Microprobe Analysis in Human Pathology

This tutorial paper reviews the literature on the application of microprobe analysis to practical problems in diagnostic human pathology. The goal is to allow the reader ready access to the literature on specific clinical problems. Specimen preparation and commonly encountered artifacts are also considered. It is concluded that energy dispersive x-ray microanalysis and backscattered electron imaging are at present the most generally useful microprobe techniques for clinical work, and are no longer solely research tools. The findings often have diagnostic, therapeutic, and/or legal implications

Identification of antischistosomal leads by evaluating peroxides of beta-dicarbonyl compounds and their heteroanalogs : bridged 1,2,4,5-tetraoxanes and alphaperoxides, and beta,delta-triketones: tricyclic monoperoxides

Although antischistosomal properties of peroxides were studied in recent years, systematic structure-activity relationships have not been conducted. We evaluated the antischistosomal potential of 64 peroxides belonging to bridged 1,2,4,5-tetraoxanes, alphaperoxides and beta,delta-triketones. Thirty-nine compounds presented IC50 values > 15 microM on newly transformed schistosomula. Active drugs featured phenyl-, adamantane- or alkyl residues at the methylene bridge. Lower susceptibility was documented on adult schistosomes, with most hit compounds being tricyclic monoperoxides (IC50: 7.7-13.4 microM). A bridged 1,2,4,5-tetraoxane characterized by an adamantane residue showed the highest activity (IC50: 0.3 microM) on adult Schistosoma mansoni. Studies with hemin and heme supplemented medium indicated that antischistosomal activation of peroxides is not necessarily triggered by iron porphyrins. Two compounds (tricyclic monoperoxide; bridged 1,2,4,5-tetraoxane) revealed high worm burden reductions in the chronic (WBR: 75.4-82.8 %) but only moderate activity in the juvenile (WBR:18.9-43.1%) S. mansoni mouse model. Our results might serve as starting point for the preparation and evaluation of related derivative

Using AI/ML to predict blending performance and process sensitivity for Continuous Direct Compression (CDC)

Utilising three artificial intelligence (AI)/machine learning (ML) tools, this study explores the prediction of fill level in inclined linear blenders at steady state by mapping a wide range of bulk powder characteristics to processing parameters. Predicting fill levels enables the calculation of blade passes (strain), known from existing literature to enhance content uniformity. We present and train three AI/ML models, each demonstrating unique predictive capabilities for fill level. These models collectively identify the following rank order of feature importance: RPM, Mixing Blade Region (MB) size, Wall Friction Angle (WFA), and Feed Rate (FR). Random Forest Regression, a machine learning algorithm that constructs a multitude of decision trees at training time and outputs the mode of the classes (classification) or mean prediction (regression) of the individual trees, develops a series of individually useful decision trees. but also allows the extraction of logic and breakpoints within the data. A novel tool which utilises smart optimisation and symbolic regression to model complex systems into simple, closed-form equations, is used to build an accurate reduced-order model. Finally, an Artificial Neural Network (ANN), though less interrogable emerges as the most accurate fill level predictor, with an r2 value of 0.97. Following training on single-component mixtures, the models are tested with a four-component powdered paracetamol formulation, mimicking an existing commercial drug product. The ANN predicts the fill level of this formulation at three RPMs (250, 350 and 450) with a mean absolute error of 1.4%. Ultimately, the modelling tools showcase a framework to better understand the interaction between process and formulation. The result of this allows for a first-time-right approach for formulation development whilst gaining process understanding from fewer experiments. Resulting in the ability to approach risk during product development whilst gaining a greater holistic understanding of the processing environment of the desired formulation.</p

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Identifying dynamical modules from genetic regulatory systems: applications to the segment polarity network

