Forensic Assessments of Racial-Ethnic Differences in Genuine and Malingered Psychotic Presentations.

Competent forensic practice has required continued training and professional practice in differentiating between genuine and malingered presentations, especially within the spectrum of psychotic disorders. Historically, practitioners valued racial, ethnic, and cultural differences but often considered them as peripheral matters. In contemporary forensic practice, however, language and culture play preponderant roles. This commentary is focused on core features of malingering via a cultural lens. Three core, race-informed principles, such as biases against the African American Language, are highlighted and discussed. Related subjects for forensic practice include relevant clinical constructs such as malingering bias and "imposed etics," specifically, the imposition of mainstream values and discounting of cultural differences.

Quick model-based viscoelastic clot strength predictions from blood protein concentrations for cybermedical coagulation control.

Cybermedical systems that regulate patient clotting in real time with personalized blood product delivery will improve treatment outcomes. These systems will harness popular viscoelastic assays of clot strength such as thromboelastography (TEG), which help evaluate coagulation status in numerous conditions: major surgery (e.g., heart, vascular, hip fracture, and trauma); liver cirrhosis and transplants; COVID-19; ICU stays; sepsis; obstetrics; diabetes; and coagulopathies like hemophilia. But these measurements are time-consuming, and thus impractical for urgent care and automated coagulation control. Because protein concentrations in a blood sample can be measured in about five minutes, we develop personalized, phenomenological, quick, control-oriented models that predict TEG curve outputs from input blood protein concentrations, to facilitate treatment decisions based on TEG curves. Here, we accurately predict, experimentally validate, and mechanistically justify curves and parameters for common TEG assays (Functional Fibrinogen, Citrated Native, Platelet Mapping, and Rapid TEG), and verify results with trauma patient clotting data.

Sheep meat consumers in Mexico: Understanding their perceptions, habits, preferences and market segments.

Sheep meat is an essential element within the multicultural mosaic of Mexican agri-food traditions. A total of 332 consumers were surveyed face-to-face in restaurants specializing in selling traditional sheep meat products. Our results showed that consumers could be segmented based on their perceptions, habits, and preferences towards sheep meat. For consumers, sheep meat is perceived as food with unique sensory attributes, coming from healthier animals than other species and traditional characters. Their willingness to pay extra is subject to the guarantee that the meat is safe, free of hormones and antibiotics, and to a lesser extent, certified organic. The multivariate analysis suggested three clusters or consumer profiles named passive, wholehearted, and deep-rooted, which explained the associations among attitudes, some demographic variables, and consumption frequency. The nascent national sheep meat industry needs to consider these concerns in developing marketing and trust strategies to attract, maintain, and build loyalty among Mexican consumers.

Personalized modulation of coagulation factors using a thrombin dynamics model to treat trauma-induced coagulopathy.

Current trauma-induced coagulopathy resuscitation protocols use slow laboratory measurements, rules-of-thumb, and clinician gestalt to administer large volumes of uncharacterized, non-tailored blood products. These one-size-fits-all treatment approaches have high mortality. Here, we provide significant evidence that trauma patient survival 24 h after hospital admission occurs if and only if blood protein coagulation factor concentrations equilibrate at a normal value, either from inadvertent plasma-based modulation or from innate compensation. This result motivates quantitatively guiding trauma patient coagulation factor levels while accounting for protein interactions. Toward such treatment, we develop a Goal-oriented Coagulation Management (GCM) algorithm, a personalized and automated ordered sequence of operations to compute and specify coagulation factor concentrations that rectify clotting. This novel GCM algorithm also integrates new control-oriented advancements that we make in this work: an improvement of a prior thrombin dynamics model that captures the coagulation process to control, a use of rapidly-measurable concentrations to help predict patient state, and an accounting of patient-specific effects and limitations when adding coagulation factors to remedy coagulopathy. Validation of the GCM algorithm's guidance shows superior performance over clinical practice in attaining normal coagulation factor concentrations and normal clotting profiles simultaneously.

Fusarium: more than a node or a foot-shaped basal cell.

