Chronic Rhinosinusitis and Mental Health.

Importance: Chronic rhinosinusitis (CRS) has been associated with anxiety and depression, but the association of socioeconomic factors and temporality has yet to be fully explored. Objective: To determine the bidirectional risk of anxiety and depression for patients with CRS. Design, Setting, and Participants: This retrospective cohort study of the National Institutes of Health All of Us database from January 1, 2008, to December 31, 2018, included 2 cohorts of adult patients with and without CRS. The data were analyzed from July 1, 2023, through April 1, 2024. Patients were classified as having CRS if they had at least 2 diagnoses during the study period. Those with a diagnosis of CRS before the study period were excluded. Patients were propensity score matched (1:5) with patients without CRS for age, sex, race, and annual household income. Main Outcomes and Measures: The primary outcome was the development of anxiety and depression. Patients with CRS were counted as having the primary outcome if it occurred after the criteria for CRS diagnosis were fulfilled. Multivariate logistic regression and survival analysis were performed to determine the odds ratios (ORs) and hazard ratios (HRs) of anxiety and depression. A secondary survival analysis determined the risk of developing CRS between patients with anxiety and depression and controls. Results: Among 33 732 patients (23 382 [69.3%] female individuals; 510 [1.5%] Asian, 6002 [17.9%] Black or African American, 576 [1.7%] multiracial, and 26 036 [77.2%] White individuals), there were 28 110 controls and 5622 patients with CRS. Along with higher odds of having anxiety (OR, 4.39; 95% CI, 3.95-4.87) and depression (OR, 2.04; 95% CI, 1.86-2.24), patients with CRS were at an increased risk of developing anxiety (HR, 2.79; 95% CI, 2.47-3.15) and depression (HR, 1.40; 95% CI, 1.27-1.55) compared with controls. Additionally, patients with anxiety (HR, 2.37; 95% CI, 2.18-2.57) and depression (HR, 1.59; 95% CI, 1.46-1.72) were at an increased risk of developing chronic rhinosinusitis compared with controls. Conclusions and Relevance: In this population-based cohort study of adults with and without CRS, a bidirectional association between common psychiatric disorders and CRS was observed. Physicians and health care clinicians who treat patients with anxiety, depression, and CRS should be vigilant regarding these risks and screen patients appropriately.

Interleukin-10 Gene Polymorphisms Modulate the Risk of Infertility in Chlamydia trachomatis Positive Kurdish Women in Erbil Province.

Background: There is evident inter-individual variability in women's responses to Chlamydial infections and reproductive tract problems. Women's genetic variations within the Interleukin-10 (IL-10) gene have been linked to variances in response to Chlamydia trachomatis infection. This study was aimed to demonstrate the profound association of IL-10 with infertility and demonstrate the role of IL-10 (-592 C/A rs1800872) and (-1082 A>G rs1800896) single nucleotide polymorphism (SNPs) gene in the susceptibility and severity of a C. trachomatis infection. Methods: In this evaluation study, serum IL-10 concentration was measured in 134 women diagnosed with infertility and 50 healthy volunteers by enzyme-linked immunosorbent assay (ELISA). The tetra-amplification refractory mutation system-PCR (T-ARMS-PCR) analysis was performed to detect the genotyping of the rs1800872 and rs1800896 SNPs genes. Results: Both female groups were positive for anti-chlamydial IgM antibody, but the intensity of response differed between cases. At the same time, the incidence of genital C. trachomatis by PCR was 46.2% in infertile women. The serum concentration of IL10 was lower in infertile women than healthy participants and higher in infertile C. trachomatis -positive women compared to infertile C. trachomatis-negative in all groups except endometriosis (Endo) infertility. In rs1800872, the CA genotype and C allele are associated with an increased risk for infertility, except in polycystic ovarian syndrome (PCOS), which is an A allele. In the case of rs1800896, the AG genotype and G allele show a greater risk for infertility. Conclusions: Our results confirmed that rs1800872 and rs1800896 gene polymorphisms were associated with an increased risk of C. trachomatis infection.

Taxonomic classification with maximal exact matches in KATKA kernels and minimizer digests.

