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Purpose: Despite the surge of melatonin supplement consumption in recent years, data on the prevalence and patterns of melatonin usage in Saudi Arabia is lacking. The aim of this study was to assess the prevalence and pattern of sleep-related melatonin usage among adults in Saudi Arabia. Methods: This was a cross-sectional, web-based, self-administered survey study conducted across all regions of Saudi Arabia. Participants were recruited from the general population (≥18 years). The survey was distributed between February and April 2023. Chi-squared tests and t-tests were performed for comparative bivariate analyses where binary logistic regression was performed to derive the main predictors of melatonin consumption. Results: Out of 5,606 participants, 536 (10 %) were consumers of melatonin. Older age (Adjusted OR = 1.01, 95 % CI = 1.01–1.02, p = 0.002), being a male (Adjusted OR = 1.76, 95 % CI = 1.46–2.14, p = 0.001), individuals with a doctorate degree or an equivalent (adjusted OR 2.37 95 % CI = 1.35–4.17, p = 0.003), perceived poor sleep quality (Adjusted OR = 1.52, 95 % CI = 1.10–2.11, p = 0.01), and being diagnosed with a sleep disorder (Adjusted OR = 2.55, 95 % CI = 2.04–3.18, p = 0.001) were all associated with increased likelihood of sleep-related melatonin usage. 35 % of consumers self-reported taking ≥1 tablet per day, while 26 % of them were uncertain about the dosage they consume. Conclusion: With a notable prevalence of 10% among the general population in Saudi Arabia, melatonin usage was more common in older adults, males, and those with higher education.

Evaporative cooling in the kingdom of Saudi Arabia is one of the most important cooling systems used inside greenhouses to obtain an acceptable temperature change in hot, dry climates. It is considered insufficient during very hot summer periods, when temperatures outside the greenhouse reach approximately 48 °C, which affects the efficiency of cooling, and thus, creates stress on the plants, leading to wilting and a decrease in the production rate. The cooling system is developed by making an insulated rectangular tunnel. The air comes out through vertical openings directly to the plants. The results of evaluating plant heat stress in the developed cooling system (DCS) showed an increase in the values of the photosynthesis rate, transpiration rate, carbon dioxide exchange, and stomatal conductance. The plants also appeared well in terms of the shape of the leaves, their freshness, the abundance of flowers, and the large size of the fruits, while in the traditional cooling system (TCS) the plants exhibited some wilting and some brown spots. The hectare yield reached 42.49 ton/ha for the DCS system, while it reached 37.53 ton/ha for the TCS with an increasing rate of 13.22 %. The total weight of fruits harvested within 60 days of cultivation was 4.25 kg/m2 for the DCS and 3.75 kg/m2 for the TCS. The dry and fresh weight of fruit, stem, and leaves, total dissolved solids, vitamin C, chlorophyll percentage in leaves, and total plant acidity, were higher in DCS compared to the TCS.

Summary: Novel insecticides were recently introduced to counter pyrethroid resistance threats in African malaria vectors. To prolong their effectiveness, potential cross-resistance from promiscuous pyrethroid metabolic resistance mechanisms must be elucidated. Here, we demonstrate that the duplicated P450s CYP6P9a/-b, proficient pyrethroid metabolizers, reduce neonicotinoid efficacy in Anopheles funestus while enhancing the potency of chlorfenapyr. Transgenic expression of CYP6P9a/-b in Drosophila confirmed that flies expressing both genes were significantly more resistant to neonicotinoids than controls, whereas the contrasting pattern was observed for chlorfenapyr. This result was also confirmed by RNAi knockdown experiments. In vitro expression of recombinant CYP6P9a and metabolism assays established that it significantly depletes both clothianidin and chlorfenapyr, with metabolism of chlorfenapyr producing the insecticidally active intermediate metabolite tralopyril. This study highlights the risk of cross-resistance between pyrethroid and neonicotinoid and reveals that chlorfenapyr-based control interventions such as Interceptor G2 could remain efficient against some P450-based resistant mosquitoes.

