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\"Artificial Intelligence (AI) in general and machine learning (ML) and deep learning (DL) in particular and related digital technologies are a couple of fledging paradigms that the next generation healthcare services are sprouting towards. These digital technologies can transform various aspects of healthcare, leveraging advances in computing and communication power. With a new spectrum of business opportunities, AI-powered healthcare services would improve the lives of patients, their families, and societies. However, the application of AI in the healthcare field requires special attention given the direct implication with human life and well-being. Rapid progress in AI leads to the possibility of exploiting healthcare data for designing practical tools for automated diagnosis of chronic diseases such as dementia and diabetes. This book highlights the current research trends in applying AI models in various disease diagnoses and prognoses to provide enhanced healthcare solutions. The primary audience of the book will be postgraduate students and researchers in the broad domain of healthcare technologies\"-- Provided by publisher.

Key Points MicroRNAs (miRNAs) have important roles in many aspects of human diseases, and their targeted inhibition may have substantial therapeutic impact. Inhibition of miRNAs can be achieved through a variety of methods and chemically modified antisense oligonucleotides (anti-miRs) have shown the most prominent effects. Targeted delivery of anti-miRs is crucial to achieve intended therapeutic effects, and further efforts are warranted to develop more efficient delivery systems. MicroRNAs (miRNAs) — 21- to 23-nucleotide single-stranded RNAs that regulate gene expression — have roles in numerous diseases, and are therefore attractive therapeutic targets. Li and Rana discuss strategies in the design of miRNA-targeting oligonucleotides with increased efficacy and improved in vivo delivery characteristics, and highlight some of the challenges that lie ahead in the clinical development of these therapeutics. MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that have crucial roles in regulating gene expression. Increasing evidence supports a role for miRNAs in many human diseases, including cancer and autoimmune disorders. The function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies for several diseases. In this Review we summarize our current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides, discuss various in vivo delivery strategies and analyse ongoing challenges to ensure the specificity and efficacy of therapeutic oligonucleotides in vivo . Finally, we review current progress on the clinical development of miRNA-targeting therapeutics.

Key Points RNA interference (RNAi) is an ancient and evolutionarily conserved gene-silencing mechanism that is triggered by double-stranded (ds)RNA. dsRNA, which is produced endogenously or introduced exogenously, is processed into small (∼21–23-nucleotide (nt)) duplexes, and the antisense strands are loaded onto RNA-induced silencing complexes (RISCs). Dictated by complementarity to its target mRNA, the antisense strand guides RISC to hybridize with the target and induces gene silencing by initiating either target cleavage or assembly into RNA–protein complexes that are destined for translation suppression and localization to cytoplasmic RNA-processing foci. These two gene-silencing pathways are discussed in terms of kinetic models and the structural basis of the underlying mechanisms. The major determinant of small RNAs that functions as specific triggers of gene silencing is the A-form helical geometry of RNA. The A-form helix and high-resolution structural studies provide a context for discussing the importance of phosphate groups at the 5′ end of the guide strand. Small RNAs can bind to mRNAs with partial complementarity and induce silencing of unintended mRNA transcripts, known as off-target effects. Drawing on the structure and function of small RNAs and kinetic models for RNAi, this review presents plausible mechanisms for off-target effects and discusses how chemical modifications can reduce unintended gene silencing. Gene silencing has been modulated and the in vivo half-life of triggers has been enhanced by effective chemical modification of RNA triggers. The review develops and discusses guidelines for the chemical modification of RNA triggers. Clarifying the structure and function of the triggers of the RNAi machinery and developing RNA-delivery technologies will increase the applicability of RNAi to biology and medicine. This, in turn, will enhance our understanding of the various cellular pathways that are controlled by small RNAs. To clarify the mechanisms by which RNA molecules silence genes, the structural and functional characteristics of various RNA triggers, such as small interfering RNAs and microRNAs, must be determined. This knowledge will also help us to optimize the efficiency of RNA interference. RNA interference (RNAi) is triggered by double-stranded RNA helices that have been introduced exogenously into cells as small interfering (si)RNAs or that have been produced endogenously from small non-coding RNAs known as microRNAs (miRNAs). RNAi has become a standard experimental tool and its therapeutic potential is being aggressively harnessed. Understanding the structure and function of small RNAs, such as siRNAs and miRNAs, that trigger RNAi has shed light on the RNAi machinery. In particular, it has highlighted the assembly and function of the RNA-induced silencing complex (RISC), and has provided guidelines to efficiently silence genes for biological research and therapeutic applications of RNAi.