BACKGROUND It is widely accepted that genetic regulatory systems are 'modular', in that the whole system is made up of smaller 'subsystems' corresponding to specific biological functions. Most attempts to identify modules in genetic regulatory systems have relied on the topology of the underlying network. However, it is the temporal activity (dynamics) of genes and proteins that corresponds to biological functions, and hence it is dynamics that we focus on here for identifying subsystems. RESULTS Using Boolean network models as an exemplar, we present a new technique to identify subsystems, based on their dynamical properties. The main part of the method depends only on the stable dynamics (attractors) of the system, thus requiring no prior knowledge of the underlying network. However, knowledge of the logical relationships between the network components can be used to describe how each subsystem is regulated. To demonstrate its applicability to genetic regulatory systems, we apply the method to a model of the Drosophila segment polarity network, providing a detailed breakdown of the system. CONCLUSION We have designed a technique for decomposing any set of discrete-state, discrete-time attractors into subsystems. Having a suitable mathematical model also allows us to describe how each subsystem is regulated and how robust each subsystem is against perturbations. However, since the subsystems are found directly from the attractors, a mathematical model or underlying network topology is not necessarily required to identify them, potentially allowing the method to be applied directly to experimental expression data

Sports Participation, Social Networks, and Sexual Violence Perpetration

Adolescent sexual violence (SV), which includes non-contact verbal sexual harassment (SH) and forced sexual contact (FSC), is a significant public health problem with long-term impacts on health and well-being. Understanding how sports participation is linked to SV can inform prevention efforts; however, the current literature is unclear about the nature of this association. Using data from 20 high schools, we investigate whether athletes in certain sports are at higher risk of SH and FSC perpetration than either other athletes or sports non-participants, and whether the risk is moderated by gender, dismissiveness of SV, or substance use intentions. We also utilize social network data to explore the role of relationships with peers and trusted adults to attenuate SH and FSC perpetration. Second, we incorporate characteristics of friends to further examine the role and composition of peer groups in the association between sports participation and perpetration of SH and FSC. Findings revealed a bivariate association between sport contact level and SH perpetration, but not FSC, and the association disappeared after adjusting for other covariates. Most prominently, dismissiveness of SV, intentions to use substances, and prior perpetration had the strongest association with perpetration regardless of sport contact level. Results also provided some support for the influence of peers and trusted adults in the sports context. Notably, the percentage of friends who perpetrated FSC and the percentage of friends who play a low-contact sport were positively associated with FSC perpetration, and the percentage of friends who play a high-contact sport was positively associated with SH perpetration. The paper concludes with a discussion of the sports context as an important venue for comprehensive prevention efforts, including a focus on changing norms around adolescent SV and substance use

Educators’ perspectives about how older hospital patients can engage in a falls prevention education programme: a qualitative process evaluation

Objectives - Falls are the most frequent adverse event reported in hospitals. Patient and staff education delivered by trained educators significantly reduced falls and injurious falls in an older rehabilitation population. The purpose of the study was to explore the educators’ perspectives of delivering the education and to conceptualise how the programme worked to prevent falls among older patients who received the education. Design - A qualitative exploratory study. Methods - Data were gathered from three sources: conducting a focus group and an interview (n=10 educators), written educator notes and reflective researcher field notes based on interactions with the educators during the primary study. The educators delivered the programme on eight rehabilitation wards for periods of between 10 and 40 weeks. They provided older patients with individualised education to engage in falls prevention and provided staff with education to support patient actions. Data were thematically analysed and presented using a conceptual framework. Results - Falls prevention education led to mutual understanding between staff and patients which assisted patients to engage in falls prevention behaviours. Mutual understanding was derived from the following observations: the educators perceived that they could facilitate an effective three-way interaction between staff actions, patient actions and the ward environment which led to behaviour change on the wards. This included engaging with staff and patients, and assisting them to reconcile differing perspectives about falls prevention behaviours. Conclusions - Individualised falls prevention education effectively provides patients who receive it with the capability and motivation to develop and undertake behavioural strategies that reduce their falls, if supported by staff and the ward environment