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Due to their exceptional properties, cellulose nanocrystals (CNCs) have been proposed for various applications in sustainable materials science. However, state-of-the-art production methods suffer from low yields and rely on hazardous and environmentally harmful chemicals, representing a bottleneck for more widespread utilization of CNCs. In this study, we present a novel two-step approach that combines previously established HCl gas hydrolysis with electrochemical TEMPO oxidation. This unique method allows the collection of easily dispersible CNCs with high carboxylate contents in excellent overall yields of 71%. The electromediated oxidation was conducted in aqueous conditions without the usually required cocatalysts, simplifying the purification of the materials. Moreover, the proposed process is designed for facile recycling of the used reagents in both steps. To evaluate the sustainability and scalability, the environmental impact factor was calculated, and a cost analysis was conducted.

Background and Objective: This study aimed to determine the cost-effectiveness of Tocilizumab (TCZ) compared with Adalimumab (ADA) in patients with Rheumatoid Arthritis (RA), who had not responded to methotrexate (MTX), from a societal perspective in Iran., Method: To conduct the cost-utility analysis, using an individual microsimulation Markov model, a hypothetical cohort of 1,000 patients was evaluated over a lifetime horizon. The efficacy and safety of each treatment were estimated using the American College of Rheumatology (ACR) criteria to determine the continuation or switching of treatment every six months. Treatment responses were captured based on Health Assessment Questionnaire (HAQ) scores and mapped into utility values to determine QALY gained for each treatment. All direct and indirect costs associated with the disease and perspective were included according to societal perspective. Deterministic and Probabilistic sensitivity analyses were performed to assess the robustness of the model., Results: The result of the study estimated that TCZ is a more cost-effective treatment option, with a probability of 76%. TCZ was associated with a higher cost ($6,990 versus $6,608) and higher QALYs gained (4.24 versus 3.95) compared to ADA with an incremental cost-effectiveness ratio (ICER) of USD 1,301, which is below the willingness-to-pay threshold of 1,448 USD in Iran., Conclusion: This study provides convincing evidence of the cost-effectiveness of TCZ compared to ADA in the treatment of active severe RA in Iran., Competing Interests: Declarations Ethics approval Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Genetic diversity is heterogeneously distributed among populations of the same species, due to the joint effects of multiple demographic processes, including range contractions and expansions, and mating systems shifts. Here, we ask how both processes shape genomic diversity in space and time in the classical Primula vulgaris model. This perennial herb originated in the Caucasus region and was hypothesized to have expanded westward following glacial retreat in the Quaternary. Moreover, this species is a long-standing model for mating system transitions, exemplified by shifts from heterostyly to homostyly. Leveraging a high-quality reference genome of the closely related Primula veris and whole-genome resequencing data from both heterostylous and homostylous individuals from populations encompassing a wide distribution of P. vulgaris, we reconstructed the demographic history of P. vulgaris. Results are compatible with the previously proposed hypothesis of range expansion from the Caucasus region approximately 79,000 years ago and suggest later shifts to homostyly following rather than preceding postglacial colonization of England. Furthermore, in accordance with population genetic theoretical predictions, both processes are associated with reduced genetic diversity, increased linkage disequilibrium, and reduced efficacy of purifying selection. A novel result concerns the contrasting effects of range expansion versus shift to homostyly on transposable elements, for the former, process is associated with changes in transposable element genomic content, while the latter is not. Jointly, our results elucidate how the interactions among range expansion, transitions to selfing, and Quaternary climatic oscillations shape plant evolution., Competing Interests: Conflict of Interest The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

This study explores the production of furfural, xylose and methylxylosides through the methanolysis of wood flour using anhydrous HCl gas. The process involves methanolysis of wood flour with HCl gas under pressure to generate methylxylosides, which are subsequently converted to xylose and furfural via autohydrolysis in a Parr batch reactor system. The methanolysis was conducted in temperature-controlled HCl gas reactor employing 24 h reaction time and 50 % methanol content in wood flour. During the methanolysis step with HCl gas, 65 % of the available xylan in wood flour was converted to water-soluble methylxylosides, xylose, xylooligosaccharides (XO) and water-soluble methyl xylooligosaccharides (MXO). Methanolysis filtrates were then autohydrolyzed with Parr 50 mL batch reactor system to xylose and furfural in two different pH values at 180 °C. The highest furfural yield of 91 % from methanolysis filtrate was achieved with pH 1.2 and 25 min reaction time., (© 2024 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

