Circulating cell-free DNA undergoes significant decline in yield after prolonged storage time in both plasma and purified form.

Codonopsis tangshen, a perennial herbaceous, has been shown to be affected by continuous cropping, with significant decline in both yield and quality. In this study, we studied the effect of continuous cropping on the abundance and composition of rhizospheric soil bacterial community. Results showed that continuous cropping causes a significant decline in both yield and quality. The nutrient content in continuous cropping soil was higher than that of soil in main cropping. Pyrosequencing analyses revealed Proteobacteria and Acidobacteria as the main phyla in two types of soils. Relative abundance of Acidobacteria, Nitrospirae, TM7, and AD3 phyla was observed to be high in continuous cropping soils, whereas Chloroflexi, Bacteroidetes, and Planctomycetes phyla were richer in main cropping soils. At the genus level, high relative abundance of Pseudomonas (γ-Proteobacteria), Rhodanobacter, Candidatus Koribacter, and Candidatus were observed in continuous cropping soil. Different patterns of bacterial community structure were observed between different soils. Redundancy analysis indicated that organic matter content and available nitrogen content exhibited the strongest effect on bacterial community structure in the continuous cropping soil. Taken together, continuous cropping led to a significant decline in yield and quality, decrease in rhizospheric soil bacterial abundance, and alteration of rhizospheric soil microbial community structure, thereby resulting in poor growth of C. tangshen in the continuous cropping system.

Discussion of the Paper by Jennison and Turnbull

How widespread are yield declines in long-term rice experiments in Asia?

Psoriasis is a chronic disease requiring long-term therapy, which makes finding treatments with favourable long-term safety and efficacy profiles crucial. The goal of this review is to provide the background needed to evaluate properly long-term studies of biologic treatments for psoriasis. Firstly, important elements of design and analysis strategies are described. Secondly, data from published trials of biologic therapies for psoriasis are reviewed in light of the design and analysis choices implemented in the studies. Published reports of clinical trials of biologic treatments (adalimumab, alefacept, etanercept, infliximab or ustekinumab) that lasted 33 weeks or longer and included efficacy results and statistical analysis were reviewed. Study designs and statistical analyses were evaluated and summarized, emphasizing patient follow-up methods and handling of missing data. Various trial designs and data handling methods are used in long-term studies of biologic psoriasis treatments. Responder analyses in long-term trials can be conducted in responder enrichment, re-treated nonresponder or intent-to-treat trials. Missing data can be handled in four ways, including, from most to least conservative, nonresponder imputation, last-observation-carried-forward, as-observed analysis and anytime analysis. Long-term clinical trials have shown that adalimumab, alefacept, etanercept, infliximab and ustekinumab are efficacious for psoriasis treatment; however, without common standards for these trials, direct comparisons of these agents are difficult. Understanding differences in trial design and data handling is essential to make informed treatment decisions.

Recent clinical trials and critical reviews of Alzheimer's disease (AD) research discourage already relatively sparing clinical uses of cholinesterase inhibitors (ChEIs) considering the prevalence of AD. As evidence against use of this class of drugs, detractors cite critical reviews of ChEIs and lack of long-term health benefits found in one long-term clinical trial. This paper describes the use of standard error of measurement to allow investigators to design clinical trials that address these issues. The new clinical trial procedures afford sufficient precision for two purposes. First, practitioners can assess individual patients with precision and certainty in their observations. Second, clinical trial researchers can study how short-term drug effects on individual patients predict long-term benefits from continued treatment. With these more clinically informative clinical trial designs, investigators would be able to avoid uncertainties currently raised by conflicts between short- and long-term AD clinical trials.