Recent publications have argued that there are potentially serious consequences for researchers in recognising distinct genera in the terminal fusarioid clade of the family Nectriaceae. Thus, an alternate hypothesis, namely a very broad concept of the genus Fusarium was proposed. In doing so, however, a significant body of data that supports distinct genera in Nectriaceae based on morphology, biology, and phylogeny is disregarded. A DNA phylogeny based on 19 orthologous protein-coding genes was presented to support a very broad concept of Fusarium at the F1 node in Nectriaceae. Here, we demonstrate that re-analyses of this dataset show that all 19 genes support the F3 node that represents Fusarium sensu stricto as defined by F. sambucinum (sexual morph synonym Gibberella pulicaris). The backbone of the phylogeny is resolved by the concatenated alignment, but only six of the 19 genes fully support the F1 node, representing the broad circumscription of Fusarium. Furthermore, a re-analysis of the concatenated dataset revealed alternate topologies in different phylogenetic algorithms, highlighting the deep divergence and unresolved placement of various Nectriaceae lineages proposed as members of Fusarium. Species of Fusarium s. str. are characterised by Gibberella sexual morphs, asexual morphs with thin- or thick-walled macroconidia that have variously shaped apical and basal cells, and trichothecene mycotoxin production, which separates them from other fusarioid genera. Here we show that the Wollenweber concept of Fusarium presently accounts for 20 segregate genera with clear-cut synapomorphic traits, and that fusarioid macroconidia represent a character that has been gained or lost multiple times throughout Nectriaceae. Thus, the very broad circumscription of Fusarium is blurry and without apparent synapomorphies, and does not include all genera with fusarium-like macroconidia, which are spread throughout Nectriaceae (e.g., Cosmosporella, Macroconia, Microcera). In this study four new genera are introduced, along with 18 new species and 16 new combinations. These names convey information about relationships, morphology, and ecological preference that would otherwise be lost in a broader definition of Fusarium. To assist users to correctly identify fusarioid genera and species, we introduce a new online identification database, Fusarioid-ID, accessible at www.fusarium.org. The database comprises partial sequences from multiple genes commonly used to identify fusarioid taxa (act1, CaM, his3, rpb1, rpb2, tef1, tub2, ITS, and LSU). In this paper, we also present a nomenclator of names that have been introduced in Fusarium up to January 2021 as well as their current status, types, and diagnostic DNA barcode data. In this study, researchers from 46 countries, representing taxonomists, plant pathologists, medical mycologists, quarantine officials, regulatory agencies, and students, strongly support the application and use of a more precisely delimited Fusarium (= Gibberella) concept to accommodate taxa from the robust monophyletic node F3 on the basis of a well-defined and unique combination of morphological and biochemical features. This F3 node includes, among others, species of the F. fujikuroi, F. incarnatum-equiseti, F. oxysporum, and F. sambucinum species complexes, but not species of Bisifusarium [F. dimerum species complex (SC)], Cyanonectria (F. buxicola SC), Geejayessia (F. staphyleae SC), Neocosmospora (F. solani SC) or Rectifusarium (F. ventricosum SC). The present study represents the first step to generating a new online monograph of Fusarium and allied fusarioid genera (www.fusarium.org).

Strongyloides Stercoralis Infection in Ethiopia: Systematic Review and Meta-analysis on Prevalence and Diagnostic Methods.

Strongyloides stercoralis is a helminthic intestinal parasite that causes the disease strongyloidiasis. Its prevalence is high in tropics and sub-tropics due to poor sanitation and hygiene. However, its true prevalence is not well known in Ethiopia as most health institutions use low sensitive diagnostic methods. This review aimed to determine the pooled prevalence of S. stercoralis at country, and regional state levels. Papers published on S. stercoralis in Ethiopia from 2010 to 2020 were collected from PubMed, Google Scholar and Science direct databases and Addis Ababa repository. Identification, screening, checking the eligibility, and inclusion of the relevant literatures were done. Articles with S. stercoralis positive results from Ethiopian populations were included. Articles which focused on Strongyloides infection in foreigners, and other than stool samples were excluded. The pooled prevalence of S. stercoralis and heterogeneity between studies and across regions were computed. From the 43 articles, the overall prevalence of S. stercoralis in Ethiopia was 1.82 %. Across regions, relatively high prevalence of S. stercoralis (8.78 %) was recorded in Addis Ababa city. High prevalence of S. stercoralis was found to be 44.02 % with a combination of formol ether concentration, Baermann concentration, and molecular methods. Low prevalence of 0.26 %, 0.31 %, and 1.20 % was evidenced respectively with Kato-Katz, direct saline microscopy, and formol ether concentration methods. Using random effect analysis, the pooled prevalence of S. stercoralis in Ethiopia, across regions and across diagnostic methods was 2.1 % (95 %CI: 1.20 - 3.60), 2.6 % (95 %CI: 0.80 - 8.20) and 3.7 % (95 %CI: 1.10 - 11.70), respectively. The heterogeneity was high (P<0.001). This review revealed that Strongyloides infection is probably underreported and its prevalence could be higher than the reported in Ethiopia. Therefore, a revision of the best combination of diagnostic methods could be advisable as it gives better diagnostic results in routine diagnosis of Strongyloides infection in Ethiopia.

