Artificial intelligence for dementia drug discovery and trials optimization

Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinical trial design has the potential to accelerate progress. Opportunities arise at multiple stages in the therapy pipeline and the growing availability of large medical data sets opens possibilities for big data analyses to answer key questions in clinical and therapeutic challenges. However, before this goal is reached, several challenges need to be overcome and only a multi-disciplinary approach can promote data-driven decision-making to its full potential. Herein we review the current state of machine learning applications to clinical trial design and drug discovery, while presenting opportunities and recommendations that can break down the barriers to implementation

Artificial intelligence for dementia drug discovery and trials optimization

Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinical trial design has the potential to accelerate progress. Opportunities arise at multiple stages in the therapy pipeline and the growing availability of large medical data sets opens possibilities for big data analyses to answer key questions in clinical and therapeutic challenges. However, before this goal is reached, several challenges need to be overcome and only a multi-disciplinary approach can promote data-driven decision-making to its full potential. Herein we review the current state of machine learning applications to clinical trial design and drug discovery, while presenting opportunities and recommendations that can break down the barriers to implementation

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) Tool

Objectives: Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. Design: Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. Setting: Fifty care homes in England. Participants: Residents (N = 726) with dementia. Measurements: Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. Results: The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer’s disease (β = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). Conclusions: The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia

Partial cold treatment of citrus fruit for export risk mitigation for Thaumatotibia leucotreta (Lepidoptera: Tortricidae) as part of a systems approach

Some of South Africa’s citrus export markets require mandatory postharvest cold treatment of citrus fruit as a phytosanitary risk mitigation treatment for Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae). An alternative to this may be partial cold treatment as one of the final steps in a systems approach to mitigate phytosanitary risk. Consequently, the efficacy of such partial cold treatments was evaluated. It was first determined that a 2C cold treatment was significantly more effective against fourth and fifth instars (the most cold-tolerant instars) than treatments at 3C and 4C for a duration of 18 d. Secondly, it was determined that 2C for 18 d and 1C for 16 d were similarly effective, but both treatments were significantly more effective than 1C for 14 d. Mean mortality of fourth and fifth instars treated with 2C for 18 d in seven replicates from four trials was 99.94%. Finally, it was determined that the inability of the majority of surviving larvae to develop to adulthood would further increase the efficacy of a 2C for 18 d treatment to 99.96%. Inclusion of reproductive nonviability of survivors increased mortality to 99.99%

‘Equally unequal or unequally equal’: Adopting a substantive equality approach to gender discrimination in Nigeria

The purpose of this article is to critically assess the approach of Nigerian courts to interpreting section 42 of the Constitution. This article argues that Nigerian courts are yet to develop a substantive equality approach to interpreting section 42 of the Constitution. Rather, the courts have tended to adopt the formal equality approach to interpreting the section. Analysing some decisions of the Court of Appeal and the Supreme Court, the article argues that in order to safeguard women’s rights and address gender inequality in the country, Nigerian courts should lean towards substantive equality approach to the interpretation of section 42 of the Constitution. This is not only consistent with Nigeria’s obligations under international law but also crucial to addressing historical imbalances between men and women in the country

Eicosapentaenoic acid influences the pathogenesis of Candida albicans in Caenorhabditis elegans via inhibition of hyphal formation and stimulation of the host immune response

