Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.
The Moderating Roles of Psychological Flexibility and Inflexibility on the Mental Health Impacts of COVID-19 Pandemic and Lockdown in Italy. Preliminary data suggest the COVID-19 pandemic has adverse effects on mental health in approximately a quarter of the general population. Few prior studies have identified contextual risk factors and no published study has explored factors that might moderate their adverse effects on mental health. Psychological flexibility is the cornerstone of psychological health and resiliency. This study investigated the roles of psychological flexibility and inflexibility in moderating the effects of COVID-19 risk factors on three mental health outcomes: COVID-19 peritraumatic distress, anxiety, depression. We hypothesized that psychological flexibility would mitigate and psychological inflexibility would exacerbate the adverse effects of COVID-19 risk factors on mental health. During the Italian national lockdown ( M = 39.29 days, SD = 11.26), 1035 adults (79% female, M = 37.5 years, SD = 12.3) completed an online survey. Twelve COVID-19 risk factors were identified (e.g. lockdown duration, family infected by COVID-19, increase in domestic violence and in unhealthy lifestyle behaviours) and constituted a COVID-19 Lockdown Index. As predicted, results showed that after controlling for sociodemographic variables, global psychological flexibility and four of its sub-processes (self-as context, defusion, values, committed action), mitigated the detrimental impacts of COVID-19 risk factors on mental health. In contrast and as expected, global psychological inflexibility and four of its sub-processes (lack of contact with present moment, fusion, self-as-content, lack of contact with personal values) exacerbated the detrimental impacts of COVID-19 risk factors on mental health. Findings converge with those from the broader psychological flexibility literature providing robust support for the use of ACT-based interventions to promote psychological flexibility and mental health during the COVID-19 pandemic.
The inexorable increase of antibiotic resistance occurring in different bacterial species is increasing the interest in developing new antimicrobial treatments that will be equally effective against multidrug-resistant strains and will not themselves induce resistance. One of these alternatives may be photodynamic inactivation (PDI), which uses a combination of nontoxic dyes, called photosensitizers (PS), excited by harmless visible light to generate reactive oxygen species (ROS) by type 1 (radical) and type 2 (singlet oxygen) pathways. In this study, we asked whether it was possible to improve the efficacy of PDI in vitro and in vivo by addition of the inert salt potassium iodide (KI) to a commonly investigated PS, the phenothiazinium dye methylene blue (MB). By adding KI, we observed a consistent increase of red light-mediated bacterial killing of Gram-positive and Gram-negative species in vitro and in vivo. In vivo, we also observed less bacterial recurrence in wounds in the days posttreatment. The mechanism of action is probably due to formation of reactive iodine species that are produced quickly with a short lifetime. This finding may have a relevant clinical impact by reducing the risk of amputation and, in some cases, the risk of death, leading to improvement in the care of patients affected by localized infections.
The COVID-19 emergency has severely affected the Italian population. During a pandemic, those with high health anxiety are at risk of adverse mental health outcomes, including peritraumatic distress and mood disturbance. No prior research has explored the role of psychological flexibility in protecting people at high risk of poorer mental health impacts due to health anxiety during a pandemic. Psychological flexibility is the cornerstone of psychological health and resiliency. According to acceptance and commitment therapy (ACT), it involves behaving consistently with one’s chosen values even in the presence of emotional and mental discomfort. This study examined the mediating and moderating roles of psychological flexibility in the link between trait health anxiety and three mental health outcomes: COVID-19 peritraumatic distress, anxiety, and depression. We hypothesized that higher psychological flexibility would decrease the negative impacts of trait health anxiety on mental health outcomes. During the mandatory national lockdown ( M = 35.70 days, SD = 8.41), 944 Italian adults (75.5% female, M = 38.86 years, SD = 13.20) completed an online survey consisting of standardized measures of psychological flexibility, trait health anxiety, COVID-19 distress, anxiety, and depression. Results indicated that psychological flexibility did not moderate the link between trait health anxiety and mental health outcomes. Rather, greater psychological flexibility mediated decreases in the adverse effects of trait health anxiety on COVID-19 distress, anxiety, and depression. In particular, two psychological flexibility processes, observing unhelpful thoughts rather than taking them literally (defusion) and values-based action (committed action), mediated decreases in the negative effects of trait health anxiety on all mental health outcomes. In contrast, the psychological flexibility process acceptance, which involves openness to inner discomfort, mediated increases in negative mental health outcomes. Overall, the combination of these processes mitigated the detrimental impacts of trait health anxiety on mental health during the emergency mandatory COVID-19 nationwide lockdown. Consistent with the ACT conceptualization of psychological flexibility, findings suggest embracing (rather than avoiding) inner discomfort and observing associated unhelpful thoughts, while also engaging in values-based action, increases resilience during adversity. Evidenced-based large-scale online public health interventions that target psychological flexibility in those experiencing health anxiety in the context of a pandemic are urgently needed. Many empirically-based ACT interventions are suited for this purpose.
