Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study

Background: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate.  Objectives: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity.  Methods: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool.  Results: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%.  Conclusions: The pCR rate was insufficient to justify phase III investigation of imiquimod vs.  Surgery: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy

Graphene-Based Nanocomposites for Energy Storage

Since the first report of using micromechanical cleavage method to produce graphene sheets in 2004, graphene/graphene-based nanocomposites have attracted wide attention both for fundamental aspects as well as applications in advanced energy storage and conversion systems. In comparison to other materials, graphene-based nanostructured materials have unique 2D structure, high electronic mobility, exceptional electronic and thermal conductivities, excellent optical transmittance, good mechanical strength, and ultrahigh surface area. Therefore, they are considered as attractive materials for hydrogen (H2) storage and high-performance electrochemical energy storage devices, such as supercapacitors, rechargeable lithium (Li)-ion batteries, Li–sulfur batteries, Li–air batteries, sodium (Na)-ion batteries, Na–air batteries, zinc (Zn)–air batteries, and vanadium redox flow batteries (VRFB), etc., as they can improve the efficiency, capacity, gravimetric energy/power densities, and cycle life of these energy storage devices. In this article, recent progress reported on the synthesis and fabrication of graphene nanocomposite materials for applications in these aforementioned various energy storage systems is reviewed. Importantly, the prospects and future challenges in both scalable manufacturing and more energy storage-related applications are discussed

Generation of Nitric Oxide in the Opossum Lower Esophageal Sphincter during Physiological Experimentation

Lipopolysaccharide (LPS), given in vivo, modulates opossum esophageal motor functions by inducing the inducible nitric oxide synthase (iNOS), which increases nitric oxide (NO) production. Superoxide, a NO scavenger, is generated during this endotoxemia. Superoxide is cleared by superoxide dismutase (SOD) and catalase (CAT) to protect the physiological function of NO. This study examined whether lower esophageal sphincter (LES) motility, NO release, and iNOS and nitrotyrosine accumulation in the LES are affected by LPS in vitro. Muscle strips from the opossum LES were placed in tissue baths containing oxygenated Krebs buffer. NO release was measured with a chemiluminescence NOx analyzer, and Western blots were performed to analyze iNOS and nitrotyrosine production. The percent change in resting LES tone after a 6-hour exposure to LPS was significantly increased compared to pretreatment values. The percent LES relaxation upon electrical stimulation was significantly decreased in the control group at 6 hours, indicating that the LPS treatment had an effect. The NO concentration in the tissue bath of LPS-treated muscle without nerve stimulation was significantly less than that of LPS treatment combined with SOD/CAT or SOD/CAT alone. iNOS and nitrotyrosine were detectable and increased over time in the LES muscle of both the control and LPS-treated groups. Antioxidant enzymes may play a role in regulating NO-mediated neuromuscular functions in the LES

Effect of Alkylation on the Kinetic Stability of Arsenodiester and Organoarsenicals against Hydrolysis: A Theoretical Study

Received: 14.06.2018. Accepted: 27.07.2018. Published: 30.07.2018.Arsenic diesters have same structural and chemical properties as Pi (phosphate) diester. Beside this structural similarity, arsenate is not considered by cellular processes to replace phosphate. Quantum calculation reveals that this happens due to very high hydrolysis rate of Asi diester (As–O-bond-based compounds) as compared to Pi, but how organoarsenicals (As–C-bond-based compounds) that are produced by alkylation of Asi survive in highly aqueous tissues of marine organisms? We found that this alkylation results in lower hydrolysis rate of Asi diester. Our work concluded that alkylating effort by our body on Asi is to avoid structural ambiguity with phosphate and excrete out arsenic in the form of organoarsenicals from body

Unveiling the environmental impact of corn production in China: evidence from panel ARDL approach

Understanding the cycle of carbon emissions resulting from agricultural practices is critical for evaluating their effect on environmental quality. This study investigates the influence of corn production on environmental quality across six major corn producing provinces in China: Hebei, Heilongjiang, Henan, Hubei, Shandong, and Sichuan, using panel datasets spanning from 1990 to 2022. Utilizing a robust methodological framework and advanced econometric techniques such as the Panel Mean Group Autoregressive Distributed Lag model (PMG-ARDL), Panel Quantile Regressions (PQR), Panel Least Square regression (PLSR), this study offers a comprehensive analysis of both short-term and long-term impacts of several agricultural inputs, agricultural GDP, and temperature on environmental quality. The findings reveal significant long-term contributions to carbon emissions from the use of agricultural water, agricultural credit, and fertilizers use, indicating the environmental costs associated with intensive agricultural practices. The study shows carbon emissions have a long-term negative relationship with corn production. The results from the PMG-ARDL model are consistent with those obtained from the PQR, and PLSQR analyses, demonstrating strong positive correlations between agricultural loans, fertilizer use, agricultural water usage, and carbon emissions. The Dumitrescu and Hurlin results show unidirectional causation of carbon emissions from pesticide use, temperature, and agricultural GDP, and bidirectional causal relationship between carbon emissions, corn production, fertilizer use, agricultural water usage, and agricultural credit. The study underscores the critical need for policies that balance agricultural productivity with environmental quality, suggesting directions for future research to explore diverse agricultural systems and incorporate more dynamic modeling approaches to better understand and mitigate the environmental impacts of agriculture

Sensor technologies for the detection and monitoring of endocrine-disrupting chemicals

Endocrine-disrupting chemicals (EDCs) are a class of man-made substances with potential to disrupt the standard function of the endocrine system. These EDCs include phthalates, perchlorates, phenols, some heavy metals, furans, dimethoate, aromatic hydrocarbons, some pesticides, and per- and polyfluoroalkyl substances (PFAS). EDCs are widespread in the environment given their frequent use in daily life. Their production, usage, and consumption have increased many-fold in recent years. Their ability to interact and mimic normal endocrine functions makes them a potential threat to human health, aquatics, and wild life. Detection of these toxins has predominantly been done by mass spectroscopy and/or chromatography-based methods and to a lesser extent by advanced sensing approaches such as electrochemical and/or colorimetric methods. Instrument-based analytical techniques are often not amenable for onsite detection due to the lab-based nature of these detecting systems. Alternatively, analytical approaches based on sensor/biosensor techniques are more attractive because they are rapid, portable, equally sensitive, and eco-friendly. Advanced sensing systems have been adopted to detect a range of EDCs in the environment and food production systems. This review will focus on advances and developments in portable sensing techniques for EDCs, encompassing electrochemical, colorimetric, optical, aptamer-based, and microbial sensing approaches. We have also delineated the advantages and limitations of some of these sensing techniques and discussed future developments in sensor technology for the environmental sensing of EDCs

Landiolol and Organ Failure in Patients With Septic Shock The STRESS-L Randomized Clinical Trial

IMPORTANCE: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. OBJECTIVES: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. DESIGN, SETTING, AND PARTICIPANTS: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. INTERVENTION: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. RESULTS: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. CONCLUSION AND RELEVANCE: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. TRIAL REGISTRATION: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN1260091