Regulatory roles of N6-methyladenosine (m6A) methylation in RNA processing and non-communicable diseases.

Post-transcriptional RNA modification is an emerging epigenetic control mechanism in cells that is important in many different cellular and organismal processes. N6-methyladenosine (m6A) is one of the most prevalent, prolific, and ubiquitous internal transcriptional alterations in eukaryotic mRNAs, making it an important topic in the field of Epigenetics. m6A methylation acts as a dynamical regulatory process that regulates the activity of genes and participates in multiple physiological processes, by supporting multiple aspects of essential mRNA metabolic processes, including pre-mRNA splicing, nuclear export, translation, miRNA synthesis, and stability. Extensive research has linked aberrations in m6A modification and m6A-associated proteins to a wide range of human diseases. However, the impact of m6A on mRNA metabolism and its pathological connection between m6A and other non-communicable diseases, including cardiovascular disease, neurodegenerative disorders, liver diseases, and cancer remains in fragmentation. Here, we review the existing understanding of the overall role of mechanisms by which m6A exerts its activities and address new discoveries that highlight m6A's diverse involvement in gene expression regulation. We discuss m6A deposition on mRNA and its consequences on degradation, translation, and transcription, as well as m6A methylation of non-coding chromosomal-associated RNA species. This study could give new information about the molecular process, early detection, tailored treatment, and predictive evaluation of human non-communicable diseases like cancer. We also explore more about new data that suggests targeting m6A regulators in diseases may have therapeutic advantages.

Phytochemicals, antioxidant ability and in vitro anthelmintic activity of crude extracts from Vitexnegundo leaves against Haemonchus contortus.

The aim of this study was to evaluate the in vitro anthelmintic effect of crude aqueous, methanol, ethanol, hydro alcohol and acetone extracts of Vitex negundo leaves against Haemonchus contortus eggs and larvae. Phytochemical analysis to identify the number of compounds in extracts was done by chemical tests and gas chromatography coupled to a mass spectrophotometer detector (GC-MS). First off all the effectiveness of dried plant materials was evaluated on larval development by mixing powdered material (no nano particles) to faecal cultures from donor sheep. Adding powder to the faecal culture resulted into 100% inhibition in larval development at 200 and 300 mg/g of faeces. The anthelmintic activity was assessed using the egg hatch assay (EHA) and the larval mortality assay (LMA). Comparison of mean inhibition percentage of egg embryonation, mean inhibition percentage of egg hatching and mean percentage of larval mortality at different concentrations with control was performed by one-way ANOVA. The means were compared for statistical significance using DMRT at P < 0.05. For both the assays, 50% inhibitory concentration (IC50) and lethal concentration (LC50) were calculated by probit analysis. Chemical test revealed presence of high concentration of saponin and flavoinoids and moderate concentration of total phenols in leaves. The antioxidant activity (radical scavenging activity, RSA %) measured was 35.47%. On GC-MS, the methanolic leaves extract revealed 30 phyto-compounds. On EHA, there was marked effect on inhibition of egg hatching by aqueous, hydro alcohol and acetone extracts. On LMA all the five extracts showed excellent larvicidal activity. V. negundo leaves methanol extract mediated silver nanoparticles were found very effective at much lower concentrations as compared to crude methanol extract. The results indicated that the V. negundo leaves crude extracts possessed excellent in vitro ovicidal and larvicidal properties against H. contortus which needs more investigation, especially in vivo trials for the control of parasite.

Evaluation of a panel of furochromenones as the activator and inhibitor of tyrosinase.