For taxonomic classification, we are asked to index the genomes in a phylogenetic tree such that later, given a DNA read, we can quickly choose a small subtree likely to contain the genome from which that read was drawn. Although popular classifiers such as Kraken use k -mers, recent research indicates that using maximal exact matches (MEMs) can lead to better classifications. For example, we can ■ build an augmented FM-index over the the genomes in the tree concatenated in left-to-right order; ■ for each MEM in a read, find the interval in the suffix array containing the starting positions of that MEM's occurrences in those genomes; ■ find the minimum and maximum values stored in that interval; ■ take the lowest common ancestor (LCA) of the genomes containing the characters at those positions. This solution is practical, however, only when the total size of the genomes in the tree is fairly small. In this paper we consider applying the same solution to three lossily compressed representations of the genomes' concatenation: ■ a KATKA kernel, which discards characters that are not in the first or last occurrence of any k max -tuple, for a parameter k max ; a minimizer digest; ■ a KATKA kernel of a minimizer digest. With a test dataset and these three representations of it, simulated reads and various parameter settings, we checked how many reads' longest MEMs occurred only in the sequences from which those reads were generated ("true positive" reads). For some parameter settings we achieved significant compression while only slightly decreasing the true-positive rate.

Disparities in seeking care for olfactory and gustatory dysfunction: A population analysis.

INTRODUCTION: Despite effects on quality of life from olfactory and gustatory dysfunction (OD and GD), screening practices are limited, and patients' self-reporting of symptoms remains the only way to understand the burden of chemosensory dysfunction (CSD). Using a large population-based database, we sought to understand factors leading to reduced likelihood of discussing CSD with a provider. METHODS: The 2013‒2014 National Health and Nutrition Examination Survey (NHANES) chemosensory protocol was queried for factors influencing discussion of OD/GD with a healthcare provider. Sociodemographic, comorbidity, and objective OD/GD testing results were assessed with a multivariate analysis. RESULTS: Out of 146.1 million US adults, there were an estimated 41.4 million individuals with self-reported OD/GD in the prior 12 months (28.3%). A total of 86.8% of participants did not discuss their problem with a healthcare provider. Men were about half as likely to speak with a healthcare provider (odds ratio [OR] 0.42; 0.26-0.66; p < 0.001) and those with a college education were about nine times more likely to discuss the problem compared to those with less than a ninth-grade educational achievement (OR 8.83; 1.86-41.98; p = 0.02). Those with objective confirmation of CSD were still unlikely to speak with a provider (OR 0.77; 0.44-1.33; p = 0.36). CONCLUSION: Men and those with less education are less likely to discuss OD/GD with a healthcare provider. These populations tend to be at increased risk for CSD, and there are severe downstream health and quality of life implications related to CSD. Dedicated screening and increased public awareness are critical to ensure more equitable care.

Reliability Risk Mitigation in Advanced Packages by Aging-Induced Precipitation of Bi in Water-Quenched Sn-Ag-Cu-Bi Solder.

Bi-doped Sn-Ag-Cu (SAC) microelectronic solder is gaining attention for its utility as a material for solder joints that connect substrates to printed circuit boards (PCB) in future advanced packages, as Bi-doped SAC is reported to have a lower melting temperature, higher strength, higher wettability on conducting pads, and lower intermetallic compound (IMC) formation at the solder-pad interface. As solder joints are subjected to aging during their service life, an investigation of aging-induced changes in the microstructure and mechanical properties of the solder alloy is needed before its wider acceptance in advanced packages. This study focuses on the effects of 1 to 3 wt.% Bi doping in an Sn-3.0Ag-0.5Cu (SAC305) solder alloy on aging-induced changes in hardness and creep resistance for samples prepared by high cooling rates (>5 °C/s). The specimens were aged at ambient and elevated temperatures for up to 90 days and subjected to quasistatic nanoindentation to determine hardness and nanoscale dynamic nanoindentation to determine creep behavior. The microstructural evolution was investigated with a scanning electron microscope in tandem with energy-dispersive spectroscopy to correlate with aging-induced property changes. The hardness and creep strength of the samples were found to increase as the Bi content increased. Moreover, the hardness and creep strength of the 0-1 wt.% Bi-doped SAC305 was significantly reduced with aging, while that of the 2-3 wt.% Bi-doped SAC305 increased with aging. The changes in these properties with aging were correlated to the interplay of multiple hardening and softening mechanisms. In particular, for 2-3 wt.% Bi, the enhanced performance was attributed to the potential formation of additional Ag3Sn IMCs with aging due to non-equilibrium solidification and the more uniform distribution of Bi precipitates. The observations that 2-3 wt.% Bi enhances the hardness and creep strength of the SAC305 alloy with isothermal aging to mitigate reliability risks is relevant for solder samples prepared using high cooling rates.