Background: The aging of skin is a multifaceted process influenced by both internal (chronological) and external (environmental) factors, which leads to the formation of wrinkles, a decline in elasticity, and alterations in pigmentation. Epigenetics, involving heritable changes in gene expression that do not modify the DNA sequence, is crucial in governing skin homeostasis and its reaction to environmental influences. Various epigenetic modifications, including DNA methylation, histone changes, and non-coding RNAs, play a significant role in modulating gene activity that is essential to aging characteristics. This review consolidates the molecular mechanisms and practical applications of epigenetic agents in anti-aging skincare, while also addressing challenges such as variability in studies and the requirement for extensive safety data over the long term.Methods: A comprehensive literature search was performed on PubMed, Scopus, and Web of Science, focusing on peer-reviewed research articles published between 2015 and 2025. The search utilized keywords such as "epigenetics," "anti-aging skincare," "DNA methylation," "histone modification," "non-coding RNA," and "clinical trials," which were combined using Boolean operators. The inclusion criteria emphasized studies that examined epigenetic processes related to skin aging, along with both natural and synthetic modulators, and clinical outcomes, while excluding non-peer-reviewed literature and studies on non-human subjects lacking translational relevance. The data extraction concentrated on molecular mechanisms, profiles of modulators, designs of clinical trials, and outcomes reported by patients.Results: Epigenetic alterations related to aging, such as hypermethylation of the COL1A1 promoter and changes in histone acetylation, play a role in the characteristics of aging skin. Both natural substances (like resveratrol, EGCG, quercetin, and dihydromyricetin) and synthetic compounds (including retinoids, senolytic peptides such as OS-01 and GHK-Cu, NAD+ precursors, and HDAC/DNMT inhibitors) have been found to influence epigenetic modifications. Clinical trials indicate that these agents are effective in decreasing biological skin age while enhancing hydration (by 20.37% to 44%), elasticity (by 5.3% to 25.6%), and reducing wrinkle depth (by 6.2% to 55.8%), often outperforming traditional methods. Outcomes reported by patients show a high level of satisfaction (for instance, 70% satisfaction with OS-01), albeit with someConclusions: Epigenetic modulators present a groundbreaking method for anti-aging skincare by focusing on reversible molecular processes. Their combination with personalized dermatological care, microbiome management, and innovative delivery systems shows potential for extending skin vitality. Rigorous, long-term clinical trials are essential to confirm their effectiveness and safety, paving the way for a transition to precision, expert-driven anti-aging approaches.

Metaproterenol (Alupent), a new bronchodilator, was administered in oral and metered aerosol forms to 134 patients with bronchial asthma in three separate studies: (1) a placebo-controlled trial of single doses of aerosol, (2) a long-term uncontrolled clinical trial of the aerosol, and (3) a long-term uncontrolled clinical trial of the oral tablet. In the first study, statistical analysis of results in 31 patients showed that a single dose of metaproterenol aerosol was significantly superior to placebo aerosol in improving the pulmonary function as measured by forced expiratory volume (P less than 0.01) and maximum mid-expiratory flow rate (P less than 0.05). In the two uncontrolled, long-term clinical trials, 37 patients were treated with metaproterenol aerosol for an average of about four months, and 66 other patients received the drug orally for an average of about three weeks, respectively. The daily dose was one or two doses of aerosol, approximately 0.65 mg. per dose, taken as required several times daily; or 20 to 80 mg. of metaproterenol tablets daily orally. Satisfactory clinical response was seen in 29 (78.4 per cent) of the patients on aerosol and in 45 (68.2 per cent) of the patients on oral therapy. On the aerosol, nine patients (24.3 per cent) experienced mild tachycardia. On oral medication, side effects developed in 16 patients (24.2 per cent). Reactions, mostly nervousness and tachycardia, were mild and usually could be controlled by reducing the dosage. Only two patients (3 per cent) discontinued the drug. Laboratory tests carried out during the aerosol trial and at the end of the oral study revealed no drug-related abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

This study purposed to evaluate the impact of climate change on green gram yield, biomass and days to maturity under the baseline and future climate scenarios in Kitui County, Kenya. A field experiment was conducted during the March–April–May (MAM) and October–November–December (OND) planting seasons of 2018 and 2019 in the South Eastern Kenya University (SEKU) farm. Data on soil physical and chemical properties, daily climate data on rainfall, maximum and minimum temperature, and solar radiation, and green gram phenology dates were collected from the site and used in the calibration and validation of the APSIM model for four varieties of green gram, namely Biashara, Tosha, N26, and KS20 varieties. The calibrated green gram model captured the observed yield, biomass and days to maturity of the four varieties of green gram well. The calibrated green gram model was used to simulate the effects of climate change using daily climate data from an equal-weight ensemble of the nine CORDEX RCA4 models under the baseline scenario (1971 to 2000), and the future RCP 4.5 and 8.5 scenarios (2021 to 2050). During the MAM and OND seasons, a statistically significant decline in yield, biomass, and days to maturity is expected under both the RCP 4.5 and RCP 8.5 scenarios. The high variability in rainfall amount under both the RCP 4.5 and RCP 8.5 scenarios will translate to a lower yield and biomass. The increase in temperature under both the RCP 4.5 and RCP 8.5 scenarios will reduce the days to maturity for green grams in Kitui County. A decline in green gram yield is expected under future climate scenarios in one of the highly suitable zones for Kitui County, Kenya. Given that the government aims to revive farming in the ASALs by promoting climate-smart agriculture through planting drought-resistance crops, there is a need to develop green gram varieties which are more tolerant to the expected change in climate.