The under-eye region is an area of significant cosmetic concern. Photobiomodulation (PBM) has emerged as an effective, safe, inexpensive, and convenient treatment for skin rejuvenation. Herein, we aim to evaluate the safety and efficacy of a LED under-eye device for under-eye rejuvenation, as measured by objective and patient reported outcomes. Eleven participants self-administered treatment using a commercially available LED device emitting red (633 nm) and near infrared (830 nm) light for six weeks. Standardized photographs and questionnaires were administered at baseline and six weeks. Photographic digital analysis indicated an improvement in under-eye wrinkles at six weeks compared to baseline, with a reduction in wrinkle score from 20.05 to 19.72. However, this finding was not statistically significant. Participants self-reported consistent improvements in under-eye wrinkles, texture, dark circles, bags, pigmentation, and erythema. All participants reported a high degree of comfortability, ease of use, and satisfaction with the eye device. The participants noted no moderate or severe adverse events and few reports of transient expected outcomes such as mild erythema. The participants' self-reported improvements and high user satisfaction, and the device's favorable safety profile, highlights the benefits of at-home LED devices for under-eye rejuvenation. Future randomized controlled trials with larger sample sizes could further establish the safety and efficacy of at-home LED under-eye treatments., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has been the primary reason behind the COVID-19 global pandemic which has affected millions of lives worldwide. The fundamental cause of the infection is the molecular binding of the viral spike protein receptor binding domain (SP-RBD) with the human cell angiotensin-converting enzyme 2 (ACE2) receptor. The infection can be prevented if the binding of RBD-ACE2 is resisted by utilizing certain inhibitors or drugs that demonstrate strong binding affinity towards the SP RBD. Sialic acid based glycans found widely in human cells and tissues have notable propensity of binding to viral proteins of the coronaviridae family. Recent experimental literature have used N-acetyl neuraminic acid (Sialic acid) to create diagnostic sensors for SARS-CoV-2, but a detailed interrogation of the underlying molecular mechanisms is warranted. Here, we perform all atom molecular dynamics (MD) simulations for the complexes of certain Sialic acid-based molecules with that of SP RBD of SARS CoV-2. Our results indicate that Sialic acid not only reproduces a binding affinity comparable to the RBD-ACE2 interactions, it also assumes the longest time to dissociate completely from the protein binding pocket of SP RBD. Our predictions corroborate that a combination of electrostatic and van der Waals energies as well the polar hydrogen bond interactions between the RBD residues and the inhibitors influence free energy of binding.Communicated by Ramaswamy H. Sarma.

Research on supergenes, non-recombining genomic regions housing tightly linked genes that control complex phenotypes, has recently gained prominence in genomics. Heterostyly, a floral heteromorphism promoting outcrossing in several angiosperm families, is controlled by the S-locus supergene. The S-locus has been studied primarily in closely related Primula species and, more recently, in other groups that independently evolved heterostyly. However, it remains unknown whether genetic architecture and composition of the S-locus are maintained among species that share a common origin of heterostyly and subsequently diverged across larger time scales. To address this research gap, we present a chromosome-scale genome assembly of Primula edelbergii, a species that shares the same origin of heterostyly with Primula veris (whose S-locus has been characterized) but diverged from it 18 million years ago. Comparative genomic analyses between these two species allowed us to show, for the first time, that the S-locus can 'jump' (i.e. translocate) between chromosomes maintaining its function in controlling heterostyly. Additionally, we found that four S-locus genes were conserved but reshuffled within the supergene, seemingly without affecting their expression, thus we could not detect changes explaining the lack of self-incompatibility in P. edelbergii. Furthermore, we confirmed that the S-locus is not undergoing genetic degeneration. Finally, we investigated P. edelbergii evolutionary history within Ericales in terms of whole genome duplications and transposable element accumulation. In summary, our work provides a valuable resource for comparative analyses aimed at investigating the genetics of heterostyly and the pivotal role of supergenes in shaping the evolution of complex phenotypes., (© 2024 The Author(s). Molecular Ecology Resources published by John Wiley & Sons Ltd.)

Syringomas are benign neoplasms derived from eccrine sweat glands. Eruptive syringomas are a subtype of syringomas and are typically located on the chest, neck, and abdomen during puberty or childhood. Herein, we present a 20-year-old African American female with an atypical case of eruptive syringomas, characterized by an unusual distribution on her chest, abdomen, and anterior and posterior bilateral extremities. This case underscores the importance of recognizing diverse presentations of skin conditions in patients with skin of color and adds to the limited reports of eruptive syringoma in these populations. We present and emphasize this atypical manifestation of eruptive syringomas in an individual with darker skin to promote awareness and improve diagnosis and patient outcomes.J Drugs Dermatol. 2024;23(7):564-566. doi:10.36849/JDD.8103.

Introduction: Bacterial infections and the rising antimicrobial resistance pose a significant threat to public health. Pseudomonas aeruginosa produces bacteriocins like pyocins, especially S-type pyocins, which are promising for biological applications. This research focuses on clinical P. aeruginosa isolates to assess their bacteriocin production, inhibitory spectrum, chemical structure, antibacterial agents, and preservative potential., Methods: The identification of P. aeruginosa was conducted through both phenotypic and molecular approaches. The inhibitory spectrum and antibacterial potential of the isolates were assessed. The kinetics of antibacterial peptide production were investigated, and the activity of bacteriocin was quantified in arbitrary units (AU ml -1 ). Physico-chemical characterization of the antibacterial peptides was performed. Molecular weight estimation was carried out using SDS-PAGE. qRT-PCR analysis was employed to validate the expression of the selected candidate gene., Result: The antibacterial activity of P. aeruginosa was attributed to the secretion of bacteriocin compounds, which belong to the S-type pyocin family. The use of mitomycin C led to a significant 65.74% increase in pyocin production by these isolates. These S-type pyocins exhibited the ability to inhibit the growth of both Gram-negative (P. mirabilis and P. vulgaris) and Gram-positive (S. aureus, S. epidermidis, E. hirae, S. pyogenes, and S. mutans) bacteria. The molecular weight of S-type pyocin was 66 kDa, and its gene expression was confirmed through qRT-PCR., Conclusion: These findings suggest that S-type pyocin hold significant potential as therapeutic agents against pathogenic strains. The Physico-chemical resistance of S-type pyocin underscores its potential for broad applications in the pharmaceutical, hygiene, and food industries., (© 2024. The Author(s).)