Perceptions of people with intellectual and developmental disabilities about COVID-19 in Spain: a cross-sectional study.

BACKGROUND: As the world battles COVID-19, there is a need to study the perceptions of people with intellectual and developmental disabilities (IDD) about the effects of the pandemic and associated lockdown on their lives. This work explores the perceptions of Spaniards with IDD during the lockdown with respect to four topics: access to information, emotional experiences, effects on living conditions and access to support. METHODS: The topics were explored using a subset of 16 closed-ended questions from an online survey. In total, 582 participants with IDD completed the survey. The frequencies and percentages of responses to the questions were calculated, and chi-square tests performed to explore the relationship between participants' sociodemographic characteristics and responses. Given that people differed in the way in which they completed the survey, the relationship between participants' responses and completion method was also analysed. RESULTS: Participants reported that the pandemic and subsequent lockdown have had a deleterious effect on their emotional well-being (around 60.0% of participants) and occupations (48.0% of students and 72.7% of workers). Although access to information and support was reportedly good overall, being under the age of 21 years and studying were associated with perceptions reflecting poorer access to information (V = .20 and V = .13, respectively) and well-being support (V = .15 and V = .13, respectively). Being supported by a third party to complete the survey was consistently related to perceptions of worse outcomes. CONCLUSIONS: The study yielded data on the perceptions of people with IDD regarding the effects that COVID-19 and the subsequent lockdown have had on their lives. Suggestions on how to overcome the difficulties reported and future lines of research are discussed.

Making change last? Exploring the value of sustainability approaches in healthcare: a scoping review.

BACKGROUND: Numerous models, tools and frameworks have been produced to improve the sustainability of evidence-based interventions. Due to the vast number available, choosing the most appropriate one is increasingly difficult for researchers and practitioners. To understand the value of such approaches, evidence warranting their use is needed. However, there is limited understanding of how sustainability approaches have been used and how they have impacted research or practice. This review aims to consolidate evidence on the application and impact of sustainability approaches in healthcare settings. METHODS: A systematic scoping review was designed to search for peer-reviewed publications detailing the use of sustainability approaches in practice. A 5-stage framework for scoping reviews directed the search strategy, and quality assessment was performed using the Mixed Method Appraisal Tool. Searches were performed through electronic citation tracking and snowballing of references. Articles were obtained through Web of Science, PubMed and Google Scholar. Six outcome variables for sustainability were explored to ascertain impact of approaches. RESULTS: This review includes 68 articles demonstrating the application of sustainability approaches in practice. Results show an increase in the use of sustainability approaches in peer-reviewed studies. Approaches have been applied across a range of healthcare settings, including primary, secondary, tertiary and community healthcare. Approaches are used for five main purposes, namely analysis, evaluation, guidance, assessment and planning. Results outline benefits (e.g. improved conceptualisation of sustainability constructs and improved ability to interpret sustainability data) and challenges (e.g. issues with approach constructs and difficulty in application) associated with using a sustainability approach in practice. Few articles (14/68) reported the sustainability outcome variables explored; therefore, the impact of approaches on sustainability remains unclear. Additional sustainability outcome variables reported in retrieved articles are discussed. CONCLUSIONS: This review provides practitioners and researchers with a consolidated evidence base on sustainability approaches. Findings highlight the remaining gaps in the literature and emphasise the need for improved rigour and reporting of sustainability approaches in research studies. To guide future assessment and study of sustainability in healthcare settings an updated list of sustainability outcome variables is proposed. TRIAL REGISTRATION: This review was registered on the PROSPERO database CRD 42016040081 in June 2016.