Tyrosinase is a copper-containing enzyme involved in the biosynthesis of melanin pigment. While the excess production of melanin causes hyperpigmentation of human skin, hypopigmentation results in medical conditions like vitiligo. Tyrosinase inhibitors could be used as efficient skin whitening agents and tyrosinase agonists could be used for enhanced melanin synthesis and skin protection from UV exposure. Among a wide range of tyrosinase-regulating compounds, natural and synthetic derivatives of furochromenones, such as 8-methoxypsoralen (8-MOP), are known to both activate and inhibit tyrosinase. We recently reported a synthetic approach to generate a variety of dihydrofuro[3,2-c]chromenones and furo[3,2-c]chromenones in a metal-free condition. In the present study, we investigated these compounds for their potential as antagonists or agonists of tyrosinase. Using fungal tyrosinase-based in vitro biochemical assay, we obtained one compound (3k) which could inhibit tyrosinase activity, and the other compound (4f) that stimulated tyrosinase activity. The kinetic studies revealed that compound 3k caused 'mixed' type tyrosinase inhibition and 4f stimulated the catalytic efficiency. Studying the mechanisms of these compounds may provide a basis for the development of new effective tyrosinase inhibitors or activators.

Biomimetic total syntheses of renifolin F and antiarone K.

The first biomimetic and concise racemic total syntheses of renifolin F and antiarone K, accomplished in 8 and 7 linear steps, respectively, are presented in this article. Our synthetic approach commences with substituted aldehydes to produce prenylated aldol products followed by ene-type intramolecular cyclization affording a five-member core ring. This key step mediated by InCl3·4H2O is a novel procedure first utilized in prenylated systems which directly culminates mainly into tertiary alcohols.

Tweaking algorithms. Technopolitical issues associated with artificial intelligence based tuberculosis detection in global health.

Computer-aided detection algorithms based on artificial intelligence are increasingly being tested and used as a means for detecting tuberculosis in countries where the epidemic is still present. Computer-aided detection tools are often presented as a global solution that can be deployed in all the geographical areas concerned by tuberculosis, but at the same time, they need to be adjusted and calibrated according to local populations' characteristics. The aim of this article is to analyze the tensions between the standardization of computer-aided detection algorithms and their local adaptation and the political issues associated with these tensions. We undertook a qualitative analysis of practices associated with tuberculosis detection algorithms in different contexts, contrasting the perspectives of various stakeholders. Algorithms embed the promise of standardization through automation and the bypassing of variable human expertise such as that of radiologists, they are nonetheless objects of local practices that we have characterized as "tweaking." This work of tweaking reveals how the technology is situated but also the many concerns of the users and workers (insertion in care, control over infrastructure, and political ownership). This should be better considered to truly make computer-aided detection innovative tools for tuberculosis management in global health.

Nunavimmi puvakkut kaggutimik aanniaqarniq: Qanuilirqitaa? Lung cancer in Nunavik: How are we doing? A retrospective matched cohort study.

BACKGROUND: Whether Inuit in Canada experience disparities in lung cancer survival remains unknown. When requiring investigation and treatment for lung cancer, all residents of Nunavik, the Inuit homeland in Quebec, are sent to the McGill University Health Centre (MUHC), in Montréal. We sought to compare survival among patients with lung cancer at the MUHC, who were residents of Nunavik and Montréal, Quebec, respectively. METHODS: We conducted a retrospective cohort study. Using lung cancer registry data, we identified Nunavik residents with histologically confirmed lung cancer diagnosed between 2005 and 2017. We aimed to match 2 Montréal residents to each Nunavik resident on sex, age, calendar year of diagnosis, and histology (non-small cell lung cancer v. small cell lung cancer). We reviewed medical records for data on additional patient characteristics and treatment, and obtained vital status from a provincial registry. We compared survival using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: We included 95 residents of Nunavik and 185 residents of Montréal. For non-small cell lung cancer, median survival times were 321 (95% confidence interval [CI] 184-626) days for Nunavik (n = 71) and 720 (95% CI 536-1208) days for Montréal residents (n = 141). For small cell lung cancer, median survival times were 190 (95% CI 159-308) days for Nunavik (n = 24) and 270 (95% CI 194-766) days for Montréal residents (n = 44). Adjusting for matching variables, stage, performance status, and comorbidity, Nunavik residents had a higher hazard of death (hazard ratio 1.68, 95% CI 1.17-2.41). INTERPRETATION: Nunavik residents experience disparities in survival after lung cancer diagnosis. Although studies in other Inuit Nunangat regions are needed, our findings point to an urgent need to ensure that interventions aimed at improving lung cancer survival, including lung cancer screening, are accessible to Inuit Nunangat residents.