Many patients with obstructive sleep apnoea (OSA) remain undiagnosed and thus untreated, and in part this relates to delay in diagnosis. Novel diagnostic strategies may improve access to diagnosis. In a multicentre, randomised study, we evaluated time to treatment decision in patients referred for suspected OSA, comparing a mandibular movement (MM) monitor to respiratory polygraphy, the most commonly used OSA detection method in the UK. Adults with high pre-test probability OSA were recruited from both northern Scotland and London. 40 participants (70 % male, mean±SD age 46.8 ± 12.9 years, BMI 36.9 ± 7.5 kg/m2, ESS 14.9 ± 4.1) wore a MM monitor and respiratory polygraphy simultaneously overnight and were randomised (1:1) to receive their treatment decision based on results from either device. Compared to respiratory polygraphy, MM monitor reduced time to treatment decision by 6 days (median(IQR): 13.5 (7.0–21.5) vs. 19.5 (13.7–35.5) days, P = 0.017) and saved an estimated 29 min of staff time per patient.

The contemporary energy sector has witnessed a notable surge in integrating renewable energy sources (RESs) within energy hubs (EHs). The intermittent characteristics inherent to RESs present a consequential challenge, notably compromising the operational flexibility of EHs. This paper proposes a two-stage adaptive robust optimization (ARO)-based interconnected energy and gas system (IPGS) with optimally sized and allocated components and energy hubs (EHs). The IPGS components and EHs are optimally sized and allocated in the first stage for optimal performance before the uncertainty realization while minimizing the investment costs. The model’s second stage incorporates optimizing operations and managing RES output uncertainty. In the second stage, the RES output uncertainty is maximized after realization while minimizing operation cost. The integration of battery energy storage systems (BESSs), thermal energy storage systems (TESSs), hydrogen storage (HSs), power-to-gas (P2G), and gas-to-power (G2P) technologies collectively serve as flexible resources that also handle uncertainty. The IPGS also incorporates a carbon capture system (CCS) to support the decarbonization of power systems. To further minimize operation costs, methane is synthesized and sold, and fuel cells are added to convert hydrogen to electricity sold to the grid. A column and constraint generation (CC&G) algorithm decomposes the ARO model using the duality theory and dual cuts. The ARO model minimizes the investment and operation costs under the worst-case realization of the uncertainties, namely, PV output, electricity demand, heat demand, and electricity and gas prices. Simulation results have demonstrated the effectiveness of the proposed method through reduced energy consumption from the grid and increased RES penetration while handling RES output intermittency. The ARO model eliminated load shedding from 31.5 MW for IEEE 24-bus and 60.3 MW for IEEE 118-bus to zero.

Pyogenic granuloma (PG) is a common benign vascular neoplasm that grows rapidly on the skin and mucosal tissues, often leading to surface ulceration and tissue damage. Pregnant women are more prone to developing PG, with up to 5% of pregnant women experiencing the condition. To the best of our knowledge, no case study has been published to date illustrating the management of PG in pregnant patients vulnerable to hemorrhage. A 27-year-old pregnant woman receiving anticoagulant therapy presented with painful lumps on the tongue. She had previously undergone surgical removal of a lump, which reappeared after a month. An external oral examination revealed swelling and a raised, reddish, oval-shaped lesion behind the lower anterior teeth. The lesion was pedunculated with a smooth surface and bleeding. Owing to recurrence and pain, the lumps were excised again using a scalpel. The excised tissue specimens were sent for histopathological assessment to confirm the diagnosis of PG. The tumor was removed with minimal trauma and pressure was applied sublingually to minimize bleeding. Tissue glue was applied for hemostasis, and the patient was instructed to prevent bleeding by applying pressure to the excised area. At the one-week follow-up, no complications were observed. This case report highlights the therapeutic significance of complete tumor excision and pressure therapy in mitigating excessive bleeding, particularly in patients receiving anticoagulant therapy.