Predictors of Facial Pain and Headache Associated With Cryotherapy Ablation of the Posterior Nasal Nerve for the Treatment of Chronic Rhinitis.

OBJECTIVE: Cryotherapy ablation of the posterior nasal nerve (PNN) for treatment of patients with refractory chronic rhinitis (CR) is associated with postoperative facial pain and headache. This study sought to understand factors that may contribute to the development of this adverse effect. METHODS: Patients undergoing PNN cryotherapy ablation for refractory CR at a single institution from January 2018 to August 2023 were included. Demographics and clinical characteristics were collected via chart review and interview. Student's T-test and Chi-square tests were used to assess the significance of quantitative and categorical data, respectively (alpha = 0.05). RESULTS:  Forty-eight patients underwent cryotherapy ablation. Twenty-eight patients (58%) reported having facial pain and headache (adverse effect group) immediately post-procedurally. The average age of the adverse effect group was 54.9 years (SD: 17.8 years) which was significantly lower (p=0.002) than the asymptomatic group (69.7 years, SD: 8.7 years). Female patients were significantly more likely to experience this adverse event than males (p=0.04). Moreover, Caucasian females were significantly more likely to experience this adverse effect when compared to all patients experiencing the adverse effect (n=15, p=0.04). Previous diagnosis of migraine disorder was more common in the adverse effect group (28%) compared to the asymptomatic group (15%) but not statistically significant (p=0.26). Previous migraine, trigeminal neuralgia, or headache disorder diagnoses were not significantly correlated with adverse effect prevalence (p = 0.26, 0.24, 0.15, respectively). CONCLUSION: Given the relative immediacy and severity of this adverse effect, physicians should strongly consider these factors when counseling and selecting certain patient groups for this procedure.

The efficacy of Hemospray in managing bleeding related to gastrointestinal tumors: systematic review and meta-analysis.

INTRODUCTION: Gastrointestinal (GI) bleeding stemming from malignant tumors is increasingly recognized, due to advancements in oncology and detection methods. Traditional endoscopic hemostatic techniques have shown variable success rates in managing hemorrhagic GI neoplasms. Hemospray, an emerging endoscopic hemostatic powder, offers promise in treating upper GI bleeding, potentially extending its utility to neoplastic bleeding sites. This meta-analysis aims to evaluate Hemospray's efficacy in managing bleeding related to GI tumors. METHODS: We searched Embase, Scopus, Web of Science, Medline/PubMed, and Cochrane. Inclusion criteria encompassed studies focusing on malignancy-related GI bleeding and interventions utilizing Hemospray. Comparative studies contrasted Hemospray with standard endoscopic treatments (SET), while noncomparative studies assessed Hemospray's efficacy independently. The risk of bias was assessed using appropriate tools, and statistical analyses were performed using Review Manager and open Meta analyst software. RESULTS: We included 19 studies in our meta-analysis. Hemospray demonstrated higher rates of immediate hemostasis compared to SET (odds ratio: 17.14, 95% confidence interval: 4.27-68.86), with consistent outcomes across studies. Rebleeding rates at 14 and 30 days were comparable between Hemospray and SET groups, suggesting similar efficacy in long-term hemostasis. Hemospray showed a significantly lower need for nonendoscopic hemostasis compared to SET (odds ratio: 0.51, 95% confidence interval: 0.30-0.87), indicating a potential reduction in supplementary interventions. Safety assessments revealed no confirmed adverse events directly linked to Hemospray. CONCLUSION: This meta-analysis highlights Hemospray's efficacy in achieving immediate hemostasis in GI tumor-related bleeding, with potential benefits in reducing supplementary interventions and improving patient outcomes. Despite comparable rebleeding rates, Hemospray emerges as a valuable adjunctive therapy in managing malignant GI bleeding.

Histopathologic evaluation of Asian-American patients with chronic rhinosinusitis with nasal polyps.

KEY POINTS: Asian-American (AA) patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have comparable rates of tissue eosinophilia compared to Caucasians when defined as >10 eosinophils/high-powered field (HPF). AA patients with CRSwNP have significantly higher incidence of mixed inflammation defined as >10 eosinophils/HPF and >10 neutrophils/HPF.

