A Conversation on an Effective, Straightforward, Quantitative Approach to the Outpatient Use of Insulin

For primary care providers, using insulin can present challenges that can be met by a straightforward approach using the following principles. Depending on when it is injected, each component of the insulin regimen has a maximal effect on a specific period of the 24-hour cycle (e.g., overnight, morning, afternoon, or evening). The glucose pattern in that period determines whether the dose of that component of the insulin regimen requires adjusting. Regarding which insulin types and insulin regimens to use, human insulin (NPH and regular) is as effective as analog insulins, and a two-injection intensified insulin regimen is as effective as a four-injection regimen.

Sensitivity and Resistance Risk Assessment of Puccinia striiformis f. sp. tritici to Triadimefon in China

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a destructive disease of wheat that seriously threatens production safety in wheat-producing areas worldwide. In China, the disease has been largely controlled with fungicide triadimefon. Although high levels of fungicide resistance in other fungal pathogens have been reported, failure to control Pst with any fungicides has seldomly been reported and fungicide sensitivity of Pst has not been evaluated in China. The distribution of triadimefon-resistant Pst isolates was investigated in the present study. The baseline sensitivity of 446 Pst isolates across the country to triadimefon was determined, and the concentration for 50% of maximal effect (EC50) showed a unimodal distribution curve, with a mean value of 0.19 μg mL-1. The results indicated a wide range of sensitivity to triadimefon, with more insensitive isolates collected from Pst winter-increasing areas and northwest over-summering areas, whereas more sensitive isolates were collected from southwest over-summering areas and epidemic areas of Xinjiang and Tibet. The majority of the tested Pst isolates were sensitive to triadimefon; only 6.79% had developed varying degrees of resistance. Characterization of parasitic fitness revealed that the triadimefon-resistant isolates exhibited strong adaptive traits in urediniospore germination rate, latent period, sporulation intensity, and lesion expansion rate. Positive cross-resistance was observed between triadimefon and tebuconazole or hexaconazole, but not between pyraclostrobin or flubeneteram. The point mutation Y134F in the 14α-demethylase enzyme (CYP51) was detected in triadimefon-resistant isolates. A molecular method (Kompetitive Allele Specific PCR) was established for the rapid detection of Y134F mutants in the Pst population. Two genotypes with one point mutation Y134F conferred resistance to triadimefon in Pst. The risk of resistance to triadimefon in Pst may be low to moderate. This study provided important data for establishment of high throughput molecular detection methods, fungicide resistance risk management, and the development of new target fungicides.

Evaluation of biological activities of highly diluted nucleotide sequences by using cellular models

Background: highly diluted specific nucleic acids (SNA®), designed to modulate viral and cytokine genes expression, are currently used in Micro-Immunotherapy to treat viral infections and immune disorders. Although some preliminary studies have showed clinical benefit of these homeopathic preparations [1], no experimental data are available to explain their mechanism of action. Aims: to investigate the in vitro effect of two sets of highly diluted (HD) SNA targeting i) latent/lytic Epstein-Barr virus (SNA EBV) and ii) TNF-α and its receptor p55 involved in rheumatoid arthritis (SNA RA) on cellular models. Methodology: serial homeopathic dilutions of SNA EBV and SNA RA (15cH-18cH) were tested on a EBV-positive B-lymphoblastoid (B95-8) and on a LPS-stimulated macrophage (THP1) cell lines respectively, in comparison with agitated/diluted water and scramble DNA sequences prepared in the same conditions (negative controls). For B95-8 proliferative model, high mobility group box 1 protein (HMGB1) was used as reference. Analyzed biological parameters on B95-8 were i) cell proliferation measured after 24 and 48h of incubation with HD SNA and ii) expression of the EBV ZEBRA protein in response to TGF-β by Western-blotting (T+24h). For THP1 model, TNF-α synthesis and release were determined by RT-qPCR and ELISA (protein), after stimulation by LPS (1µg/ml) and HD SNA co-administration. Results: we demonstrated that HD SNA RA significantly down-regulated TNF-α synthesis and release. This biological activity was showed to be specific (no effect of HD scramble SNA) and related to the level of dilution (maximal effect with higher dilutions). Unexpectedly, a biological effect of agitated/diluted water was also detected in both cellular models. For B95-8 model, this effect resulted in a significant decrease of B95-8 proliferation (comparable to the HMGB1 reference) and an inhibition of ZEBRA expression. Similarly, a reproducible stimulation effect of HD water was obtained in the LPS-stimulated THP1 model. Conclusions: these findings indicate that highly diluted SNA RA can regulate TNF-α synthesis and release by LPS-stimulated THP1 and support the hypothesis that these homeopathic preparations may act in modulating mRNA expression of the targeted genes. This in vitro work underlines the potential effect of agitated water in context of cellular models for testing biological properties of HD. [1] Jenaer M, Henry MF, Garcia A, Marichal B. Evaluation of 2LHERP in preventing recurrences of genital herpes. Br Homeopath J. 2000 Oct;89(4):174-7.