Self-tests for COVID-19: What is the evidence? A living systematic review and meta-analysis (2020-2023).

COVID-19 self-testing strategy (COVIDST) can rapidly identify symptomatic and asymptomatic SARS-CoV-2-infected individuals and their contacts, potentially reducing transmission. In this living systematic review, we evaluated the evidence for real-world COVIDST performance. Two independent reviewers searched six databases (PubMed, Embase, Web of Science, World Health Organization database, Cochrane COVID-19 registry, Europe PMC) for the period April 1st, 2020, to January 18th, 2023. Data on studies evaluating COVIDST against laboratory-based conventional testing and reported on diagnostic accuracy, feasibility, acceptability, impact, and qualitative outcomes were abstracted. Bivariate random effects meta-analyses of COVIDST accuracy were performed (n = 14). Subgroup analyses (by sampling site, symptomatic/asymptomatic infection, supervised/unsupervised strategy, with/without digital supports) were conducted. Data from 70 included studies, conducted across 25 countries with a median sample size of 817 (range: 28-784,707) were pooled. Specificity and DOR was high overall, irrespective of subgroups (98.37-99.71%). Highest sensitivities were reported for: a) symptomatic individuals (73.91%, 95%CI: 68.41-78.75%; n = 9), b) mid-turbinate nasal samples (77.79%, 95%CI: 56.03-90.59%; n = 14), c) supervised strategy (86.67%, 95%CI: 59.64-96.62%; n = 13), and d) use of digital interventions (70.15%, 95%CI: 50.18-84.63%; n = 14). Lower sensitivity was attributed to absence of symptoms, errors in test conduct and absence of supervision or a digital support. We found no difference in COVIDST sensitivity between delta and omicron pre-dominant period. Digital supports increased confidence in COVIDST reporting and interpretation (n = 16). Overall acceptability was 91.0-98.7% (n = 2) with lower acceptability reported for daily self-testing (39.5-51.1%). Overall feasibility was 69.0-100.0% (n = 5) with lower feasibility (35.9-64.6%) for serial self-testing. COVIDST decreased closures in school, workplace, and social events (n = 4). COVIDST is an effective rapid screening strategy for home-, workplace- or school-based screening, for symptomatic persons, and for preventing transmission during outbreaks. These data will guide COVIDST policy. Our review demonstrates that COVIDST has paved the way for self-testing in pandemics worldwide.

Impact of a pharmacist-led patient-centred care intervention along with textmessage reminders, on the management of newly diagnosed tubercular patients: A protocol for a randomized controlled trial.

Objectives: Non-adherence to tuberculosis (TB) treatment is the leading cause of the increase in drug resistance cases. This study will determine the effectiveness of pharmaceutical-care-based interventions coupled with short messages delivered by a pharmacist on treatment outcomes and adherence among TB patients. Methods: The study will be conducted in TB Control Center of Pakistan Institute of Medical Sciences Hospital, Islamabad and District Bannu TB Control Center time period will be from August 2019 to September 2021. The patients will be included into the control group (usual care) or the intervention group pharmaceutical care and SMS reminder. The primary outcome includes a change in mean score from baseline in treatment outcomes and adherence, measured by Morisky Medication Adherence Scale, and clinic appointment attendance registration. Secondary outcomes include health-related quality of life of patients, disease knowledge, and patient satisfaction with the intervention. Result: The major issues in patients with TB are cure rate and medication adherence. The method anticipated in this manuscript could set the foundation of pharmaceutical care and mobile SMS for the future provision of care to improve TB treatment outcomes. Conclusion: The study will make available fundamental information about the influence of the patient centered program on the adherence and clinical outcomes of patients with TB.Trial status and registration: Clinical Trials.gov assigned Identifier NCT04645836.

Diagnostic Accuracy of Computer-Aided Detection During Active Case Finding for Pulmonary Tuberculosis in Africa: A Systematic Review and Meta-analysis.