Nowadays the significant role of biobanks in medical, diagnostic, industrial, and environmental research is well known. Bacterial biobanks could be used as a good resource for designing new treatments, biomedical and industrial researches, and laboratory diagnostics. To have a collection of bacteria from clinical samples and maintain their long-term viability, their preservation needs appropriate protective agents, like cryoprotectants and lyoprotectants. In this study, we collected and characterized Gram-negative and Gram-positive bacteria carrying important antibiotic resistance markers from different clinical samples of hospitalized children. Sucrose (10%), skimmed milk (10%), skimmed milk plus sodium glutamate (10% + 1%), and bovine serum albumin (BSA, 10%) were used as lyoprotectants during the freeze-drying procedure. The survival rate of the lyophilized samples was calculated by dilution plating and measuring the colony forming unit (CFU) after 3 months of storage. The culture analysis results indicated that 25 of the 27 studied bacterial genera (Dilutions 10 -3 to 10 -6 ), including Shigella, Methicillin-resistant S. aureus, Acinetobacter spp., Escherichia spp., Pseudomonas spp., Klebsiella spp., Enterococcus spp., were recovered in cultured fractions from all preservation conditions, while 2 genera were only detected in a single preservation condition (2/27, 7.4%). Based on the results, sucrose (10%) and skimmed milk (10%) presented the most protective features. The survival rates varied significantly according to types of the bacteria. Collectively, our results showed a diversity in the recovery of different bacterial genera after lyophilization. While statistically no significant difference was detected among the studied protective agents, sucrose (10%) and skimmed milk (10%) exhibited more effective lyoprotective properties for both Gram-positive and Gram-negative bacteria among the clinical isolates in our study., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Society for Cryobiology. Published by Elsevier Inc. All rights reserved.)

Considering the plethora of work on the exceptional environmental performance of 2D nanomaterials, there is still a missing link in addressing their practical application in point-of-use (POU) water treatment. By reviewing the exceptional environmental performance of 2D nanomaterials with specific emphasis on graphene and its derivatives, this review aims at inspiring further discussions and research in graphene-based POU water treatment with particular focus on the removal of emerging contaminants of concern (ECCs), which is largely missing in the literature. We outlined the prevalence of ECCs in the environment, their health effects both on humans and marine life, and the potential of efficiently removing them from water using three-dimensional graphene-based macrostructures to ensure ease of adsorbent recovery and reuse compared to nanostructures. Given various successful studies showing superior adsorption capacity of graphene nanosheets, we give an account of the recent developments in graphene-based adsorbents. Moreover, several cost-effective materials which can be easily self-assembled with nanosheets to improve their environmental performance and safety for POU water treatment purposes were highlighted. We highlighted the strategy to overcome challenges of adsorbent regeneration and contaminant degradation; and concluded by noting the need for policy makers to act decisively considering the conservative nature of the water treatment industry, and the potential health risks from ingesting ECCs through drinking water. We further justified the need for the development of advanced POU water treatment devices in the face of the growing challenges regarding ECCs in surface water, and the rising cases of drinking water advisories across the world., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nariman Yousefi reports financial support was provided by Natural Sciences and Engineering Research Council of Canada. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This umbrella review amalgamates the outcomes of economic evaluations pertaining to bariatric surgeries, pharmacotherapy, and gastric balloon for adult obesity treatment. Six databases were systematically searched. The inclusion criteria were established following the Patient/population Intervention Comparison and Outcomes (PICO) statement. Fifteen reviews met all the inclusion criteria. Eight studies focused on surgical interventions, four on pharmacotherapy, and three on both interventions. No systematic review of the economic evaluation of gastric balloons was identified. The majority of reviews advocated bariatric surgery as a cost-effective approach; however, there was discordance in the interpretation of pharmacological cost-effectiveness. Most of the economic evaluations were conducted from the payer and the healthcare system perspectives. We propose that future economic evaluations assessing weight loss interventions in adults adopt a societal perspective and longer-term time horizons., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to enhance carboxymethyl cellulose (CMC)-based films by incorporating zinc oxide nanoparticles (ZnO NPs) and cress seed mucilage (CSM), with a view to augmenting the physical, mechanical, and permeability properties of the resulting nanocomposite films. For the first time, CSM was exploited as a green surfactant to synthetize ZnO NPs using hydrothermal method. Seven distinct film samples were meticulously produced and subjected to a comprehensive array of analyses. The findings revealed that the incorporation of CSM/ZnO-5 % improved the physical properties of the films, demonstrating a significant reduction in moisture content and water vapor permeability (WVP). Increasing the concentration of NPs in conjunction with CSM markedly decreased the solubility of the nanocomposites by up to 56 %. The films containing CSM/ZnO showed higher tensile strength and elongation at the break values. The UV absorption of the films exhibited a substantial rise with the addition of ZnO NPs, particularly with an increased content in the presence of CSM. The thermal stability of nanocomposites containing a high concentration of CSM/ZnO exhibited an improvement compared to the control sample. In light of these results, the CMC/CSM/ZnO-5 % film emerges as a promising candidate for a biocompatible packaging material, exhibiting favorable physical characteristics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Distyly, a floral dimorphism that promotes outcrossing, is controlled by a hemizygous genomic region known as the S -locus. Disruptions of genes within the S -locus are responsible for the loss of distyly and the emergence of homostyly, a floral monomorphism that favors selfing. Using whole-genome resequencing data of distylous and homostylous individuals from populations of Primula vulgaris and leveraging high-quality reference genomes of Primula we tested, for the first time, predictions about the evolutionary consequences of transitions to selfing on S -genes. Our results reveal a previously undetected structural rearrangement in CYPᵀ associated with the shift to homostyly and confirm previously reported, homostyle-specific, loss-of-function mutations in the exons of the S -gene CYPᵀ . We also discovered that the promoter and intronic regions of CYPᵀ in distylous and homostylous individuals are conserved, suggesting that down-regulation of CYPᵀ via mutations in its promoter and intronic regions is not a cause of the shift to homostyly. Furthermore, we found that hemizygosity is associated with reduced genetic diversity in S -genes compared with their paralogs outside the S -locus. Additionally, the shift to homostyly lowers genetic diversity in both the S -genes and their paralogs, as expected in primarily selfing plants. Finally, we tested, for the first time, long-standing theoretical models of changes in S -locus genotypes during early stages of the transition to homostyly, supporting the assumption that two copies of the S -locus might reduce homostyle fitness., Competing Interests: The authors declare no competing interests., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

