattle. Moreover, as these two species have infrequent direct contact, environmental transmission is likely to play a role, but the quantitative importance of the environment has not been assessed. Therefore, the objective of this study is to better understand bTB transmission between cattle and badgers via the environment in a spatially explicit context and to identify high-risk areas. We developed an environmental transmission model that incorporates both within-herd/territory transmission and between-species transmission, with the latter facilitated by badger territories overlapping with herd areas. Model parameters such as transmission rate parameters and the decay rate parameter of M. bovis were estimated by maximum likelihood estimation using infection data from badgers and cattle collected during a 4-year badger vaccination trial. Our estimation showed that the environment can play an important role in the transmission of bTB, with a half-life of M. bovis in the environment of around 177 days. Based on the estimated transmission rate parameters, we calculate the basic reproduction ratio (R) within a herd, which reveals how relative badger density dictates transmission. In addition, we simulated transmission in each small local area to generate a first between-herd R map that identifies high-risk areas.

Eye growth pattern of myopic children wearing spectacle lenses with aspherical lenslets compared with non-myopic children.

To evaluate eye growth of children wearing spectacle lenses with highly aspherical lenslets (HAL), slightly aspherical lenslets (SAL) and single-vision lenses (SVL) compared to eye growth patterns in non-myopes in Wenzhou, China. The randomised trial had 170 myopic children (aged 8-13 years) randomly assigned to the HAL, SAL or SVL group. Normal eye growth was examined using 700 non-myopic schoolchildren (aged 7-9 years) in the Wenzhou Medical University-Essilor Progression and Onset of Myopia (WEPrOM) cohort study using logistic function models. Slow, normal and fast eye growth was defined as range of values <25th, 25th-75th and >75th percentiles, respectively. The predicted upper limits of slow eye growth (25th percentile) among non-myopes aged 7-10 years and 11-13 years were 0.20-0.13 and 0.08-0.01 mm (after 2-year period; 0.37-0.33 and 0.29-0.14 mm), respectively, while the upper limits of normal eye growth (75th percentile) were 0.32-0.31 and 0.28-0.10 mm (after 2-year period; 0.58-0.55 and 0.50-0.24 mm), respectively. The 2-year trial had 157 children, 96 of whom wore their lenses full time (everyday ≥12 h/day). The mean 2-year axial length change for HAL, SAL and SVL was 0.34, 0.51 and 0.69 mm (0.28, 0.46 and 0.69 mm in full-time wear), respectively. Slow eye growth was found in 35%, 17% and 2% (44%, 29% and 3% in full-time wear); normal eye growth in 35%, 26% and 12% (44%, 32% and 9% in full-time wear) and fast eye growth in 30%, 57% and 86% (12%, 39% and 88% in full-time wear), respectively (p < 0.001). The eye growth pattern in approximately 90% wearing HAL full time (compared with about 10% wearing SVL full time) was similar or slower than that of non-myopic children both after 1- and 2-year periods.

Optimizing water and nitrogen management strategies to improve their use efficiency, eggplant yield and fruit quality.

With improvement in living standards, consumer preferences for vegetables are changing from quantity- to quality-oriented. Water and nitrogen supply, as two major determinants of vegetable crop yield and quality, can be optimally managed to improve the yield and quality. To evaluate the response in yield, fruit quality, and water and nitrogen utilization of eggplant to different water and nitrogen management strategies, a 2-year (2021 and 2022) field trial under mulched drip irrigation was conducted. The growth period was divided into seedling, flowering and fruit set, fruit development, and fruit ripening stages. Three irrigation levels were applied during the flowering and fruit set stage: W0, adequate water supply (70%-80% of field water capacity, FC); W1, mild water deficit (60%-70% FC); and W2, moderate water deficit (50%-60% FC). In addition, three nitrogen application rates were applied: N1, low nitrogen level (215 kg ha-1); N2, medium nitrogen level (270 kg ha-1); and N3, high nitrogen level (325 kg ha-1). The irrigation and nitrogen rates were applied in all combinations (i.e., nine treatments in total). Adequate water supply throughout the reproductive period in combination with no nitrogen application served as the control (CK). The yield of the W1N2 treatment was significantly increased by 32.62% and 35.06% in 2021 and 2022, respectively, compared with that of the CK. Fruit soluble protein, soluble solids, and vitamin C contents were significantly higher under W1 than W2. Fruit quality was significantly higher under the N2 rate compared with the other nitrogen rates. The W1N2 treatment showed the highest water productivity, with a significant increase of 11.27%-37.84% (2021) and 14.71%-42.48% (2022) compared with that under the other treatments. Based on the average water-deficit degree and nitrogen application rate, W0 and N1 had the highest partial factor productivity of nitrogen. Assessment of the results using the TOPSIS (technique for order preference by similarity to an ideal solution) method indicated that mild water deficit in combination with the medium nitrogen application rate (W1N2) was the optimal water and nitrogen management strategy for cultivated eggplant. The present findings contribute novel insights into the sustainable cultivation of eggplant in an oasis arid environment.

Insights into the daily life of ventricular assist device coordinators-Outcome of an international questionnaire.

As the incidence of heart failure in developed countries is on the rise, mechanical circulatory support (MCS) often remains the only treatment option for patients with end-stage heart failure and is well established worldwide. Even though VAD coordinators play a key role in VAD programs, their responsibilities and daily duties are not clearly defined and characterized. Recently published data from the first 5-year multicenter clinical trial assessing experience with the HeartMate 3 left ventricular system (Abbott, Abbott Park, IL) show an overall survival of 61% at 5 years. When it comes to possible improvements to these systems, it is necessary for developers not only to know the status quo but also to determine and consider the visions and wishes of those individuals who take care of patients, provide education and deal with possible complications. This would be helpful a meaningful effort towards implementing a standard of care. To fill this knowledge gap, we conducted an online survey using the SurveyMonkey tool, addressing representatives of programs implanting VADs worldwide. Representatives answered a standardized block of 14 questions and were asked to provide responses within 3 months. A total of 91 VAD coordinators from centers of various regions of the world completed the survey. The majority came from European countries. The numbers of patients followed up by the centers ranged from <20 to 390 patients. The majority of VAD coordinators had a nursing background (68%). Seventy-seven percent of the centers operate a 24-h hotline and 3-monthly visits to the outpatient department are most common. Fifty-nine percent of the centers do not use an infection scoring system for driveline wound care. The majority of the centers indicated that an optimized follow-up concept including wound care, medication, and social care is crucial and the key issue for an improved outcome. Smaller components and intensified psychosocial support ranked highest in questions about how to improve quality of life. Surprisingly, the future prospects of telemetric monitoring were not rated high in significance. There is a wide variability in the composition and tasks of VAD programs worldwide. Implementing a standard of care and improving psychosocial care as well as equipment is regardedmost important to improve outcomes and quality of life. From the point of view of those responsible, the significance of telemetric monitoring seemed overrated.