Agronomical valorization of eluates from the industrial production of microorganisms: Chemical, microbiological, and ecotoxicological assessment of a novel putative biostimulant

Plant Biostimulants (BSs) are a valid supplement to be considered for the integration of conventional fertilization practices. Research in the BS field keeps providing alternative products of various origin, which can be employed in organic and conventional agriculture. In this study, we investigated the biostimulant activity of the eluate obtained as a by-product from the industrial production of lactic acid bacteria on bare agricultural soil. Eluates utilization is in line with the circular economy principle, creating economical value for an industrial waste product. The research focused on the study of physical, chemical, biochemical, and microbiological changes occurring in agricultural soil treated with the biowaste eluate, applied at three different dosages. The final aim was to demonstrate if, and to what extent, the application of the eluate improved soil quality parameters and enhanced the presence of beneficial soil-borne microbial communities. Results indicate that a single application at the two lower dosages does not have a pronounced effect on the soil chemical parameters tested, and neither on the biochemical proprieties. Only the higher dosage applied reported an improvement in the enzymatic activities of β-glucosidase and urease and in the chemical composition, showing a higher content of total, nitric and ammonia N, total K, and higher humification rate. On the other hand, microbial communities were strongly influenced at all dosages, showing a decrease in the bacterial biodiversity and an increase in the fungal biodiversity. Bioinformatic analysis revealed that some Operative Taxonomic Units (OTUs) promoted by the eluate application, belong to known plant growth promoting microbes. Some other OTUs, negatively influenced were attributed to known plant pathogens, mainly Fusarium spp. Finally, the ecotoxicological parameters were also determined and allowed to establish that no toxic effect occurred upon eluate applications onto soil

LABs Fermentation Side-Product Positively Influences Rhizosphere and Plant Growth in Greenhouse Lettuce and Tomatoes

New agronomical policies aim to achieve greener agricultural systems, sustainable fertilizers and fungicides, a reduction in Greenhouse gases (GHG), and an increase in circular economic models. In this context, new solutions are needed for the market, but it is necessary to carefully assess both their efficacy and their ecological impact. Previously, we reported the biostimulatory activity on soil microbiome for a side-product from Lactic Acid Bacteria (LABs) fermentation: a concentrated post-centrifugation eluate. In the present study, we investigated whether this solution could partially substitute mineral N (N70% + N30% from eluate) in a fertigation (N100% vs. N70%) regime for tomato and lettuce under greenhouse conditions. The impact of the application was investigated through plant physiological parameters (number and weight of ripened fruits, shoots, and roots biomass) and biodiversity of the rhizosphere microbial composition of bacteria and fungi (High-Throughput Sequencing-HTS). The eluate (i) enhanced the plant canopy in lettuce; (ii) increased the shoot/root biomass ratio in both tomato and lettuce; and (iii) increased the harvest and delayed fruit ripening in tomato. Moreover, we found a strong correlation between the eluate and the enrichment for OTUs of plant-growth-promoting microbes (PGPMs) such as Sphingomonas sediminicola, Knoellia subterranean, and Funneliformis mosseae. These findings suggest that integrating the eluate was beneficial for the plant growth, performance, and yield in both tomato and lettuce, and additionally, it enriched specialized functional microbial communities in the rhizosphere. Further studies will investigate the underlying mechanisms regulating the selective activity of the eluate toward PGPMs and its biostimulatory activity towards target crops

Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Viral Nanotemplates Armed with Oxygenic Polyoxometalates for Hydrogen Peroxide Detoxification

Layer-by-layer (LbL) assembly strategies were exploited to decorate wild-type TMV (tobacco mosaic virus) 1D nanoscaffolds with a totally inorganic, multiredox, tetraruthenate complex belonging to the class of polyoxometalate catalysts. The hybrid capsids give rise to an entangled network of fibrils and ribbon-like nanoassemblies, whose functional activity was probed towards H2O2 dismutation in neutral water. Combined solid-state and surface characterization evidence, including Z-potential, electronic microscopy, thermogravimetry and XPS, delineate a favorable tunability of the nanohybrid material as a function of the added cationic binder. A polyoxometalate with oxygenic activity was anchored on the TMV (tobacco mosaic virus). The rod-like biogenic template enables the formation of catalytic nanoarrays for H2O2 dismutation

Tolerability and efficacy of vortioxetine versus SSRIs in elderly with major depression. Study protocol of the VESPA study: a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial

Introduction: Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on studies to date, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after 6 months of follow up will be the primary outcome. Methods and analysis: This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow up. At each time point, the following validated rating scales will be administered: Montgomery-\uc5sberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. Ethics and dissemination: This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants' data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. Trial registration: Clinicaltrials.gov: NCT03779789, Registered on 19 December 2018. Submitted on 19 December. EudraCT number: 2018-001444-66. Trial status: Protocol version 1.5; 09/06/2018. Recruitment started In February 2019 and it is ongoing. It is expected to end approximately on 30 September 2021

Moderators of remission with interpersonal counselling or drug treatment in primary care patients with depression: Randomised controlled trial

Background: Despite depressive disorders being very common there has been little research to guide primary care physicians on the choice of treatment for patients with mild to moderate depression. Aims: To evaluate the efficacy of interpersonal counselling compared with selective serotonin reuptake inhibitors (SSRIs), in primary care attenders with major depression and to identify moderators of treatment outcome. Method: A randomised controlled trial in nine centres (DEPICS, Australian New Zealand Clinical Trials Registry number: ACTRN12608000479303). The primary outcome was remission of the depressive episode (defined as a Hamilton Rating Scale for Depression score 647 at 2 months). Daily functioning was assessed using the Work and Social Adjustment Scale. Logistic regression models were used to identify moderators of treatment outcome. Results: The percentage of patients who achieved remission at 2 months was significantly higher in the interpersonal counselling group compared with the SSRI group (58.7% v. 45.1%, P = 0.021). Five moderators of treatment outcome were found: depression severity, functional impairment, anxiety comorbidity, previous depressive episodes and smoking habit. Conclusions: We identified some patient characteristics predicting a differential outcome with pharmacological and psychological interventions. Should our results be confirmed in future studies, these characteristics will help clinicians to define criteria for first-line treatment of depression targeted to patients' characteristics