Background: Computer-aided detection (CAD) may be a useful screening tool for tuberculosis (TB). However, there are limited data about its utility in active case finding (ACF) in a community-based setting, and particularly in an HIV-endemic setting where performance may be compromised. Methods: We performed a systematic review and evaluated articles published between January 2012 and February 2023 that included CAD as a screening tool to detect pulmonary TB against a microbiological reference standard (sputum culture and/or nucleic acid amplification test [NAAT]). We collected and summarized data on study characteristics and diagnostic accuracy measures. Two reviewers independently extracted data and assessed methodological quality against Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Results: Of 1748 articles reviewed, 5 met with the eligibility criteria and were included in this review. A meta-analysis revealed pooled sensitivity of 0.87 (95% CI, 0.78-0.96) and specificity of 0.74 (95% CI, 0.55-0.93), just below the World Health Organization (WHO)-recommended target product profile (TPP) for a screening test (sensitivity ≥0.90 and specificity ≥0.70). We found a high risk of bias and applicability concerns across all studies. Subgroup analyses, including the impact of HIV and previous TB, were not possible due to the nature of the reporting within the included studies. Conclusions: This review provides evidence, specifically in the context of ACF, for CAD as a potentially useful and cost-effective screening tool for TB in a resource-poor HIV-endemic African setting. However, given methodological concerns, caution is required with regards to applicability and generalizability.

Assessment of health-related quality of life among Afghan refugees in Quetta, Pakistan.

The study aims to assess the health-related Quality of Life (HRQOL) and its association with socio-demographic factors among the Afghan refugees residing in Quetta, Pakistan. For this purpose, a cross-sectional, descriptive study design by adopting Euro QOL five dimensions questionnaire (EQ-5D) for the assessment of HRQOL was conducted by approaching Afghan refugees from the camp and other areas of Quetta, Pakistan. Furthermore, this study also involved descriptive analysis to expound participant's demographic characteristics while inferential statistics (Kruskal-Wallis and Mann-Whitney test, P < 0.05) were used to compare EQ-5D scale scores. All analyses were performed using SPSS v 20. Herein, a total of 729 participants were enrolled and were subsequently (n = 246, 33.7%) categorized based on their age of 22-31 years (31.30 ± 15.40). The results of mean EQ-5D descriptive score (0.85 ± 0.20) and EQ-VAS score (78.60 ± 11.10) indicated better HRQOL in the current study respondents as compared to studies conducted in other refugee camps around the globe. In addition, demographic characteristics including age, marital status, locality, years of living as refugees, life as a refugee residing out of Pakistan, place of residence in Afghanistan, educational qualification, occupation, and arrested for crime were the statistically significant predictors (P < 0.05) of EQ-5D index scores. However, gender, living status, monthly income, preferred place of treatment were non-significant predictors (P > 0.05). The results of current study provided evidence for a model that correlated with participant's socio-demographic information and HRQOL. Moreover, this study also revealed a baseline assessment for the health status of Afghan refugees, interestingly, these results could be applied for improving HRQOL of the given participants. In conclusion, the HRQOL of Afghan refugees residing in Quetta, Pakistan can largely be improved by providing adequate healthcare facilities, education and employment opportunities, mental and social support, and providing adequate housing and basic necessities of life.

Atypical Complications during the Course of COVID-19: A Comprehensive Review.