A number of studies have been conducted on the application of 3D models for drug discovery, drug sensitivity assessment, and drug toxicity. Most of these studies focused on disease modelling and attempted to control cellular differentiation, heterogeneity, and key physiological features to mimic organ reconstitution so that researchers could achieve an accurate response in drug evaluation. Recently, organoids have been used by various scientists due to their highly organotypic structure, which facilitates the translation from basic research to the clinic, especially in cancer research. With this tool, researchers can perform high-throughput analyses of compounds and determine the exact effect on patients based on their genetic variations, as well as develop personalized and combination therapies. Although there is a lack of standardization in organoid culture, patientderived organoids (PDOs) have become widely established and used for drug testing. In this review, we have discussed recent advances in the application of organoids and tumoroids not only in cancer research for drug screening but also in clinical trials to demonstrate the potential of organoids in translational medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introgression is an important source of genetic variation that can determine species adaptation to environmental conditions. Yet, definitive evidence of the genomic and adaptive implications of introgression in nature remains scarce. The widespread hybrid zones of Darwin's primroses (Primula elatior, Primula veris, and Primula vulgaris) provide a unique natural laboratory for studying introgression in flowering plants and the varying permeability of species boundaries. Through analysis of 650 genomes, we provide evidence of an introgressed genomic region likely to confer adaptive advantage in conditions of soil toxicity. We also document unequivocal evidence of chloroplast introgression, an important precursor to species-wide chloroplast capture. Finally, we provide the first evidence that the S-locus supergene, which controls heterostyly in primroses, does not introgress in this clade. Our results contribute novel insights into the adaptive role of introgression and demonstrate the importance of extensive genomic and geographical sampling for illuminating the complex nature of species boundaries., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Background: There is a general theme in studying employees in the research and development (R&D) department individual performance studies, where tremendous attention has been paid to innovation performance compared to behavioral and particularly extra-role behavior of employees in this department., Objectives: This study investigates the relationship between sustainable human resource management (s-HRM) and organizational citizenship behavior (OCB) through the mediating role of organizational identification (OI) in R&D employees., Methods: A standard questionnaire was used to evaluate s-HRM, OI, and OCB. Five hundred questionnaires were delivered to all employees of the research and development departments of 59 Iranian pharmaceutical companies, and finally, 316 completed questionnaires were collected., Results: The results of data analysis with WarpPls software revealed a positive and significant relationship between s-HRM and OI, as well as OI and OCB. Investigating the mediating role of OI showed that OI partially mediates the relationship between s-HRM and OCB. The model was checked in terms of its fit indices, which were evaluated as favorable., Conclusions: The findings suggest that s-HRM improves employees' willingness to go beyond their defined job description to display in OCB. Additionally, they imply that strengthening OI can improve OCB in employees., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023, Sheikhi and Yousefi.)