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N⁶-methylation of adenosine (m⁶A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m⁶A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m⁶A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m⁶A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.

Adults with osteoarthritis are vulnerable to mental health disorders, which may have a significant impact on their Health-Related Quality of Life (HRQoL). Thus, the purpose of this study was to look at the relationship between anxiety and depression and HRQoL in adults with osteoarthritis. Adult patients diagnosed with osteoarthritis who were 18 years of age or older were identified using data from the Medical Expenditure Panel Survey for the years 2018-2021. HRQoL was computed using the veteran's RAND 12-item health survey which has two domains the Physical and Mental Component Summary (PCS & MCS) ratings. The link between anxiety and depression and HRQoL in individuals with osteoarthritis was examined using multivariable linear regression after the adjustment for a variety of covariates. Of the 3,658 individuals with osteoarthritis that were identified, 12.0% experienced depression, 12.5% had anxiety, and 9.9% had both illnesses. The PCS and MCS mean scores of the HRQoL were lowest for persons with comorbid depression and anxiety compared to adults with osteoarthritis only. Moreover, from the adjusted regression analysis, adults with osteoarthritis who had depression (MCS: adjusted β = -5.408, p < 0.001), anxiety (MCS: adjusted β = -3.485, p < 0.001), or both depression and anxiety (MCS: adjusted β = -10.348, p-value<0.0001) had significantly lower HRQoL MCS scores compared to those with osteoarthritis only. Those who were physically active and employed had notably better scores on the PCS and MCS than those who were not. This nationally representative sample has shed light on the relationships between anxiety, depression, and a low HRQoL in adults with osteoarthritis. The study also revealed the impact of socioeconomic factors such as education level and income on HRQoL, and the benefits of employment and regular exercise. Importantly, the findings underscore the need for lifestyle modifications to reduce anxiety and depression in individuals with osteoarthritis. They also highlight the practical implications for healthcare planning and resource allocation, providing valuable insights for policymakers and healthcare professionals.

Methamphetamine (METH) is a potent stimulant that induces a euphoric state but also causes cognitive impairment, neurotoxicity and neurodevelopmental deficits. Yet, the molecular mechanisms by which METH causes neurodevelopmental defects have remained elusive. Here we utilized human cerebral organoids and single-cell RNA sequencing (scRNA-seq) to study the effects of prenatal METH exposure on fetal brain development. We analyzed 20,758 cells from eight untreated and six METH-treated cerebral organoids and found that the organoids developed from embryonic stem cells contained a diverse array of glial and neuronal cell types. We further identified transcriptionally distinct populations of astrocytes and oligodendrocytes within cerebral organoids. Treatment of organoids with METH-induced marked changes in transcription in multiple cell types, including astrocytes and neural progenitor cells. METH also elicited novel astrocyte-specific gene expression networks regulating responses to cytokines, and inflammasome. Moreover, upregulation of immediate early genes, complement factors, apoptosis, and immune response genes suggests a neuroinflammatory program induced by METH regulating neural stem cell proliferation, differentiation, and cell death. Finally, we observed marked METH-induced changes in neuroinflammatory and cytokine gene expression at the RNA and protein levels. Our data suggest that human cerebral organoids represent a model system to study drug-induced neuroinflammation at single-cell resolution.

Background Older patients are commonly prescribed multiple medications therefore; medication misadventures are common and expected among older patients. The use of potentially inappropriate medicines (PIMs) further contributes to this risk. Therefore, this study aimed to examine PIMs use among older patients using the 2015 Beers criteria. Methods A cross-sectional retrospective study using electronic medical records data from a large tertiary hospital in Saudi Arabia was conducted. Older adult patient’s (age ≥ 65 years) who were treated in the ambulatory care setting were included. PIMs use was defined using the 2015 Beers criteria. Descriptive statistics and logistic regression were used to describe and identify potential predictors of PIMs use. All statistical analyses were carried out using the Statistical Analysis Software version 9.2 (SAS® 9.2). Results This study included 4073 older adults with a mean age of 72.6 (± 6.2) years. The majority of the study population was female (56.8%). The Prevalence of PIMs to be avoided among older adults was 57.6% where 39.9% of the older adults population were prescribed one PIMs, 14.5% two PIMs, and 3.3% were on three or more PIMs. The most commonly prescribed PIMs were gastrointestinal agents (35.6%) and endocrine agents (34.3%). The prevalence of PIMs to be used with caution was 37.5%. Polypharmacy and existence of certain chronic comorbidities were associated with high risk of PIMs use among older patients. Conclusions Given high prevalence of PIMs occurrence among this population, future research on strategies and interventions rationing PIMs use in the geriatric population are warranted.