COVID-19 is primarily a respiratory disease, but numerous studies have indicated the involvement of various organ systems during the course of illness. We conducted a comprehensive review of atypical complications of COVID-19 with their incidence range (IR) and their impact on hospitalization and mortality rates. We identified 97 studies, including 55 research articles and 42 case studies. We reviewed four major body organ systems for various types of atypical complications: (i) Gastro-intestinal (GI) and hepatobiliary system, e.g., bowel ischemia/infarction (IR: 1.49-83.87%), GI bleeding/hemorrhage (IR: 0.47-10.6%), hepatic ischemia (IR: 1.0-7.4%); (ii) Neurological system, e.g., acute ischemic stroke/cerebral venous sinus thrombosis/cerebral hemorrhage (IR: 0.5-90.9%), anosmia (IR: 4.9-79.6%), dysgeusia (IR: 2.8-83.38%), encephalopathy/encephalitis with or without fever and hypoxia (IR: 0.19-35.2%); (iii) Renal system, e.g., acute kidney injury (AKI)/acute renal failure (IR: 0.5-68.8%); (iv) Cardiovascular system, e.g., acute cardiac injury/non-coronary myocardial injury (IR: 7.2-55.56%), arrhythmia/ventricular tachycardia/ventricular fibrillation (IR: 5.9-16.7%), and coagulopathy/venous thromboembolism (IR: 19-34.4%). This review encourages and informs healthcare practitioners to keenly monitor COVID-19 survivors for these atypical complications in all major organ systems and not only treat the respiratory symptoms of patients. Post-COVID effects should be monitored, and follow-up of patients should be performed on a regular basis to check for long-term complications.

The multifaceted role of Fragile X-Related Protein 1 (FXR1) in cellular processes: an updated review on cancer and clinical applications.

RNA-binding proteins (RBPs) modulate the expression level of several target RNAs (such as mRNAs) post-transcriptionally through interactions with unique binding sites in the 3'-untranslated region. There is mounting information that suggests RBP dysregulation plays a significant role in carcinogenesis. However, the function of FMR1 autosomal homolog 1(FXR1) in malignancies is just beginning to be unveiled. Due to the diversity of their RNA-binding domains and functional adaptability, FXR1 can regulate diverse transcript processing. Changes in FXR1 interaction with RNA networks have been linked to the emergence of cancer, although the theoretical framework defining these alterations in interaction is insufficient. Alteration in FXR1 expression or localization has been linked to the mRNAs of cancer suppressor genes, cancer-causing genes, and genes involved in genomic expression stability. In particular, FXR1-mediated gene regulation involves in several cellular phenomena related to cancer growth, metastasis, epithelial-mesenchymal transition, senescence, apoptosis, and angiogenesis. FXR1 dysregulation has been implicated in diverse cancer types, suggesting its diagnostic and therapeutic potential. However, the molecular mechanisms and biological effects of FXR1 regulation in cancer have yet to be understood. This review highlights the current knowledge of FXR1 expression and function in various cancer situations, emphasizing its functional variety and complexity. We further address the challenges and opportunities of targeting FXR1 for cancer diagnosis and treatment and propose future directions for FXR1 research in oncology. This work intends to provide an in-depth review of FXR1 as an emerging oncotarget with multiple roles and implications in cancer biology and therapy.

Respiratory health and its determinants among Nunavimmiut: results from the Qanuilirpitaa? 2017 Nunavik Health Survey.

OBJECTIVES: Respiratory diseases are the leading cause of hospitalization in Nunavik (northern Québec, Canada) and contribute to disparities in life expectancy with the rest of Canada. As part of Qanuilirpitaa? 2017, a cross-sectional population-based health survey, we sought to describe the prevalence of respiratory health indicators, including the first estimate of airway obstruction based on spirometry in an Inuit population, and explore their associated characteristics. METHODS: We analyzed data from 1296 participants aged 16 years and older, using multivariate logistic regression to assess characteristics associated with spirometry-determined airway obstruction and self-reported respiratory symptoms, i.e., wheezing in the last year and chronic cough during at least 3 months. RESULTS: In this relatively young population (83% aged 16 to 54), the prevalences of wheezing, chronic cough, and airway obstruction were, respectively, 27% (95% CI 24-30), 21% (18-23), and 17% (14-20). These estimates are prone to biases due to the relatively low participation rate (about 37%). The most consistent associations were with smoking (≥ 15 pack-years; odds ratio [OR] 3.13, 3.39, and 2.86 for the three indicators, respectively) and food security (OR 0.55 with wheezing and OR 0.26 with chronic cough), as defined in the Household Food Security Survey Module. Wheezing was also associated with allergic sensitization to dogs (2.60) and obesity (2.18). Chronic cough was associated with respiratory infections during childhood (2.12), housing in need of major repairs (1.72), and housing crowding (1.50), and was negatively associated with participation to traditional activities (0.62) and going on the land (0.64). Airway obstruction was associated with being underweight (3.84) and post-secondary education (0.40). Among young adults and women, wheezing was also associated with any inhalation of solvents for recreational purposes during their lifetime (2.62 and 1.56, respectively), while airway obstruction was associated with regular marijuana use (2.22 and 1.84, respectively). CONCLUSION: Smoking and food insecurity are both highly prevalent and strongly associated with respiratory symptoms in Nunavik. Together with essential smoking prevention and cessation programs, our findings suggest that solving food security and housing crises, improving socioeconomic conditions, and promoting traditional lifestyle may improve respiratory health in Nunavik.