Features of Importance in Nasal Endoscopy: Deriving a Meaningful Framework.

OBJECTIVE: Critical components of the nasal endoscopic examination have not been definitively established for either the normal examination or for clinical disorders. This study aimed to identify concordance among rhinologists regarding the importance of examination findings for various nasal pathologies. STUDY DESIGN: A consortium of 19 expert rhinologists across the United States was asked to rank the importance of findings on nasal endoscopy for 5 different sinonasal symptom presentations. SETTING: An online questionnaire was distributed in July 2023. METHODS: The questionnaire utilized JotForm® software and featured 5 cases with a set of 4 identical questions per case, each covering a common indication for nasal endoscopy. Rankings were synthesized into Normalized Attention Scores (NASs) and Weighted Normalized Attention Scores (W-NASs) to represent the perceived importance of each feature, scaled from 0 to 1. RESULTS: General concordance was found for examination findings on nasal endoscopy within each case. The perceived features of importance differed between cases based on clinical presentation. For instance, in evaluating postnasal drip, the middle meatus was selected as the most important structure to examine (NAS, 0.73), with mucus selected as the most important abnormal finding (W-NAS, 0.66). The primary feature of interest for mucus was whether it was purulent or not (W-NAS, 0.67). Similar analyses were performed for features in each case. CONCLUSION: The implicit framework existing among rhinologists may help standardize examinations and improve diagnostic accuracy, augment the instruction of trainees, and inform the development of artificially intelligent algorithms to enhance clinical decision-making during nasal endoscopy.

Sigmoni: classification of nanopore signal with a compressed pangenome index.

SUMMARY: Improvements in nanopore sequencing necessitate efficient classification methods, including pre-filtering and adaptive sampling algorithms that enrich for reads of interest. Signal-based approaches circumvent the computational bottleneck of basecalling. But past methods for signal-based classification do not scale efficiently to large, repetitive references like pangenomes, limiting their utility to partial references or individual genomes. We introduce Sigmoni: a rapid, multiclass classification method based on the r-index that scales to references of hundreds of Gbps. Sigmoni quantizes nanopore signal into a discrete alphabet of picoamp ranges. It performs rapid, approximate matching using matching statistics, classifying reads based on distributions of picoamp matching statistics and co-linearity statistics, all in linear query time without the need for seed-chain-extend. Sigmoni is 10-100× faster than previous methods for adaptive sampling in host depletion experiments with improved accuracy, and can query reads against large microbial or human pangenomes. Sigmoni is the first signal-based tool to scale to a complete human genome and pangenome while remaining fast enough for adaptive sampling applications. AVAILABILITY AND IMPLEMENTATION: Sigmoni is implemented in Python, and is available open-source at https://github.com/vshiv18/sigmoni.

Air pollution, genetic factors, and chronic rhinosinusitis: A prospective study in the UK Biobank.

BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent upper respiratory condition that manifests in two primary subtypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). While previous studies indicate a correlation between air pollution and CRS, the role of genetic predisposition in this relationship remains largely unexplored. We hypothesized that higher air pollution exposure would lead to the development of CRS, and that genetic susceptibility might modify this association. METHODS: This cohort study involving 367,298 adult participants from the UK Biobank, followed from March 2006 to October 2021. Air pollution metrics were estimated at residential locations using land-use regression models. Cox proportional hazard models were employed to explore the associations between air pollution exposure and CRS, CRSwNP, and CRSsNP. A polygenic risk score (PRS) was constructed to evaluate the joint effect of air pollution and genetic predisposition on the development of CRS. RESULTS: We found that the risk of CRS increased under long-term exposure to PM2.5 [the hazard ratios (HRs) with 95 % CIs: 1.59 (1.26-2.01)], PM10 [1.64 (1.26-2.12)], NO2 [1.11 (1.04-1.17)], and NOx [1.18 (1.12-1.25)], respectively. These effects were more pronounced among participants with CRSwNP, although the differences were not statistically significant. Additionally, we found that the risks for CRS and CRSwNP increased in a graded manner among participants with higher PRS or higher exposure to PM2.5, PM10, or NOx concentrations. However, no multiplicative or additive interactions were observed. CONCLUSIONS: Long-term exposure to air pollution increases the risk of CRS, particularly CRSwNP underscoring the need to prioritize clean air initiatives and environmental regulations.