Purpose: This study aimed to evaluate the cost-effectiveness of cetuximab in different genetic populations of metastatic colorectal carcinoma patients, including KRAS and RAS wild types and mutants, when added to FOLFIRI treatment regimens for evidence-based disease management in Iran., Method: A Markov decision model was designed in TreeAge software with the three states of stable, progress, and death. Clinical outcomes were extracted from published clinical studies, and costs were extracted from the Iranian local data. The primary outcome was an incremental cost-effectiveness ratio (ICER) in the simulated population., Results: The cost-utility model from the perspective of the health system indicated that the average direct medical costs of a patient that has not been genetically screened are $56,985.27 and $20,767.74 in FOLFIRI + cetuximab and FOLFIRI regimens, respectively. However, costs per patient in the KRAS wild-type population were $21,845.52 in FOLFIRI and $78,321.22 in FOLFIRI + cetuximab. In RAS wild-type patients, FOLFIRI and FOLFIRI + cetuximab costs per patient were $23,111.62 and $84,976.39, respectively. Incremental QALYs for the above scenarios were 0.069, 0.193, and 0.285, respectively. Therefore, the ICER of add-on cetuximab in Iran compared to the treatment alternatives in the scenarios with and without KRAS screening was $520,771.55/QALY, $292,768.16/QALY, and $217,460.51/QALY., Conclusion: Although genetic screening in precision medicine reduces costs per outcome, according to the willingness-to-pay threshold of $4349.50 in the Iranian health system, add-on cetuximab to the FOLFIRI regimen is not a cost-effective strategy even with genetic screening and a 20% price reduction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nanocellulose is isolated from cellulosic fibers and exhibits many properties that macroscale cellulose lacks. Cellulose nanocrystals (CNCs) are a subcategory of nanocellulose made of stiff, rodlike, and highly crystalline nanoparticles. Algae of the order Cladophorales are the source of the longest cellulosic nanocrystals, but manufacturing these CNCs is not well-studied. So far, most publications have focused on the applications of this material, with the basic manufacturing parameters and material properties receiving little attention. In this article, we investigate the entirety of the current manufacturing process from raw algal biomass ( Cladophora glomerata ) to the isolation of algal cellulose nanocrystals. Yields and cellulose purities are investigated for algal cellulose and the relevant process intermediates. Furthermore, the effect of sulfuric acid hydrolysis, which is used to convert cellulose into CNCs and ultimately determines the material properties and some of the sustainability aspects, is examined and compared to literature results on wood cellulose nanocrystals. Long (>4 μm) CNCs form a small fraction of the overall number of CNCs but are still present in measurable amounts. The results define essential material properties for algal CNCs, simplifying their future use in functional cellulosic materials.

Background: A heavy financial burden is imposed on patients suffering from chronic diseases due to medicine out-of-pocket payments., Objectives: This study focuses on assessing the affordability of medications used for chronic respiratory diseases (CRDs) such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) in Iran, specifically on the category R medicines listed in the 2017 Iran drug list (IDL) that are used for the treatment of these diseases, based on the anatomical therapeutic chemical (ATC) drug code., Methods: The affordability of medicines in mono and combination therapy approaches was assessed in CRDs using the World Health Organization/Health Action International (WHO/HAI) methodology. Accordingly, if out-of-pocket payment for 30-days of pharmacotherapy exceeds one day for the lowest-paid unskilled government worker (LPGW), it's considered non-affordable., Results: Based on the monotherapy approach, our finding demonstrates that all generic medicines of category R were affordable. However, branded drugs such as Symbicort®, Pulmicort Respules®, Flusalmex®, Seretide®, Fluticort Plus®, Seroflo®, and Salmeflo® cost between 1.2 and 2.5 days' wage of LPGW and considered unaffordable despite 70% insurance coverage. Moreover, based on the affordability ratio in the combination therapy approach, all medicines used in asthma, COPD, and CF patients with mild respiratory problems are affordable except omalizumab (inj), which is non-affordable due to its high price and no insurance coverage., Conclusion: Results showed that the existing insurance coverage does not protect households from hardship, so more considerations are needed such as different insurance schedules and patient support programs., (© 2023. The Author(s).)

Highlights: This tutorial provides a user-friendly guide to mathematically formulating constrained optimization problems and implementing them using Python.Two examples are presented to illustrate how constrained optimization is used in health applications, with accompanying Python code provided., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for the research, authorship, and/or publication of this article.