RéSUMé: OBJECTIFS: Les maladies respiratoires sont la première cause d'hospitalisation au Nunavik (Nord-du-Québec, Canada) et contribuent aux écarts d'espérance de vie avec le reste du Canada. Dans le cadre de l'enquête transversale et populationnelle Qanuilirpitaa? 2017, cette étude décrit la prévalence d'indicateurs de santé respiratoire et explore les caractéristiques qui leur sont associées. Elle fournit le premier estimé de la prévalence d'obstruction respiratoire par spirométrie dans la population inuite. MéTHODES: Les données de 1 296 participants âgés de 16 ans et plus ont été analysées par régression logistique multivariée pour évaluer les caractéristiques associées avec le wheezing (dans la dernière année), la toux chronique (durant au moins 3 mois) et l'obstruction bronchique (mesurée par spirométrie). RéSULTATS: Dans cette population relativement jeune (83 % entre 16 et 54 ans), les prévalences de wheezing, de toux chronique et d'obstruction bronchique étaient de 27 % (IC95% 24-30), 21 % (18-23) et 17 % (14-20). Ces estimés pourraient être biaisés puisque le taux de participation à l'enquête était relativement faible (environ 37 %). Les associations les plus fortes et consistantes sont observées avec le tabagisme (≥ 15 paquets-années; RC 3,13, 3,39 et 2,86 pour les trois indicateurs, respectivement) et avec la sécurité alimentaire (RC 0,55 avec le wheezing et 0,26 avec la toux chronique), définie à partir du Module d'enquête sur la sécurité alimentaire des ménages. Le wheezing était notamment associé avec la sensibilisation allergique aux chiens (2,60) et l'obésité (2,18). La toux chronique était associée avec les infections respiratoires sévères dans l'enfance (2,12), un logement ayant besoin de réparations majeures (1,72) et un logement surpeuplé (1,50); tandis que participer aux activités traditionnelles (0,62) et aller souvent dans la nature (0,64) semblaient protecteurs. L'obstruction bronchique était associée avec un faible indice de masse corporelle (3,84) et un niveau de scolarité postsecondaire (0,40). Le wheezing était aussi associé avec le fait d'avoir déjà inhalé des solvants chez les jeunes adultes (2,62) et chez les femmes (1,56), tandis que l'obstruction bronchique était associée avec la consommation régulière de cannabis chez les jeunes adultes (2,22) et chez les femmes (1,84). CONCLUSION: Le tabagisme et l'insécurité alimentaire sont fort prévalents et fortement associés avec des symptômes respiratoires au Nunavik. En plus de rappeler l'importance de la prévention du tabagisme, ces résultats supportent la pertinence des efforts communautaires et gouvernementaux pour résoudre les crises de l'insécurité alimentaire et du logement, améliorer les conditions socioéconomiques et promouvoir la culture inuite afin d'améliorer la santé respiratoire au Nunavik.

Intramolecular CH-Hydrogen Bonding During the Dissociation of the Oxaphosphetane Intermediate Facilitates Z/E-Selectivity in Wittig Olefination.