Ecological assessment of the toxicity of nitrogen compounds for aquatic organisms using the Lemna minor L. Biotest

This research is motivated because of increasing eutrophication problems in water bodies. This happens as a result of excess nitrogen and phosphorus. Too many of these nutrients can cause algae to grow, leading to blooms. Harmful algal blooms consume dissolved oxygen in water. As a result, the oxygen level decreases, affecting the aquatic ecosystem. The stenobiont plant, which belongs to the group of the most sensitive bioassays, is the small duckweed Lemna minor L. This plant is sensitive to increasing levels of nutrients and blooms of algae. This research aimed to determine the level of water toxicity using the bioassay of duckweed (Lemna minor L.) to establish dangerous concentrations of nitrogen compounds (NO2-, NO3-, NH4+) (CA) for higher plants of aquatic ecosystems with subsequent risk forecast for Dnipro basin. The research was carried out in accordance with DSTU 32426-2013 “Testing of chemicals of environmental hazard. Lemna sp. Growth Inhibition. Test”. The number of effects associated with nitrogen compounds (NO2-, NO3-, NH4+) on plant growth and development during the testing period was detected. The number of green layers is the main variable that was investigated in the experiment. Changes in the morphological features of duckweed were also studied, in accordance with the standard, the toxicity of water was assessed by changes in leaf colour, manifestations of chlorosis, the transformation of whole plants into individuals, the appearance of young leaves. To estimate the number of effects associated with the nitrogen compounds toxicity, the half-maximal effect (EC50) was studied. It should be noted that studies of water toxicity on NO2- content using the Lemna minor L. test showed that even at the lowest concentration of 0.1 mgNO2-/L aquatic biota will be significantly affected by the toxicity with possible subsequent death. Summarizing the results of the research of the Lemna minor L reaction to the toxicity of water with different concentrations of NO3- came to the conclusion that even the lowest concentration (0.1 mgNO3-/L) will have a negative impact on their growth and development of the plant. Generally, 40.0 mgNO3-/L is considered “safe” for fish farming. However, this is not a case for aquatic vegetation, as shown by this result – such concentration will be toxic and cause death. If we take into account NH4+ salts, the reaction was even more progressive, the deterioration of the leaf layers of duckweed began to occur immediately from the first days of the research, and the number of damaged duckweed was 30% more on day 24 than in salts NO3-, NO2-. For algae of aquatic ecosystems the highest level of toxicity is shown by nitrogen compounds in the form of NO3-, the median concentration of EC50 (96 hours) is 7.7 mg/L. Therefore, the regulation of pollution of aquatic ecosystems by nitrogen compounds should be based primarily on the content of NO3-. To avoid the negative effects of compounds such as NH4+ and NO2- it is necessary to take into account their toxicity level: EC50 (96 hours) NH4+ – 250 mg/L, EC50 (96 hours) NO2- – 720 mg/L. From the above, the free-floating hydrophyte Lemna minor L. is a promising object of testing, as it easily absorbs all the elements and quickly shows the result. It is able to quickly accumulate harmful substances, because in the process of life, its leaves absorb absolutely all the elements that fall into the water.