Steno type 1 risk engine and preclinical atherosclerosis in Mediterranean individuals with type 1 diabetes.

BACKGROUND AND AIMS: Tools to detect type 1 diabetes (T1D) individuals at overt cardiovascular disease (CVD) risk are scarce. We aimed to assess the usefulness of the score 'Steno Type 1 Risk Engine' (Steno-Risk) to identify T1D patients with advanced carotid atherosclerosis. MATERIAL AND METHODS: T1D patients without CVD with at least one of the following were included: ≥40 years, diabetic nephropathy, or diabetes duration ≥10 years with ≥1 CVD risk factor. Intima-media thickness (IMT) and plaque presence (IMT ≥1.5 mm) were assessed by standardized B-mode ultrasonography. Steno-Risk was used to estimate 10-year risk (<10% low; 10%-20% moderate; ≥20% high risk). Associations between Steno-Risk and preclinical atherosclerosis were assessed after adjusting for other CVD risk factors. RESULTS: We evaluated 302 patients (55% men, age 47.8 ± 9.8 years, T1D duration 26.3 ± 9.3 years). The prevalence of carotid plaque and ≥2 plaques were 36.4% and 19.2%, respectively; without sex differences. Age (57.4 ± 7.4 vs 37.1 ± 6.2 years), T1D duration (31.3 ± 10.4 vs 21.5 ± 7.1 years), hypertension (52.3% vs 6.3%), nephropathy (25.6% vs 5.1%) and retinopathy (53.5% vs 32.9%) were higher in high-risk (n = 86) vs low-risk participants (n = 79; P < .001 for all). Preclinical atherosclerosis (IMT and plaque) increased in parallel with Steno-Risk (P < .001). In logistic regression analysis, both age ≥40 years and Steno-Risk ≥20% were associated with the presence of plaque (OR 4.22 [1.57-11.36] and 3.79 [1.61-6.80]; respectively), but only high Steno-Risk remained independently associated with ≥2 plaques (OR 3.31 [1.61-6.80]). CONCLUSION: Steno-Risk is independently associated with preclinical atherosclerosis. Further studies are needed to ascertain its usefulness in this high-risk population.

Malingering and Defensiveness on the Spanish Personality Assessment Inventory: An Initial Investigation with Mostly Spanish-Speaking Outpatients.

Psychological assessments can be essentially invalidated by examinees' intentional response styles, such as feigning (i.e., fabrication or marked overreporting of symptoms/impairment) and defensiveness (i.e., denial or minimization of symptoms/impairment). As a psychometric strength, the Personality Assessment Inventory (PAI) has established validity indicators for identifying both response styles. With the United States' increasing ethnic and cultural diversity, predominantly Spanish-speaking individuals are now estimated in the range of 15 million persons. Unfortunately, very little research has been conducted on the Spanish-translated PAI regarding its effectiveness in clinical populations. Using a between-subjects design, a sample of mostly Spanish-speaking outpatients was randomly assigned to genuine, feigning, or defensive conditions. For feigning, PAI malingering indicators using rare symptoms strategies (i.e., Negative Impression [NIM] and Negative Distortion [NDS] scales) demonstrated moderate to large effect sizes. For defensiveness, the Defensive (DEF) index proved the most effective with a very large effect size (M = 1.68). Different cut scores were examined to increase the clinical utility of the Spanish PAI for determining response styles.

[Current limits of the long duration rhythmic holter: A real life study]. / Limites actuelles du holter rythmique de longue durée : une étude vie réelle.

BACKGROUND: Syncope or stroke remain frequently without any explained diagnosis. Long duration holter ECG is an available tool to diagnose arrhythmias. However, this tool is subject to availability of the recorders. AIM: Report a single center experience with long duration holter ECG in clinical practice, in the different cardiology and neurology indications, and to assess the different delays until achievement of a diagnosis. METHODS AND RESULTS: The device (Sorin Spiderflash) was used for 48 patients between January 2018 and June 2018. The holter was applied for a mean duration of 10±4days. The mean age was 55+19 years-old. 20 patients (42%) were explored for a stroke or transient ischemic attack (TIA), 18 (36%) for palpitations, 6 (12%) for syncope and 4 (8%) for evaluation of arrhythmias management. An abnormality has been recorded in 11 (22%) patients and a treatment has been administered in 5 patients (10%). Regarding, the timing of the exam, the mean time between the index event and the indication was 39 days. The mean time between the indication and the availability of the device was 32 days. 16 Days was the mean time for lecture and 23 days was the mean time between the result and the appointment with the cardiologist and neurologist. CONCLUSION: In this registry, the management of patients by non-invasive long duration holter ECG monitoring may be improved regarding the timing of the exams, their lecture and new appointments with the physicians.