Hepatocellular carcinoma (HCC) exhibits high mortality rates in the advanced stage (>90 %). Sorafenib (SORA) is a targeted therapy approved for the treatment of advanced HCC; however, the reported response rate to such a therapeutic is suboptimal (

RESUMO Este artigo se baseia na necessidade do Estado de prover educação pública de qualidade para aumentar a produtividade, o crescimento e, em última instância, o bem-estar da população.

Abstract Molecular mechanisms driving the escalation of pyrethroid resistance in the major malaria mosquitoes of Central Africa remain largely uncharacterized, hindering effective management strategies. Here, resistance intensity and the molecular mechanisms driving it were investigated in a population of Anopheles coluzzii from northern Cameroon. High levels of pyrethroid and organochloride resistance were observed in An. coluzzii population, with no mortality for 1× permethrin; only 11% and 33% mortalities for 5× and 10× permethrin diagnostic concentrations, and

Chrysin (CR) is a water-insoluble drug reported for different therapeutic effects. The microwave irradiation method was used in this study to create a multicomponent inclusion complex (CR-MC) containing CR (drug) and carrier hydroxyl propyl beta cyclodextrin (HP β CD) and L-arginine (LA). The prepared inclusion complex (CR-MC) was evaluated for dissolution study and results were compared with chrysin physical mixture (CR-PM). Further, the samples were assessed for infra-red (IR), nuclear magnetic resonance (NMR), differential scanning calorimeter (DSC), scanning electron microscope (SEM) and molecular docking. Finally, the cell viability, reactive oxygen species and flow cytometer studies were also assessed to check the potential of the prepared inclusion complex on the human primary glioblastoma cell line (U87-MG cell). The phase solubility findings revealed a stability constant (773 mol L−1) as well as a complexation efficiency of 0.027. The dissolution study displayed a significant increase in CR release from CR-MC (99.03 ± 0.39%) > CR-PM (70.58 ± 1.16%) > pure CR (35.29 ± 1.55%). NMR and IR spectral data revealed no interaction between CR and carriers. SEM and DSC study results revealed the conversion into amorphous form. The molecular docking results illustrated a high docking score, which supports the findings of complex formation. The cell viability, reactive oxygen species, and flow cytometry studies results showed enhanced activity from CR-MC against the tested human primary glioblastoma cell line. From the results it has been observed that chrysin solubility significantly increased after complexation and there in vitro activity also enhanced against cancer cell line.

Abstract Background Information on common markers of metabolic resistance in malaria vectors from countries sharing similar eco-climatic characteristics can facilitate coordination of malaria control. Here, we characterized populations of the major malaria vector Anopheles coluzzii from Sahel region, spanning four sub-Saharan African countries: Nigeria, Niger, Chad and Cameroon. Results Genome-wide transcriptional analysis identified major genes previously implicated in pyrethroid and/or cross-resistance to other insecticides, overexpressed across the Sahel, including CYP450s, glutathione S-transferases, carboxylesterases and cuticular proteins. Several, well-known markers of insecticide resistance were found in high frequencies—including in the voltage-gated sodium channel (V402L, I940T, L995F, I1527T and N1570Y), the acetylcholinesterase-1 gene (G280S) and the CYP4J5-L43F (which is fixed). High frequencies of the epidemiologically important chromosomal inversion polymorphisms, 2La, 2Rb and 2Rc, were observed (~80% for 2Rb and 2Rc). The 2La alternative arrangement is fixed across the Sahel. Low frequencies of these inversions (C), between Forkhead box L1 and c-EST putative binding sites, were responsible for the high overexpression of GSTe2 in the resistant mosquitoes. Transgenic flies expressing CYP6Z2 exhibited marginal resistance towards 3-phenoxybenzylalcohol (a primary product of pyrethroid hydrolysis by carboxylesterases) and a type II pyrethroid, α-cypermethrin. However, significantly higher mortalities were observed in CYP6Z2 transgenic flies compared with controls, on exposure to the neonicotinoid, clothianidin. This suggests a possible bioactivation of clothianidin into a toxic intermediate, which may make it an ideal insecticide against populations of An. coluzzii overexpressing this P450. Conclusions These findings will facilitate regional collaborations within the Sahel region and refine implementation strategies through re-focusing interventions, improving evidence-based, cross-border policies towards local and regional malaria pre-elimination.