Racemic ketamine as an alternative to electroconvulsive therapy for unipolar depression. A randomized, open-label, non-inferiority trial. (KetECT)

BACKGROUND Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared to electroconvulsive therapy (ECT), the most effective therapy for depression. METHODS Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT, in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale [MADRS] score ≤10). Secondary outcomes included adverse events (AEs), time to remission and relapse. Treatment sessions (maximum of twelve) were administered until remission or maximal effect was achieved. Remitters were followed for twelve months after the final treatment session. RESULTS 186 inpatients were included and received treatment. Among patients receiving ECT 63% remitted, compared to 46% receiving ketamine infusions (p=0.026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of six treatment sessions to induce remission. Distinct adverse events (2015) were associated with each treatment. Serious and long-lasting AE, including cases of persisting amnesia, were more common with ECT, while treatment emergent AE led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within twelve months in the ketamine and ECT group respectively (p=0.52). CONCLUSION Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.

The Effects of L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine on Body Mass in Type 2 Diabetes Mellitus Patients

Purpose: The study aimed to explore the effects of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine on Body Mass in type 2 diabetes mellitus (T2DM) patients.Methods: Randomized controlled trial (RCT) studies of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine in T2DM patients were searched. The change rates of Body Mass index (BMI) from baseline values were used as an evaluation indicator. The maximal effect (Emax) model by non-linear mixed-effect modeling (NONMEM) was used as the evaluation method.Results: A total of 10 RCT studies, 1239 T2DM patients were included for analysis, including eight studies of l-carnitine, one study of acetyl-l-carnitine, and one study of propionyl-l-carnitine. The study found that l-carnitine could reduce the Body Mass of T2DM patients. Based on only one study each for acetyl-l-carnitine and propionyl-l-carnitine, no significant effects were found in acetyl-l-carnitine or propionyl-l-carnitine. In addition, in order to achieve a plateau of efficacy (80% Emax), 2 g/day l-carnitine was required for at least 2 weeks.Conclusions: Two g/day l-carnitine was required for at least 2 weeks to affect Body Mass in T2DM patients, and no significant effects were found in acetyl-l-carnitine or propionyl-l-carnitine.

An Investigation into the Interaction between Double Hydroxide-Based Antioxidant Benzophenone Derivatives and Cyclooxygenase 2

Cyclooxygenases 2 (COX2) is a therapeutic target for many inflammation and oxidative stress associated diseases. A high-throughput technique, biolayer interferometry, was performed to primarily screen the potential COX2 binding activities of twelve newly synthesized double hydroxide-based benzophenone derivatives. Binding confirmation was achieved by molecular docking and multi-spectroscopy studies. Such a combined method provided a comprehensive understanding of binding mechanism and conformational changes. Compounds DB2, SC2 and YB2 showed effective COX2 binding activity and underlined the benefits of three phenolic hydroxyl groups adjacent to each other on the B ring. The twelve tested derivatives were further evaluated for antioxidant activity, wherein compound SC2 showed the highest activity. Its concentration for the 50% of maximal effect (EC50) value was approximately 1000 times greater than that of the positive controls. SC2 treatment effectively improved biochemical indicators caused by oxidative stress. Overall, compound SC2 could serve as a promising candidate for further development of a new potent COX2 inhibitor.