Assessing support needs in children with intellectual disability and motor impairments: measurement invariance and group differences.

BACKGROUND: This study assessed the equivalence of the measurement of support needs between children with intellectual disability (ID) and children with intellectual and motor disabilities (IMD) and compared both groups in the different domains of support. METHOD: The Supports Intensity Scale-Children's Version was used to assess the support needs of 713 children with ID and 286 children with IMD, mainly associated with cerebral palsy. RESULTS: The results supported measurement invariance between the group of ID and IMD, which allowed to conduct comparison between them. Children with IMD scored higher on support needs than did children without IMD, suggesting that children with IMD needed more support than their peers without motor impairments. Furthermore, the ID levels interacted with motor impairments: at the highest levels of ID, groups tended to be similar in support needs, with high scores and low variability. The greatest differences were found in the domains of Home and Community activities. CONCLUSIONS: This study points to the across-condition of the construct of support needs in populations with intellectual and developmental disabilities. However, additional mobility impairments should be considered during the evaluation and planning of systems of support. In this regard, the Supports Intensity Scale-Children's Version might have limitations when discriminating between samples with high support needs.

Livestock hauliers' attitudes, knowledge and current practices towards animal welfare, occupational wellbeing and transport risk factors: A Mexican survey.

Mexico is the 7th largest producer of beef in the world. The livestock transport is a vital component of today's world agrifood economy that directly impacts on the development of animal production, animal welfare, public policies, labor regulations, food safety, markets and consumers. In this study two aims were established; the first aim was to identify the attitudes and perceptions of commercial hauliers towards animal welfare and their influence on the accident risks. The second aim was to characterize the current practices of the commercial cattle transport in Mexico and to detect the risk factors for animal welfare and hauliers' wellbeing. The interviews were conducted individually at the hauliers' rest points, sanitary inspection points localized along the Federal Highway 57 or at the companies' offices of cattle transportation. We used univariate, bivariate and multivariate statistics based on a hierarchical cluster analysis. The results showed that cattle transport in Mexico is characterized for long travel distances because the cattle departed from farms in the southern states of Mexico to the feedlots located in central and northern regions of the country. The journeys of short and middle distances departed from the feedlots to the slaughterhouses. The hauliers' characteristics were: age from 29 to 48 years-old, elementary or secondary studies completed, 65% of hauliers mentioned six years of experience in cattle transport, they learned about cattle transportation by means of a family member who was already engaged in this activity. The cluster analysis identified four hauliers' groups: groups 1 and 3 were related to animal welfare and groups 2 and 4 less related to animal welfare. This study showed that empathy towards cattle was a key element in identifying hauliers at risk of road accidents during cattle transportation. Years of experience in cattle transport played an important role in emphasizing closer perceptions towards welfare. Considering current trends towards increased transport times and logistics stops, there is a need to develop systems of welfare assessment and decision-making that provide tools and protocols that can minimize the biological cost to animals and hauliers, which may have been underestimated in the past.

Guía de la enfermedad de Wilson

Contiene: ¿Qué es la Enfermedad de Wilson?, ¿cuál es la causa?, ¿a cuántas personas afecta?, ¿qué síntomas tiene?, ¿quién le atenderá?, ¿cómo se diagnóstica?, ¿cuál es el tratamiento?, ¿cómo afecta este tratamiento a la calidad de vida?, ¿por qué se debe llevar una dieta?, ¿cómo seguir informado?.

Long-distance transport of hair lambs: effect of location in pot-belly trailers on thermo-physiology, welfare and meat quality.