There is a severe lack of information about molecular mechanisms of pesticide resistance in the rust-red flour beetle, a major pest destroying grains and flour across Nigeria, hindering evidence-based control. Here, we identified to the species level three populations of the red flour beetle from Kano, Nigeria, as Tribolium castaneum (Herbst 1797) and investigated the mechanism driving their insecticide resistance. The IRAC susceptibility bioassays established cypermethrin resistance, with LC50s of 4.35–5.46 mg/mL in the three populations, NNFM, R/Zaki and Yankaba. DDT and malathion resistance were observed in NNFM, with LC50s of 15.32 mg/mL and 3.71 mg/mL, respectively. High susceptibility was observed towards dichlorvos in all three populations with LC50s of 0.17–0.35 mg/mL. The synergist bioassay with piperonylbutoxide significantly restored cypermethrin susceptibility, with mortality increasing almost threefold, from 24.8% obtained with 1.5 mg/mL of cypermethrin to 63.3% in the synergised group (p = 0.013), suggesting a preeminent role of P450s. The two major knockdown resistance (kdr) mutations, T929I and L1014F, in the IIS4 and IIS6 fragments of the voltage-gated sodium channel were not detected in both cypermethrin-alive and cypermethrin-dead beetles, suggesting a lesser role of target-site insensitivity mechanisms. These findings highlight the need to explore alternative control tools for this pest and/or utilise synergists, such as piperonyl butoxide, as additional chemistries in pesticide formulations to improve their efficacy.

Cross-resistance to insecticides in multiple resistant malaria vectors is hampering resistance management. Understanding its underlying molecular basis is critical to implementation of suitable insecticide-based interventions. Here, we established that the tandemly duplicated cytochrome P450s, CYP6P9a/b are driving carbamate and pyrethroid cross-resistance in Southern African populations of the major malaria vector Anopheles funestus. Transcriptome sequencing revealed that cytochrome P450s are the most over-expressed genes in bendiocarb and permethrin-resistant An. funestus. The CYP6P9a and CYP6P9b genes are overexpressed in resistant An. funestus from Southern Africa (Malawi) versus susceptible An. funestus (Fold change (FC) is 53.4 and 17 respectively), while the CYP6P4a and CYP6P4b genes are overexpressed in resistant An. funestus in Ghana, West Africa, (FC is 41.1 and 17.2 respectively). Other up-regulated genes in resistant An. funestus include several additional cytochrome P450s (e.g. CYP9J5, CYP6P2, CYP6P5), glutathione-S transferases, ATP-binding cassette transporters, digestive enzymes, microRNA and transcription factors (FC

A significant amount of clinical research is observational by nature and derived from medical records, clinical trials, and large-scale registries. While there is no substitute for randomized, controlled experimentation, such experiments or trials are often costly, time consuming, and even ethically or practically impossible to execute. Combining classical regression and structural equation modeling with matching techniques can leverage the value of observational data. Nevertheless, identifying variables of greatest interest in high-dimensional data is frequently challenging, even with application of classical dimensionality reduction and/or propensity scoring techniques. Here, we demonstrate that projecting high-dimensional medical data onto a lower-dimensional manifold using deep autoencoders and post-hoc generation of treatment/control cohorts based on proximity in the lower-dimensional space results in better matching of confounding variables compared to classical propensity score matching (PSM) in the original high-dimensional space (P