Background: The prevalence of common cold can impose financial burden on the healthcare systems, despite its simple and self-limiting symptoms., Objective: This study examines the behavior of patients suffering from symptoms of the common cold and explores the factors that may influence such behaviors., Methods: A descriptive-analytic cross-sectional study was conducted in 2019, in Tehran, Iran, using cluster sampling in socioeconomically diverse areas within the city. The participants' behaviors and related factors were evaluated using a 10-item questionnaire. Data collection process involved selecting 5 shopping centers and 404 individuals participated the study. SPSS version 24 was used for analysis., Results: The results showed that 42.1% of the respondents would consult a physician immediately upon experiencing cold symptoms, while 11.4% would consult a pharmacist.In addition, 14.3% would try self-medication, 28.3% relied on traditional home remedies, and 15%indicated not to make use of any remedies or interventions. The study indicated a correlation between people's behaviors concerning the common cold and their level of health self-confidence, knowledge of the common cold, lifestyle, gender, marital status, occupational status, insurance status, and average family spending., Conclusion: The findings of this study are significant in that they shed light on the behaviors of individuals and associated factors related to seeking medical assistance for the common cold. This knowledge can assist healthcare systems in developing strategies aimed at enhancing treatment outcomes, and decreasing costs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: Governments apply different pricing policies to ensure public accessibility, availability, and affordability of medicines. In this way, external reference pricing (ERP) because of its easy implementation is used widely across countries. However, ERP is completely path dependent, and it would both bring pros and cons, related to its implementing strategy which makes understanding of its impact in different countries challenging. In this study, we examine the performance of the ERP approach in Iran as a pricing tool. Method: We conducted a cross-sectional descriptive study. Although Iran officially uses a reference country basket for ERP, in this study, we use different reference countries based on socioeconomic comparability, access to their price data, medicine pricing approaches, and pharmaceutical expenditure to examine the effect of reference countries as well as the method performance. Then, an empirical study was applied to a list of selected samples of medicines in the Iranian market to compare their price with our new reference countries. Then, we discuss the performance of ERP process based on the real prices in the Iranian pharmaceutical market. Result: The prices of 57 medicines, which contain about 69.2% of the imported Iran pharma market in value, were compared with their prices in selected reference countries. It was found that 49.1% of prices were more expensive in at least one of the reference countries, and in 21% of products, the average price in Iran was higher than the average price in reference countries. Conclusion: Achieving efficient and fair pricing of pharmaceuticals between and within countries is still a complex conceptual and policy problem that ERP in short term can handle. ERP cannot be considered a perfect tool for pricing alone, although its effectiveness is acceptable. It is expected that using other pricing methods alongside the ERP will improve patients' access to medicines. In Iran, we use value base pricing as the main pricing method for every new molecule. Then, we use other methods such as ERP as a complementary method., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Babaie, Motevalli, Mehralian, Peiravian and Yousefi.)

While research into drug-target interaction (DTI) prediction is fairly mature, generalizability and interpretability are not always addressed in the existing works in this field. In this paper, we propose a deep learning (DL)-based framework, called BindingSite-AugmentedDTA, which improves drug-target affinity (DTA) predictions by reducing the search space of potential-binding sites of the protein, thus making the binding affinity prediction more efficient and accurate. Our BindingSite-AugmentedDTA is highly generalizable as it can be integrated with any DL-based regression model, while it significantly improves their prediction performance. Also, unlike many existing models, our model is highly interpretable due to its architecture and self-attention mechanism, which can provide a deeper understanding of its underlying prediction mechanism by mapping attention weights back to protein-binding sites. The computational results confirm that our framework can enhance the prediction performance of seven state-of-the-art DTA prediction algorithms in terms of four widely used evaluation metrics, including concordance index, mean squared error, modified squared correlation coefficient ($r^2_m$) and the area under the precision curve. We also contribute to three benchmark drug-traget interaction datasets by including additional information on 3D structure of all proteins contained in those datasets, which include the two most commonly used datasets, namely Kiba and Davis, as well as the data from IDG-DREAM drug-kinase binding prediction challenge. Furthermore, we experimentally validate the practical potential of our proposed framework through in-lab experiments. The relatively high agreement between computationally predicted and experimentally observed binding interactions supports the potential of our framework as the next-generation pipeline for prediction models in drug repurposing., (© The Author(s) 2023. Published by Oxford University Press.)

Objectives: Pulmonary arterial hypertension (PAH) is a chronic and progressive disease that, if left untreated, shortens the life expectancy of patients. Endothelin receptor antagonists, such as macitentan and bosentan, play an essential role in improving the patient's symptoms, quality of life, and life expectancy. This study aimed to evaluate the cost-utility of macitentan compared with bosentan in treating PAH from the health system perspective in Iran., Methods: For evaluating the cost-effectiveness of macitentan, a Markov model consisting of 5 states, functional class (FC) I, FC II, FC III, FC IV, and death, was designed using the TreeAge software. The lifetime time horizon and a 3-month cycle length were set. Patients entered the model from FC II or FC III states based on the initial probabilities. Costs were measured in US dollars (USD), and outcomes were measured in terms of quality quality-adjusted life-years (QALYs). Consequently, the incremental cost-effectiveness ratio (ICER) was calculated. In addition, sensitivity analysis was performed to determine the robustness of the model by examining the possible effects of uncertainties on the final result., Results: The costs of treatment with macitentan and bosentan in PAH in Iran were calculated at 19 429 and 17 246 USD, and the outcomes were 4.02 and 3.04 QALYs, respectively. Therefore, ICER was calculated at 2233.46 USD/QALY. One-way sensitivity analysis demonstrates that the model is robust; nevertheless, it is most sensitive to the price of macitentan and bosentan., Conclusion: Treatment with macitentan was associated with both higher costs and QALYs than bosentan. Nevertheless, it is considered the cost-effective treatment strategy in Iran given that the calculated ICER falls below the willingness to pay threshold., (Copyright © 2022 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