DATA AVAILABILITY : All data generated during this study are included in this article and supplementary data.The intake of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), is associated with health benefits due to its anti-inflammatory properties. This fatty acid also exhibits antifungal properties in vitro. In order to determine if this antifungal property is valid in vivo, we examined how EPA affects Candida albicans pathogenesis in the Caenorhabditis elegans infection model, an alternative to mammalian host models. The nematodes were supplemented with EPA prior to infection, and the influence of EPA on C. elegans lipid metabolism, survival and immune response was studied. In addition, the influence of EPA on hyphal formation in C. albicans was investigated. It was discovered that EPA supplementation changed the lipid composition, but not the unsaturation index of C. elegans by regulating genes involved in fatty acid and eicosanoid production. EPA supplementation also delayed killing of C. elegans by C. albicans due to the inhibition of hyphal formation in vivo, via the action of the eicosanoid metabolite of EPA, 17,18-epoxyeicosatetraenoic acid. Moreover, EPA supplementation also caused differential expression of biofilm-related gene expression in C. albicans and stimulated the immune response of C. elegans. This provides a link between EPA and host susceptibility to microbial infection in this model.The National Research Foundation (NRF) of South Africa. Open access funding provided by University of the Free State.https://link.springer.com/journal/430hj2024BiochemistryGeneticsMicrobiology and Plant PathologyNon

GUP1 and its close homologue GUP2, encoding multi-membrane-spanning proteins involved in active glycerol uptake in Saccharomyces cerevisiae

Many yeast species can utilise glycerol, both as sole carbon source and as an osmolyte. In Saccharomyces cerevisiae, physiological studies have previously shown the presence of an active uptake system driven by electrogenic proton symport. We have used transposon mutagenesis to isolate mutants affected in the transport of glycerol into the cell. Here we present the identification of YGL084c, encoding a multi-membrane-spanning protein, as being essential for proton symport of glycerol into Saccharomyces cerevisiae. The gene is named GUP1 (Glycerol UPtake) and is important for growth on glycerol as carbon and energy source, as well as for osmotic protection by added glycerol, of a strain deficient in glycerol production. Another ORF, YPL189w, presenting a high degree of homology to YGL084c, similarly appears to be involved in active glycerol uptake in salt-containing glucose-based media in strains deficient in glycerol production. Analogously, this gene is named GUP2. To our knowledge, this is the first report on a gene product involved in active transport of glycerol in yeasts. Mutations with the same phenotypes occurred in two other open reading frames of previously unknown function, YDL074c and YPL180w.Comunidade Europeia (CE) - contract BIO4-CT95-0161

Myofascial trigger points in cluster headache patients: a case series

Active myofascial trigger points (MTrPs) have been found to contribute to chronic tension-type headache and migraine. The purpose of this case series was to examine if active trigger points (TrPs) provoking cluster-type referred pain could be found in cluster headache patients and, if so, to evaluate the effectiveness of active TrPs anaesthetic injections both in the acute and preventive headache's treatment. Twelve patients, 4 experiencing episodic and 8 chronic cluster headache, were studied. TrPs were found in all of them. Abortive infiltrations could be done in 2 episodic and 4 chronic patients, and preemptive infiltrations could be done in 2 episodic and 5 chronic patients, both kind of interventions being successful in 5 (83.3%) and in 6 (85.7%) of the cases respectively. When combined with prophylactic drug therapy, injections were associated with significant improvement in 7 of the 8 chronic cluster patients. Our data suggest that peripheral sensitization may play a role in cluster headache pathophysiology and that first neuron afferent blockade can be useful in cluster headache management

High-Throughput SuperSAGE for Digital Gene Expression Analysis of Multiple Samples Using Next Generation Sequencing

We established a protocol of the SuperSAGE technology combined with next-generation sequencing, coined “High-Throughput (HT-) SuperSAGE”. SuperSAGE is a method of digital gene expression profiling that allows isolation of 26-bp tag fragments from expressed transcripts. In the present protocol, index (barcode) sequences are employed to discriminate tags from different samples. Such barcodes allow researchers to analyze digital tags from transcriptomes of many samples in a single sequencing run by simply pooling the libraries. Here, we demonstrated that HT-SuperSAGE provided highly sensitive, reproducible and accurate digital gene expression data. By increasing throughput for analysis in HT-SuperSAGE, various applications are foreseen and several examples are provided in the present study, including analyses of laser-microdissected cells, biological replicates and tag extraction using different anchoring enzymes