Herein, DFT studies corroborating experimental results revealed that the shortest intramolecular hydrogen bonding distance of cis/trans-oxaphosphetane (OPA) oxygen with the CH-hydrogen of a triphenylphosphine phenyl ring provides good evidence for the attained olefin Z/E-selectivity in Wittig olefination of the studied examples. 2-Nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-nitro-3-bromobenzaldehyde, 2-nitro-5-bromobenzaldehyde and 2-nitro-5-arylbenzaldehydes provided Z-nitrostilbenes with (2-chloro-4-hydroxy-3-methoxy-5-(methoxycarbonyl)benzyl) triphenylphosphonium chloride as the major products. However, 4-nitrobenzaldehyde and 2-nitro-6-bromobenzaldehydes furnished E-nitrostilbenes as the major products in high yields. Furthermore, the DFT computed intramolecular CH1/CH2-hydrogen bond distances with Cl/NO2 of selected stilbene derivatives were in good agreement with intramolecular hydrogen bond distances measured from single-crystal X-ray diffraction measurements.

The prevalence of tuberculosis infection among foreign-born Canadians: a modelling study.

BACKGROUND: The prevalence of tuberculosis infection is critical to the design of tuberculosis prevention strategies, yet is unknown in Canada. We estimated the prevalence of tuberculosis infection among Canadian residents born abroad. METHODS: We estimated the prevalence of tuberculosis infection by age and year of migration to Canada for people from each of 168 countries by constructing country-specific and calendar year-specific trends for annual risk of infection using a previously developed model. We combined country-specific prevalence estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to estimate the overall prevalence of tuberculosis infection among foreign-born Canadian residents. RESULTS: The estimated overall prevalence of tuberculosis infection among foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%-35%) for census year 2001, 24% (95% UI 20%-33%) for 2006, 23% (95% UI 19%-30%) for 2011, 22% (95% UI 19%-28%) for 2016 and 22% (95% UI 19%-27%) for 2021. The prevalence increased with age at migration and incidence of tuberculosis in the country of origin. In 2021, the estimated prevalence of infection among foreign-born residents was lowest in Quebec (19%, 95% UI 16%-24%) and highest in Alberta (24%, 95% UI 21%-28%) and British Columbia (24%, 95% UI 20%-30%). Among all foreign-born Canadian residents with tuberculosis infection in 2021, we estimated that only 1 in 488 (95% UI 185-1039) had become infected within the 2 preceding years. INTERPRETATION: About 1 in 4 foreign-born Canadian residents has tuberculosis infection, but very few were infected within the 2 preceding years (the highest risk period for progression to tuberculosis disease). These data may inform future tuberculosis infection screening policies.

Metabolic Disorder Therapeutics and their Effects on Memory.

Diabetes is one of the major metabolic disorders of this era. It not only impacts a person's lifestyle but also has a long-term impact on the brain. It has a detrimental effect on a person's health when combined with hypertension and hyperlipidaemia. Several studies have suggested that the incidence of dementia is higher in people with metabolic syndrome. Investigations are underway to determine whether antidiabetic, hypolipidemic, hypercholesteraemic, anti-hypertensive, and other combination medicines can minimize the incidence of cognitive impairment. Some studies have suggested that anti-diabetic drugs like metformin, liraglutide, and dapagliflozin might enhance memory in long-term users. At the same time, other studies indicate that long-term insulin use may cause memory decline. Similarly, drugs like ACEIs, CCBs, fibrates, statins, and various nutraceuticals have been shown to improve cognition via multiple mechanisms. Literature suggests that drugs that can treat metabolic syndrome can also partially reduce the accumulation of beta-amyloid, whereas some studies contradict these findings. We review the past thirty years' of research work and summarize the effects of most commonly used drugs and nutraceuticals for treating metabolic syndrome on memory. Here, we review the effects of antidiabetic, hypolipidemic, anti-hypertensive, and hypercholesteremic, and their combination in learning and memory.

Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression.

Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Pharmacists' approach to oncology medicine shortages: results of a cross-sectional survey in Pakistan.