This study focuses on the development and characterization of solid dispersions (SDs) of Gefitinib (GEF) to improve its aqueous solubility and therapeutic activity against lung cancer. SDs were prepared by the co-precipitation method with tocopheryl-polyethylene-glycol succinate-1000 (TPGS) (F1), sodium lauryl sulfate (SLS) (F2) and complexation of F1 with hydroxypropyl β-cyclodextrin (HP-β-CD) (F3). Optimal formulations (F1 and F3) were used against A549 cells to determine the apoptosis, expressions of p53 and caspases. F3 has shown the highest solubility (1271.21 µg/mL), followed by F1 (1003.69 µg/mL), F2 (707.81 µg/mL) and GEF pure (303.85 µg/mL) in 0.1N HCl. Dissolution at 1.2 pH significantly enhanced the release from F3 (99.19%), followed by F1 (94.76%), F2 (85.70%) and GEF pure (37.26%) during 120 min. Complexation of GEF–TPGS with HP-β-CD significantly improved drug release with high dissolution efficiency (78.57%) in 24.9 min of mean dissolution time. Differential scanning calorimetry revealed crystalline to amorphous conversion of GEF in SDs, which was confirmed by scanning electron microscopy. Fourier transform infrared and proton nuclear magnetic resonance spectral analysis revealed no interaction between GEF and excipients. The IC50 values were 2.239, 3.135 and 4.471 µM for F3, F1 and GEF pure, respectively, against A549 cells. Increased expressions of p53 (5.9-, 4.6- and 3.04-fold), caspase-3 (5.38-, 3.78- and 3.01-fold) and caspase-9 (5.35-, 3.76- and 2.47-fold) in the case of F3, F1 and GEF pure, respectively, as compared to the untreated A549 cells indicated improved apoptotic potential of the SDs. TPGS SDs and their complexation with HP-β-CD improved the solubility, dissolution and efficacy of GEF against A549 cells. So, they can be a suitable alternative to the conventional GEF formulations against non-small-cell lung cancers.

Hirsutism is a distressing condition that can affect women’s self-esteem due to the excessive amount of hair growth in different body parts, including the face. A temporary managing option is to develop a self-care routine to remove unwanted hair through shaving or waxing. Laser or electrolysis are alternative methods, but in some cases, the use of medications, such as the topical cream Vaniqa®, can help in reducing the growth of unwanted hair. Electrospun fibers have been used in several drug delivery applications, including skin care products, owing to their biocompatibility, biodegradability, high surface area-to-volume ratio, and dry nature that can release the encapsulated drugs with maximum skin penetration. Therefore, polyvinyl pyrrolidone (PVP) fibers were fabricated in combination with hyaluronic acid to deliver the active compound of Vaniqa®, i.e., Eflornithine hydrochloride (EFH), as a face mask to inhibit excess facial hair growth. The prepared drug-loaded fibers showed a diameter of 490 ± 140 nm, with an encapsulation efficiency of 88 ± 7% and a drug loading capacity of 92 ± 7 μg/mg. The in vitro drug release of EFH-loaded fibers exhibited an initial burst release of 80% in the first 5 min, followed by a complete release after 360 min, owing to the rapid disintegration of the fibrous mat (2 s). The in vitro cytotoxicity indicated a high safety profile of EFH at all tested concentrations (500–15.625 μg/mL) after 24-h exposure to human dermal fibroblast (HFF-1) cells. Therefore, this drug-loaded nanofibrous system can be considered a potentially medicated face mask for the management of hirsutism, along with the moisturizing effect that it possesses. Topical applications of the developed system showed reduced hair growth in mice to a certain extent.