Novel adaptive design for allergen immunotherapy clinical trials.

Root distribution, soil water depletion, and water productivity of sweet corn under deficit irrigation and biochar application

Clinical trials have become the preeminent tool for investigating new diagnostic, therapeutic, and preventive treatment strategies. During these trials, periodic interim data analyses are conducted by data monitoring committees (DMCs) to ensure participant safety. If accumulated data indicate harm to participants, clear evidence of superior efficacy, or futility of collecting additional data, studies may be terminated before their planned conclusion. Editorial p 2173 These termination decisions are invariably complex and involve important subjective and ethical elements.1 Of greatest concern when studies are terminated because of clear benefit is the possibility that the superior intervention has toxicities that remain undiscovered. Early termination entails the abbreviation of clinical experience that would permit assessment of the longer-term safety profile. However, study continuation when treatments are not equally effective also means that some participants will continue to receive a less effective therapy. The tension between protecting both trial participants and future patients has been increasingly acute since rofecoxib (Vioxx [Merck]) and other cyclooxygenase-2 inhibitors were implicated in a greater risk of myocardial infarction. Thrombotic side effects of cyclooxygenase-2 inhibition were postulated as a result of the propensity for selective antagonists to decrease vascular prostacyclin production and possibly affect the balance between prothrombotic and antithrombotic eicosanoids.2 Little evidence of toxicity was evident in preapproval trials, however, and rofecoxib was approved in 1999 for relief of the signs and symptoms of osteoarthritis, the management of acute pain, and the treatment of primary dysmennorhea.3 The possibility of cardiac toxicity in human trials was recognized in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial.4 Meta-analyses, database studies, and prospective trials further corroborated cardiac toxicity,5–8 and Merck voluntarily withdrew rofecoxib from the US market on September 30, 2004,9 amid widespread criticism of both Merck and the Food and Drug Administration.10,11 In the wake …

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

On Clinical Trials.

Nonclinical Toxicology in Support of Licensure of Gene Therapies

The north-western region of India is extremely important for food security and has contributed substantially to the country's past agricultural growth. This has been possible largely because the region is endowed with good natural resources such as soils and water, and is relatively well developed in respect of markets and infrastructure. Rice and wheat are now commonly grown in double-cropping rotation and their average productivity varies from 2 to 5 t/ha. This needs to be increased substantially to meet growing demands due to the increasing population, urbanization and income growth. Concerns have been expressed lately that the rice–wheat system is causing environmental degradation in the region, and that there is a stagnation/decline in its productivity threatening food security. In this paper, the authors analyse the historical trends in yields of rice and wheat crops using regional statistics, long-term fertility experiments, other conventional field experiments and crop simulation models. Rice yields showed a very modest decline in many districts in the region, as well as in field experiments. The simulated yields showed a similar decline. Wheat yields of normally sown crops showed an increasing trend in most districts due to a greater application of fertilizers. Long-term experiments conducted elsewhere in the Indo-Gangetic plains also showed a large decline in rice yields and a small or no decline in wheat yields during the same period. The simulation results indicated that the rate of decline was related to the initial yield of crops. A significant annual yield decline was shown only when yield levels were high. It is concluded that the evidence of a yield decline in north-western India is not very strong at present. The yield trends may be partly related to the gradual change in weather conditions during the last two decades in selected research centres located in and around urban areas. The relationship of these trends to changes in nutrient use efficiencies, water use, insects and disease prevalence is discussed. Results indicate that there are only limited management options for increasing yields of rice and wheat crops in north-western India.