In the present study, the functionality of H 2 O 2 and sodium hexametaphosphate (SHMP) on solubilization of whey protein hydrolysate (WPH) and isolate (WPI), resistant to sterilization temperature at various concentrations, was investigated. The physical state of the treated WPH and WPI dispersions at the presence of various concentrations of H 2 O 2 and SHMP was related to their colloidal structures and thermal stability. Using optimum concentration of H 2 O 2 , both dispersions stabilized against heat treatment likely because free SH groups blocked by H 2 O 2 . The solubilization range by SHMP was comparably low (up to 6 and 15% w/w for WPI and WPH, respectively). Moreover, the desirable stability was reached when H 2 O 2 and SHMP were simultaneously used. The pH adjustment (7.2), prior to sterilization, also improved the stability range. This research highlights the potential of these substances to restrain the denaturation of whey proteins. Further investigations are still required to elucidate the accurate mechanism of solubilization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Biodiversity hotspots, such as the Caucasus mountains, provide unprecedented opportunities for understanding the evolutionary processes that shape species diversity and richness. Therefore, we investigated the evolution of Primula sect. Primula, a clade with a high degree of endemism in the Caucasus. We performed phylogenetic and network analyses of whole-genome resequencing data from the entire nuclear genome, the entire chloroplast genome, and the entire heterostyly supergene. The different characteristics of the genomic partitions and the resulting phylogenetic incongruences enabled us to disentangle evolutionary histories resulting from tokogenetic vs cladogenetic processes. We provide the first phylogeny inferred from the heterostyly supergene that includes all species of Primula sect. Primula. Our results identified recurrent admixture at deep nodes between lineages in the Caucasus as the cause of non-monophyly in Primula. Biogeographic analyses support the 'out-of-the-Caucasus' hypothesis, emphasizing the importance of this hotspot as a cradle for biodiversity. Our findings provide novel insights into causal processes of phylogenetic discordance, demonstrating that genome-wide analyses from partitions with contrasting genetic characteristics and broad geographic sampling are crucial for disentangling the diversification of species-rich clades in biodiversity hotspots., (© 2022 The Authors New Phytologist © 2022 New Phytologist Foundation.)

Objective: This study was designed to compare the effects of shockwave therapy and corticosteroid injection in the treatment of piriformis syndrome., Methods and Materials: In this randomized clinical trial, thirty-five patients with piriformis syndrome were randomly divided into two groups of 18 in the shockwave group and 17 in the corticosteroid group. The Shockwave group underwent three sessions of shockwave therapy per week (2000 pulses per session with 5Hz frequency and pressure equal to 4 Bar) and the corticosteroid group underwent an injection of 40 mg methylprednisolone with 1 mL of 1% lidocaine under ultrasound guidance. All patients were assessed by SF-36 questionnaire and visual analogue scale (VAS). The SF-36 questionnaire was used to evaluate the quality of life before and 4 weeks after the intervention. VAS scale was used to evaluate pain before the intervention, and 1, 4, 8, and 12 weeks after the intervention., Results: The baseline characteristics of the two groups were not significantly different. At the end of the study, both groups had a significant improvement in pain and quality of life compared to before the intervention. However, according to the VAS, in the shockwave group improvement was seen in the first follow-up while not seen in the corticosteroid group (P-value <0.001 and P-value 1.00, respectively). According to the SF-36 questionnaire, the overall score in both groups had a significant improvement (P-value <0.05)., Conclusions: It seems that shockwave therapy and corticosteroid injection are both effective in the treatment of piriformis syndrome. There was no significant difference between the two groups in the quarterly follow-up. Because shockwave therapy is a relatively non-invasive treatment with fewer side effects, it can be useful to improve pain and the quality of life of patients with piriformis syndrome., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: Impaired proprioception and muscle weakness may not only be a consequence of knee osteoarthritis (OA) but also part of its pathogenesis. Thus, the enhancement of quadriceps strength and proprioceptive accuracy can play a pivotal role in the management of knee OA. This study aimed to investigate the effects of Kinesio tape and flexible knee orthosis in terms of clinical and neuromuscular outcomes in patients with knee OA., Methods: This clinical trial was conducted on 56 patients with knee OA, randomly allocated to two groups: knee orthosis or Kinesio tape. The knee orthosis group wore a neoprene knee support for 4 weeks. For participants in the Kinesio tape group, tape was applied once a week, for 4 weeks. The primary outcomes were pain intensity and physical function evaluated through the visual analog scale and the Western Ontario and McMaster OA index. The secondary outcomes were concentric and isometric quadriceps strength, Joint Position Sense (JPS), Threshold to Detect Passive Motion (TTDPM), and force sense (FS), all measured by isokinetic dynamometry., Results: All outcome measures were significantly improved in the orthosis group. The Kinesio tape group also demonstrated significant changes in all outcome measures except three proprioception components namely JPS (70° target), FS, and TTDPM. At the end of the fourth week, there were no significant between-group differences for measured parameters., Conclusion: Wearing a flexible knee orthosis and/or Kinesio tape for 4 weeks significantly improved knee pain, physical function, and quadriceps strength. Although knee orthosis showed significant beneficial effects on various components of proprioception, there were no significant differences between the two groups at the end of the 4-week intervention., Competing Interests: None