Livestock transport exposes animals to a range of potential stressors that may compromise their welfare and final product quality, and those effects typically increase with the distance travelled. In North America, producers often use pot-belly vehicles for long hauls but little is known about their suitability for transporting lambs. We followed two long-distance trips using pot-belly trailers carrying 500 lambs (each) from Northern to Central Mexico in winter, to measure possible effects on animal welfare and meat quality. Sixty lambs per trip were placed at different locations within the pot-belly trailer. Animals were equipped with iButton Thermochron® temperature devices, which registered body temperature throughout pre- and post-slaughter stages. Despite the rather cool winter conditions, lambs placed in the "belly" and "nose" compartments had higher body temperatures at loading, during transport and lairage and after slaughter (carcass temperature). Those lambs also had higher levels of plasma cortisol, glucose and creatine kinase (CK), and a higher neutrophil/lymphocyte ratio. Regarding meat quality, ultimate pH (24 h) was higher in all locations, especially in LT4 location. Overall, the results suggest a link between thermal stress during transport, elevated physiological indicators of stress and poorer meat quality.

Targeted clinical control of trauma patient coagulation through a thrombin dynamics model.

We present a methodology for personalizing the clinical treatment of severely injured patients with acute traumatic coagulopathy (ATC), an endogenous biological response of impaired coagulation that occurs early after trauma and shock and that is associated with increased bleeding, morbidity, and mortality. Despite biological characterization of ATC, it is not easily or rapidly diagnosed, not always captured by slow laboratory testing, and not accurately represented by coagulation models. This lack of knowledge, combined with the inherent time pressures of trauma treatment, forces surgeons to treat ATC patients according to empirical resuscitation protocols. These entail transfusing large volumes of poorly characterized, nontargeted blood products that are not tailored to an individual, the injury, or coagulation dynamics. Massive transfusion mortality remains at 40 to 70% in the best of trauma centers. As an alternative to blunt treatments, time-consuming tests, and mechanistic models, we used dynamical systems theory to create a simple, biologically meaningful, and highly accurate model that (i) quickly forecasts a driver of downstream coagulation, thrombin concentration after tissue factor stimulation, using rapidly measurable concentrations of blood protein factors and (ii) determines the amounts of additional coagulation factors needed to rectify the predicted thrombin dynamics and potentially remedy ATC. We successfully demonstrate in vitro thrombin control consistent with the model. Compared to another model, we decreased the mean errors in two key trauma patient parameters: peak thrombin concentration after tissue factor stimulation and the time until this peak occurs. Our methodology helps to advance individualized resuscitation of trauma-induced coagulation deficits.

Mexican consumers' perceptions and attitudes towards farm animal welfare and willingness to pay for welfare friendly meat products.

Increasing concerns about farm animal welfare have led to an increase in the availability of welfare-friendly-products (WFP), but little is known about how much more consumers are willing-to-pay (WTP) for WFP or about their buying trends in Latin America. In this study, a survey was given to 843 meat consumers in the city of Toluca, Mexico. The results show that consumers were interested in farm animal welfare issues and their ethical, sociological and economic implications, as in Europe. The people surveyed also conveyed a high level of empathy with animal feelings and emotions, however they clearly demanded more information and regulations related to farm animal welfare. The majority of respondents expressed that they were WTP more for properly certified WFP, but mostly based on the benefits in terms of product quality and human health. If the demand for WFP begins to increase in Mexico, the supply chain should consider a certification system to guarantee product origin based on current conditions.

Conventional versus modern abattoirs in Colombia: Impacts on welfare indicators and risk factors for high muscle pH in commercial Zebu young bulls.

The aim of the study was to determine the effects of abattoir type (conventional abattoir -CA- versus modern abattoir -MA-) on stress parameters and risk factors for high muscle pH in Colombia. A total of 522 Zebu young bulls were studied in two groups: 285 at CA, and 237 at MA. Blood samples were taken to measure cortisol, glucose, lactate, creatine kinase, ß-hydroxybutyrate, total protein, albumin, creatinine, urea, haematocrit, leukocytes and N/L ratio. Cattle were monitored during the unloading, lairage, handling and stunning. The logistic regression model showed that stocking density, transport time, abattoir type, and inefficient stunning were variables associated with the prevalence of dark cutting carcasses. This study demonstrated that modern improvements at abattoir level, proper infrastructure, and stunning equipment, do not always guarantee quality in terms of animal welfare. As a first attempt in the Colombian beef industry, this research suggested how handling practices could affect cattle welfare and the prevalence of high muscle pH even at MA.

Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR).

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer's disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via π-π interactions and (c) possible CH/π interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme.

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives.

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5µM for EeAChE and 153.8µM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4µM (EeAChE) and 277.8µM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.