Deriving disease subtypes from electronic health records (EHRs) can guide next-generation personalized medicine. However, challenges in summarizing and representing patient data prevent widespread practice of scalable EHR-based stratification analysis. Here we present an unsupervised framework based on deep learning to process heterogeneous EHRs and derive patient representations that can efficiently and effectively enable patient stratification at scale. We considered EHRs of 1,608,741 patients from a diverse hospital cohort comprising a total of 57,464 clinical concepts. We introduce a representation learning model based on word embeddings, convolutional neural networks, and autoencoders (i.e., ConvAE) to transform patient trajectories into lowdimensional latent vectors. We evaluated these representations as broadly enabling patient stratification by applying hierarchical clustering to different multi-disease and disease-specific patient cohorts. ConvAE significantly outperformed several baselines in a clustering task to identify patients with different complex conditions, with 2.61 entropy and 0.31 purity average scores. When applied to stratify patients within a certain condition, ConvAE led to various clinically relevant subtypes for different disorders, including type 2 diabetes, Parkinson's disease, and Alzheimer's disease, largely related to comorbidities, disease progression, and symptom severity. With these results, we demonstrate that ConvAE can generate patient representations that lead to clinically meaningful insights. This scalable framework can help better understand varying etiologies in heterogeneous sub-populations and unlock patterns for EHR-based research in the realm of personalized medicine.
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1–3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1–TbPTR1 and Leishmania major–LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.
Antimicrobial photodynamic inactivation (APDI) using phenothiazinium dyes is mediated by reactive oxygen species consisting of a combination of singlet oxygen (quenched by azide), hydroxyl radicals and other reactive oxygen species. We recently showed that addition of sodium azide paradoxically potentiated APDI of Gram-positive and Gram-negative bacteria using methylene blue as the photosensitizer, and this was due to electron transfer to the dye triplet state from azide anion, producing azidyl radical. Here we compare this effect using six different homologous phenothiazinium dyes: methylene blue, toluidine blue O, new methylene blue, dimethylmethylene blue, azure A, and azure B. We found both significant potentiation (up to 2 logs) and also significant inhibition (>3 logs) of killing by adding 10 mM azide depending on Gram classification, washing the dye from the cells, and dye structure. Killing of E. coli was potentiated with all 6 dyes after a wash, while S. aureus killing was only potentiated by MB and TBO with a wash and DMMB with no wash. More lipophilic dyes (higher log P value, such as DMMB) were more likely to show potentiation. We conclude that the Type I photochemical mechanism (potentiation with azide) likely depends on the microenvironment, i.e. higher binding of dye to bacteria. Bacterial dye-binding is thought to be higher with Gram-negative compared to Gram-positive bacteria, when unbound dye has been washed away, and with more lipophilic dyes.
To highlight the revolving door (RD) phenomenon in an acute psychiatric ward, we retrospectively identified the patients hospitalized three or more times in a calendar year from 1/1/2009 to 31/12/2013 as RD patients (RDP). We collected sociodemographic and clinical variables of RDP and statistically analyzed the potential RD risk factors. We divided RDP into "high" and "extremely high" utilizers and evaluated the variables related to more frequent readmissions. RDP represented 5.68% of all patients and their hospitalizations (RDH) 25% of all admissions. The statistically significant risk factors for all RDH were "disability pension," "substance abuse/dependence," "mild/severe aggressiveness," and "psychiatric and social rehabilitative programs". The comparison between "high" and "extremely high" utilizers showed that "manic episodes" and "personality disorders," among the diagnoses, "familial relational conflicts" and "violence/suicidality", among the hospitalization reasons, were statistically significant risk factors for more frequent readmissions. RD phenomenon was greatly affected by severe clinical conditions with social disability.
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