Background The coronavirus disease 2019 pandemic has accelerated the adoption of virtual care strategies for the management of patients with obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Research question What is the effectiveness of virtual consultations compared to in-person consultations for the management of continuous positive airway pressure (CPAP) therapy in adult patients with OSAHS? Methods A systematic review and meta-analysis (PROSPERO; CRD42022297532) based on six electronic databases plus manually selected journals was conducted in January 2022. Two researchers independently selected, quality appraised and extracted data. The co-primary outcomes were patient-reported sleepiness, assessed by the Epworth Sleepiness Scale (ESS), and reported cost-effectiveness. Results 12 studies (n=1823 adults) were included in the review. Seven studies (n=1089) were included in the meta-analysis which showed no difference in the magnitude of improvement in patient-reported sleepiness scores between virtual and in-person consultations (mean difference −0.39, 95% CI −1.38–0.60; p=0.4), although ESS scores improved in both groups. Virtual care strategies modestly increased CPAP therapy adherence and were found to be less costly than in-person care strategies in the three Spanish trials that reported cost-effectiveness. Conclusion The findings of this review suggest that virtual care delivered by telephone or video consultations is as effective as in-person consultations for improving subjective sleepiness in patients with OSAHS treated with CPAP. This clinical management strategy may also improve CPAP adherence without increasing the costs, supporting its potential as a follow-up management strategy, where patients prefer this approach.

Umifenovir is one of the most often prescribed antiviral medications for the prevention and treatment of COVID-19 and other viral infections. Herein, a UPLC-MS/MS method is developed through using ibrutinib as an internal standard (IS) for quantifying umifenovir in plasma samples. Both umifenovir and the IS were analytically separated on an Acquity BEH C18 column with a total run time of only 2.5 min. At a flow rate of 0.3 mLmin−1, acetonitrile:15 mM ammonium acetate (80:20) was employed as the mobile phase composition. Electrospray ionization in positive mode was used for ionization of the samples. Detection and quantification were performed in multiple reaction monitoring mode with parent-to-daughter ionization of 477.05 → 279.02 and 441.16 → 84.4 for umifenovir and the IS, respectively. The method was validated through following international guidelines for bioanalytical method validation, and all parameters were within the acceptable limits. Moreover, the eco-scale method using AGREE software was used for the evaluation of greenness, and results showed that the method is very environmentally friendly. The validated assay was successfully employed in the bioavailability assessment of a newly developed formulation of kneaded ternary umifenovir/β-cyclodextrin with 1% poloxamer 188 (KDB).

5-Fluorouracil (5-FU) is now used in eye drops for the management of conjunctival malignant melanoma, intraepithelial neoplasia, and corneal and conjunctival squamous cell carcinoma. The previously used methods for 5-FU quantification in AqH were time-consuming and less sensitive. Herein, a highly perceptive bioanalytical UPLC–MS/MS method was developed for the quantitative determination of 5-FU in the aqueous humor (AqH) of rabbits using allopurinol as the internal standard (IS). The 5-FU and IS were well separated in an Acquity™ HILIC column. Acetonitrile and 10 mM of ammonium acetate at 95:5 (v/v) were isocratically pumped at a 0.3 mL/min flow rate with a total runtime of 2.5 min. AqH samples were processed with a liquid–liquid extraction method in ethyl acetate. The 5-FU and IS were identified in the negative mode with electrospray ionization. The parent to daughter ion transitions for the 5-FU and IS occurred at m/z 128.92→41.68 and 134.80→64.10, respectively, as quantified using the multiple reaction monitoring mode. The developed method was validated with the ICH-Harmonized Guideline for Bioanalytical Method Validation, and the parameters were within acceptable limits. The calibration curve was linear at the 10.5–2000 ng/mL concentration range, with a correlation coefficient (R2) of 0.9946, and the lower limit of detection was 3.55 ng/mL. The developed and validated method was rapid, sensitive, accurate and robustly able to quantify 5-FU in rabbit AqH. The method was effectively applied to establish the ocular pharmacokinetics of 5-FU following the topical instillation of 5-FU-containing preparations in rabbits.