Mosquitoes of the genera Aedes , Anopheles and Culex vector a wide range of pathogens seriously affecting humans and livestock on a global scale. Over-reliance on insecticides and repellents has driven research into alternative, naturally-derived compounds to fulfil the same objectives. Steam distilled extracts of four plants with strong, yet attractive, volatile profiles were initially assessed for repellency in a dual-port olfactometer using Aedes aegypti as the model species. Picea sitchensis was found to be the most repellent, proving comparable to leading products when applied at 100% (p = 1.000). Key components of conifer-derived volatile profiles were then screened via electroantennography before those components eliciting an electrophysiological response were assayed individually in the olfactometer; according to WHO protocol. The most promising 5 were selected for reductive analyses to produce an optimised semiochemical blend. This combination, and a further two variations of the blend, were then progressed to a multi-species analysis using the BG-test whereby bite-attempt frequency on hands was assessed under different repellent treatments; assays were compared between Aedes aegypti , Anopheles gambiae and Culex quinquefasciatus . Efficacy was found against all three species, although it was found that Ae. aegypti was the most susceptible to the repellent, with An. gambiae being the least. Here, a novel, naturally-derived blend is presented with weak spatial repellency, as confirmed in laboratory assays. Further work will be required to assess the full extent of the potential of the products, both in terms of field application and species screening; however, the success of the products developed demonstrate that plant metabolites have great capacity for use in the repellent sector; both to improve upon known compounds and to reduce the usage of toxic products currently on the market.

Optic neuritis (ON) is the most common cause of acute optic neuropathy in patients younger than 50 years of age and is most frequently idiopathic or associated with multiple sclerosis. However, the discovery of aquaporin-4 immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein (MOG)-IgG as biomarkers for two separate central nervous system inflammatory demyelinating diseases has revealed that neuromyelitis optica spectrum disorder (NMSOD) and MOG-IgG-associated disease (MOGAD) are responsible for clinically distinct subsets of ON. NMOSD-ON and MOGAD-ON both demonstrate tendencies for bilateral optic nerve involvement and often exhibit a relapsing course with the potential for devastating long-term visual outcomes. Early and accurate diagnosis is therefore essential. This review will summarize the current understanding of the clinical spectra of NMOSD and MOGAD, the radiographic and serological findings which support their diagnoses, and the current evidence behind various acute and long-term therapeutic strategies for ON related to these conditions. A particular emphasis is placed on a number of recent multi-centre randomized placebo-controlled trials, which provide the first level I evidence for long-term treatment of NMOSD.

Abstract Background/Aims: Butein (2’,3,4,4’-Tetrahydroxychalcone), a polyphenol produced by several plants including Butea monoserpma, has been reported to exert potent anti-inflammatory activity but the mechanism remains unknown. In the present work we investigated the mechanism of Butein-mediated suppression of IL-6 expression in normal and human osteoarthritis (OA) chondrocytes under pathological conditions. Methods: Expression level of interleukin-6 (IL-6) protein in OA cartilage was analyzed by immunohistochemistry using a validated antibody. Chondrocytes derived from normal or OA cartilage by enzymatic digestion were pretreated with Butein followed by stimulation with interleukin-1β (IL-1β) and the levels of IL-6 mRNA were quantified by TaqMan assay and the protein levels were measured by Western immunoblotting. Autophagy activation was determined by Western blotting and confocal microscopy. Autophagy was inhibited by siRNA mediated knockdown of ATG5. Results: Expression of IL-6 protein was high in the OA cartilage compared to smooth cartilage from the same patient. OA chondrocytes and cartilage explants stimulated with IL-1β showed high level expression of IL-6 mRNA and protein. Butein increased the phosphorylation of AMPKαThr-172, TSC2Ser-1387 and ULK1Ser-317 and inhibited the phosphorylation of mTORSer-2448 and its downstream target p70S6K and increased autophagy flux that correlated with the suppression of the IL-1β mediated expression of IL-6 in normal and OA chondrocytes. In OA chondrocytes with siRNA-mediated knockdown of ATG5 expression, treatment with Butein failed to activate autophagy and abrogated the suppression of IL-1β induced IL-6 expression. Conclusion: Our findings demonstrate for the first time that Butein activate autophagy in OA chondrocytes via AMPK/TSC2/ULK1/mTOR pathway. Additionally, activation of autophagy was essential to block the IL-1β-induced expression of IL-6 in OA chondrocytes. These data support further studies to evaluate the use of Butein or compounds derived from it for the management of OA.