What Questions Do Patients Ask About Biologic Therapies for Chronic Sinusitis With Nasal Polyps?

Objective: The objective of this study is to explore the questions commonly asked online about biologic therapies for use in treatment of chronic sinusitis with nasal polyps (CRSwNP) and the quality of the available content. Methods: Most common search terms were identified via Google Trends. People Also Ask (PAA) questions were identified and extracted with their associated website using an online data-scraping program [Search Engine Optimization (SEO) Minion, Keywords Everywhere]. Sources were evaluated using Flesch Kincaid Grade Level (FKGL) and Flesch Reading Ease (FRE, higher number = better) score for readability; Journal of American Medical Association (JAMA) Benchmark criteria for quality assessment (0-4, 4 = all criteria met). Results: A total of 143 unique PAA questions and unique websites were identified. Questions were organized into 3 categories: questions about biologic therapies overall (38.46%), about CRSwNP (37.76%), and about treatment options for CRSwNP (23.78%). Websites answering PAA questions were from commercial (60.14%), medical practice (13.99%), academic (13.29%), and government (12.59%) sources. FKGL scores found the average reading level to be at approximately a 12th grade level (SD = 3.297) alongside a low reading ease FRE score of 37.6 (SD = 16.77). Mean JAMA criteria scores were 0.9895 (SD = 0.848), indicating largely low-quality materials. Conclusion: Biologic therapies are a novel treatment option for CRSwNP, and participants are seeking more information about these treatments and disease state. Online resources regarding biologics should be presented at a lower reading level. Sources with evidence-based information are needed. Physicians should be aware of these limitations in online material and counsel accordingly by curating and directing patients to good sources.Level of Evidence: Step 4.

Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states.

Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.

Patient Questions Surrounding Posterior Nasal Nerve Ablation for Chronic Rhinitis.

Objective: In-office ablation of the posterior nasal nerve (PNN) has emerged as an effective treatment option for chronic rhinitis patients. This study explored questions patients commonly search online regarding this therapy and the quality of content available. Study Design: A retrospective analysis of online search criteria and sources was performed with subsequent analysis of results. Setting: Search and data acquisition was in September of 2023. Methods: Most common search terms related to cryotherapy and radiofrequency neurolysis of the PNN were identified with associated People Also Ask (PAA) questions. Questions were categorized and organized into subtopics and sources evaluated using readability and quality metrics. Results: A total of 255 unique PAA questions and 175 unique websites were identified. The most common subtopics were related to facts about chronic rhinitis (26.7%) and rhinitis treatment options (25.1%). Nearly a quarter (24.3%) of websites were from commercial sources. Quality metrics indicate difficult-to-read and low-quality materials. Conclusion: Existing online resources need improvement to provide patients material that is easier to read. Physicians counseling patients should be aware of these areas for adequate shared decision making.

MEM-based pangenome indexing for k-mer queries.

Pangenomes are growing in number and size, thanks to the prevalence of high-quality long-read assemblies. However, current methods for studying sequence composition and conservation within pangenomes have limitations. Methods based on graph pangenomes require a computationally expensive multiple-alignment step, which can leave out some variation. Indexes based on k-mers and de Bruijn graphs are limited to answering questions at a specific substring length k. We present Maximal Exact Match Ordered (MEMO), a pangenome indexing method based on maximal exact matches (MEMs) between sequences. A single MEMO index can handle arbitrary-length queries over pangenomic windows. MEMO enables both queries that test k-mer presence/absence (membership queries) and that count the number of genomes containing k-mers in a window (conservation queries). MEMO's index for a pangenome of 89 human autosomal haplotypes fits in 2.04 GB, 8.8× smaller than a comparable KMC3 index and 11.4× smaller than a PanKmer index. MEMO indexes can be made smaller by sacrificing some counting resolution, with our decile-resolution HPRC index reaching 0.67 GB. MEMO can conduct a conservation query for 31-mers over the human leukocyte antigen locus in 13.89 seconds, 2.5x faster than other approaches. MEMO's small index size, lack of k-mer length dependence, and efficient queries make it a flexible tool for studying and visualizing substring conservation in pangenomes.

Cliffy: robust 16S rRNA classification based on a compressed LCA index.