Colorado’s first year of extreme risk protection orders

Background Extreme Risk Protection Orders (ERPOs) are a relatively new type of law that are being considered or implemented in many states in the United States. Colorado’s law went into effect on January 1, 2020, after significant controversy and concern over potential misuse of the law to confiscate weapons; many (n = 37 of 64) counties declared themselves “2nd Amendment (2A) sanctuaries” and said they would not enforce the law. Here, reviewed the patterns of use of the law during its first year. Methods We obtained all court records for ERPO petitions filed between January 1 and December 31, 2020. Data elements were abstracted by trained staff using a standardized guide. We calculated the proportion of petitions that were approved or denied/dismissed, identified cases of obvious misuse, and examined patterns by 2A county status. Finding and results In 2020, 109 ERPO petitions were filed in Colorado; of these, 61 were granted for a temporary ERPO and 49 for a full (year-long) ERPO. Most petitions filed by law enforcement officers were granted (85%), compared to only 15% of petitions filed by family or household members. Of the 37 2A sanctuary counties, 24% had at least one petition filed, versus 48% of non-2A sanctuary counties. Across the 2A counties, there were 1.52 ERPOs filed per 100,000 population, compared to 2.05 ERPOs filed per 100,000 in non-2A counties. There were 4 cases of obvious law misuse; none of those petitions resulted in an ERPO or firearm confiscation. Conclusion State-level studies suggest ERPOs may prevent firearm injuries. Robust implementation, however, is critical for maximal effect. Understanding ERPO experiences and challenges can inform policy creation and enaction in other states, including identifying how best to address concerns and facilitate evaluation.

Quantitative prediction model for affinity of drug–target interactions based on molecular vibrations and overall system of ligand-receptor

Background The study of drug–target interactions (DTIs) affinity plays an important role in safety assessment and pharmacology. Currently, quantitative structure–activity relationship (QSAR) and molecular docking (MD) are most common methods in research of DTIs affinity. However, they often built for a specific target or several targets, and most QSAR and MD methods were based either on structure of drug molecules or on structure of receptors with low accuracy and small scope of application. How to construct quantitative prediction models with high accuracy and wide applicability remains a challenge. To this end, this paper screened molecular descriptors based on molecular vibrations and took molecule-target as a whole system to construct prediction models with high accuracy-wide applicability based on dissociation constant (Kd) and concentration for 50% of maximal effect (EC50), and to provide reference for quantifying affinity of DTIs. Results After comprehensive comparison, the results showed that RF models are optimal models to analyze and predict DTIs affinity with coefficients of determination (R2) are all greater than 0.94. Compared to the quantitative models reported in literatures, the RF models developed in this paper have higher accuracy and wide applicability. In addition, E-state molecular descriptors associated with molecular vibrations and normalized Moreau-Broto autocorrelation (G3), Moran autocorrelation (G4), transition-distribution (G7) protein descriptors are of higher importance in the quantification of DTIs. Conclusion Through screening molecular descriptors based on molecular vibrations and taking molecule-target as whole system, we obtained optimal models based on RF with more accurate-widely applicable, which indicated that selection of molecular descriptors associated with molecular vibrations and the use of molecular-target as whole system are reliable methods for improving performance of models. It can provide reference for quantifying affinity of DTIs.

Outcome uncertainty influences probability perception and risk attitudes

Subjective inferences of probability play a critical role in decision-making. How we learn about choice options, through description or experience, influences how we perceive their likelihoods, an effect known as the description–experience (DE) gap. Classically, the DE gap details how low probability described options are perceptually inflated as compared to equiprobable experience ones. However, these studies assessed probability perception relative to a ‘sure-bet’ option, and it remained unclear whether the DE gap occurs when humans directly trade-off equiprobable description and experience options and whether choice patterns are influenced by the prospects of gain and loss. We addressed these questions through two experiments where humans chose between description and experience options with equal probabilities of either winning or losing points. Contrary to early studies, we found that gain-seeking participants preferred experience options across all probability levels and, by contrast, loss-mitigating participants avoided the experience options across all probability levels, with a maximal effect at 50%. Our results suggest that the experience options were perceived as riskier than descriptive options due to the greater uncertainty associated with their outcomes. We conclude by outlining a novel theory of probabilistic inference where outcome uncertainty modulates probability perception and risk attitudes.