OBJECTIVES: The study estimated the shortages of oncology medicines in Pakistan, their causes, impacts, mitigation strategies, and possible interventions. DESIGN: Cross-sectional survey. SETTING: Oncology pharmacists working at 43 oncology settings (out of 80) from five regions of Pakistan (four provinces (Punjab, Sindh, Khyber Pakhtunkhwa and Baluchistan) and one federal territory (Islamabad)) were approached. PARTICIPANTS: Oncology pharmacists with more than 1 year of experience were selected using stratified random sampling, and data were collected using a questionnaire from September 2021 to January 2022. PRIMARY AND SECONDARY OUTCOME MEASURES: To estimate the prevalence of oncology medicine shortages in Pakistan and establish recommendations to overcome them. RESULTS: Of 167 responded pharmacists, 87% experienced shortages in their practice. Most respondents (50%) experienced both oncology and support agent shortages. It was a current problem in hospitals (58%) and increased with time, but the situation varied across regions (p=0.007). Mainly shortages occur half-yearly (p=0.001) and last for <3 months. Injectable (56.8%) and branded drugs (44.9%) were short. The most frequently mentioned drugs affected by shortages were etoposide, paclitaxel, dacarbazine, bleomycin and carboplatin. Usually, distributors (51.5%) notify the pharmacists about the shortages, and federal agencies (36%) are responsible for these shortages. Distributors (53.4%) were the main source of supply, and shortages were encountered by them as well. The impacts included delayed care (25%) and suboptimal outcomes (23%) on patients, extra time (32%) for staff, prioritisation issues (31%) for pharmacists, delayed clinical trials (60.5%) and increased drugs prices (52.1%). Some hospitals have reporting systems (39.5%) and recording (29.3%) drug shortages. The shortages were managed using available alternative options (21%) and redistributing (21%) the currently available stock. CONCLUSION: Pakistan's healthcare system is affected by oncology medicine shortages. The government should establish a cancer registry and drug shortage platform, revise drug prescribing/pricing policies and practice penalties for breaching regulations. Oncology medicines must be widely available to avoid the grey market.

Assessment of health-related quality of life among patients with obesity, hypertension and type 2 diabetes mellitus and its relationship with multimorbidity.

Obesity, hypertension (HTN) and type 2 diabetes (T2D) are among the multifactorial disorders that occur at higher prevalence in a population. This study aims to assess the health-related quality of life (HRQoL) of patients with obesity, HTN and T2D individually and in the form of multimorbidity. A questionnaire-based cross-sectional study was conducted among the patients in 15 private clinics of Punjab, Pakistan. A stratified random sampling technique was used to collect the data from patients with obesity, HTN and T2D or their comorbidity. A total of 1350 patients responded by completing the questionnaire. The HRQoL of these patients was assessed using the EQ-5D-5L questionnaire (a standardized instrument for measuring generic health status). Statistical analysis was performed using chi-square test, Mann-Whitney U test, and Kruskal-Wallis test. Multivariate linear regression model was used to model the visual analogue scale (VAS) score. In total, 15% of patients had combined obesity, HTN and T2D; 16.5% had HTN and T2D; 13.5% had obesity and HTN and 12.8% had obesity and T2D. Only 15.8% of patients had obesity, 14.3% had HTN, and 12% had T2D. Mann Whitney-U test gave the statistically significant (p = <0.001) HRQoL VAS score55.1 (±23.2) of patients with the obesity. HRQoL VAS scores of patients with obesity were found to be higher when compared to patients with both T2D 49.8 (±15.4) and HTN 48.2 (±21). Diagnosis of one, two and three diseases showed significant results in VAS with all variables including gender (p = 0.004), educational level (p = <0.001), marital status (p<0.001), residence (p = <0.001), financial situation (p = <0.001) and monthly income (p = <0.001). The most frequently observed extremely problematic dimension was anxiety/ depression (47%) and the self-care (10%) was the least affected. Patient HRQoL is decreased by T2D, HTN, and obesity. The impact of these diseases coexisting is more detrimental to HRQoL.