Taxonomic sequence classification is a computational problem central to the study of metagenomics and evolution. Advances in compressed indexing with the r -index enable full-text pattern matching against large sequence collections. But the data structures that link pattern sequences to their clades of origin still do not scale well to large collections. Previous work proposed the document array profiles, which use 𝒪 ( rd ) words of space where r is the number of maximal-equal letter runs in the Burrows-Wheeler transform and d is the number of distinct genomes. The linear dependence on d is limiting, since real taxonomies can easily contain 10,000s of leaves or more. We propose a method called cliff compression that reduces this size by a large factor, over 250x when indexing the SILVA 16S rRNA gene database. This method uses Θ( r log d ) words of space in expectation under a random model we propose here. We implemented these ideas in an open source tool called Cliffy that performs efficient taxonomic classification of sequencing reads with respect to a compressed taxonomic index. When applied to simulated 16S rRNA reads, Cliffy's read-level accuracy is higher than Kraken2's by 11-18%. Clade abundances are also more accurately predicted by Cliffy compared to Kraken2 and Bracken. Overall, Cliffy is a fast and space-economical extension to compressed full-text indexes, enabling them to perform fast and accurate taxonomic classification queries. 2012 ACM Subject Classification: Applied computing → Computational genomics.

A Post-International Gastrointestinal Cancers' Conference (IGICC) Position Statements.

Hepatocellular carcinoma (HCC), the most prevalent liver tumor, is usually linked with chronic liver diseases, particularly cirrhosis. As per the 2020 statistics, this cancer ranks 6th in the list of most common cancers worldwide and is the third primary source of cancer-related deaths. Asia holds the record for the highest occurrence of HCC. HCC is found three times more frequently in men than in women. The primary risk factors for HCC include chronic viral infections, excessive alcohol intake, steatotic liver disease conditions, as well as genetic and family predispositions. Roughly 40-50% of patients are identified in the late stages of the disease. Recently, there have been significant advancements in the treatment methods for advanced HCC. The selection of treatment for HCC hinges on the stage of the disease and the patient's medical status. Factors such as pre-existing liver conditions, etiology, portal hypertension, and portal vein thrombosis need critical evaluation, monitoring, and appropriate treatment. Depending on the patient and the characteristics of the disease, liver resection, ablation, or transplantation may be deemed potentially curative. For inoperable lesions, arterially directed therapy might be an option, or systemic treatment might be deemed more suitable. In specific cases, the recommendation might extend to external beam radiation therapy. For all individuals, a comprehensive, multidisciplinary approach should be adopted when considering HCC treatment options. The main treatment strategies for advanced HCC patients are typically combination treatments such as immunotherapy and anti-VEGFR inhibitor, or a combination of immunotherapy and immunotherapy where appropriate, as a first-line treatment. Furthermore, some TKIs and immune checkpoint inhibitors may be used as single agents in cases where patients are not fit for the combination therapies. As second-line treatments, some treatment agents have been reported and can be considered.

An adaptable and personalized framework for top-N course recommendations in online learning.

In recent years, the proliferation of Massive Open Online Courses (MOOC) platforms on a global scale has been remarkable. Learners can now meet their learning demands with the help of MOOC. However, learners might not understand the course material well if they have access to a lot of information due to their inadequate expertise and cognitive ability. Personalized Recommender Systems (RSs), a cutting-edge technology, can assist in addressing this issue. It greatly increases resource acquisition through personalized availability for various people of all ages. Intelligent learning methods, such as machine learning and Reinforcement Learning (RL) can be used in RS challenges. However, machine learning needs supervised data and classical RL is not suitable for multi-task recommendations in online learning platforms. To address these challenges, the proposed framework integrates a Deep Reinforcement Learning (DRL) and multi-agent approach. This adaptive system personalizes the learning experience by considering key factors such as learner sentiments, learning style, preferences, competency, and adaptive difficulty levels. We formulate the interactive RS problem using a DRL-based Actor-Critic model named DRR, treating recommendations as a sequential decision-making process. The DRR enables the system to provide top-N course recommendations and personalized learning paths, enriching the student's experience. Extensive experiments on a MOOC dataset such as the 100 K Coursera course review validate the proposed DRR model, demonstrating its superiority over baseline models in major evaluation metrics for long-term recommendations. The outcomes of this research contribute to the field of e-learning technology, guiding the design and implementation of course RSs, to facilitate personalized and relevant recommendations for online learning students.