Purpose: This study aimed to identify the impact of prominent drivers on drug expenditure for diabetes., Method: Following the examination of previous studies, this study identified possible factors contributing to diabetes pharmaceutical expenditures. The explanatory variables for the study were the median population age, access to innovative drugs, GDP per capita, prevalence, price, and consumption of diabetes drugs. Then, to estimate the per capita expenditure among diabetic patients, this study developed the panel data model and two time-series regression models for OECD countries and Iran, respectively., Results: In the panel data regression model, R2 was 0.43. The influence of the age, prevalence, consumption volume and GDP per capita coefficients were + 1.79, + 0.704, + 3.86057, + 0.00054, respectively. Also, the probability level of all variables was less than 0.05. In Iran's comparative time-series regression model, R2 was 0.9, and the only significant influence coefficient was the age (β=+0.91). In the another model for Iran, R2 was 0.99, the influence coefficient of age was + 0.249, the prevalence was + 0.131, innovation was + 0.029, and the price was + 0.00054; all the probability levels were less than 0.05., Conclusion: Pharmaceutical per capita expenditure is affected by several factors. These factors are not the same in various counties. Passing a judgment on drug utilization only based on pharmaceutical per capita expenditure cannot be perfect. Also, judging whether the per capita drug expenditure in one country is desirable without attention to the affecting factors and only relying on the value of utilized medicines is defective., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s), under exclusive licence to Tehran University of Medical Sciences 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Diclofenac (DCF) as a non-steroidal pharmaceutical has been detected in aquatic samples more than other compounds due to its high consumption and limited biodegradability. In this study, ultrasound waves were applied along with an advanced nano-Fenton process (US/ANF) to remove DCF, and subsequently, the synergistic effect was determined. Before that, the efficiency of the US and ANF processes was separately studied. The central composite design was used as one of the most applicable responses surface method techniques to determine the main and interactive effect of the factors influencing DCF removal efficiency in US/ANF. The mean DCF removal efficiency under different operational conditions and at the time of 1-10 min was obtained to be about 4%, 83%, and 95% for the US, ANF, and US/ANF, respectively. Quadratic regression equations for two frequencies of US were developed using multiple regression analysis involving main, quadratic, and interaction effects. The optimum condition for DCF removal was obtained at time of 8.17 min, H/F of 10.5 and DCF concentration of 10.12 at 130 kHz US frequency. The synergy index values showed a slight synergistic effect for US/ANF (1.1). Although the synergistic effect of US/ANF is not very remarkable, it can be considered as a quick and efficient process for the removal of DCF from wastewater with a significant amount of mineralization., (© 2022. The Author(s).)

Due to the implications of poly- and perfluoroalkyl substances (PFAS) on the environment and public health, great attention has been recently made to finding innovative materials and methods for PFAS removal. In this work, PFAS is considered universal contamination which can be found in many wastewater streams. Conventional materials and processes used to remove and degrade PFAS do not have enough competence to address the issue particularly when it comes to eliminating short-chain PFAS. This is mainly due to the large number of complex parameters that are involved in both material and process designs. Here, we took the advantage of artificial intelligence to introduce a model (XGBoost) in which material and process factors are considered simultaneously. This research applies a machine learning approach using data collected from reported articles to predict the PFAS removal factors. The XGBoost modeling provided accurate adsorption capacity, equilibrium, and removal estimates with the ability to predict the adsorption mechanisms. The performance comparison of adsorbents and the role of AI in one dominant are studied and reviewed for the first time, even though many studies have been carried out to develop PFAS removal through various adsorption methods such as ion exchange, nanofiltration, and activated carbon (AC). The model showed that pH is the most effective parameter to predict PFAS removal. The proposed model in this work can be extended for other micropollutants and can be used as a basic framework for future adsorbent design and process optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clinical pathways are standardized processes that outline the steps required for managing a specific disease. However, patient pathways often deviate from clinical pathways. Measuring the concordance of patient pathways to clinical pathways is important for health system monitoring and informing quality improvement initiatives. In this paper, we develop an inverse optimization-based approach to measuring pathway concordance in breast cancer, a complex disease. We capture this complexity in a hierarchical network that models the patient's journey through the health system. A novel inverse shortest path model is formulated and solved on this hierarchical network to estimate arc costs, which are used to form a concordance metric to measure the distance between patient pathways and shortest paths (i.e., clinical pathways). Using real breast cancer patient data from Ontario, Canada, we demonstrate that our concordance metric has a statistically significant association with survival for all breast cancer patient subgroups. We also use it to quantify the extent of patient pathway discordances across all subgroups, finding that patients undertaking additional clinical activities constitute the primary driver of discordance in the population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study was aimed to systematically review published economic studies to determine whether dapagliflozin, a sodium-glucose co-transporter inhibitor, plus standard care therapy (SCT) is cost-effective in heart failure with reduced ejection fraction (HFrEF)., Method: We searched relevant keywords in PubMed, Scopus, Web of science, and Google Scholar to find related articles. Costs, QALYs, ICERs were extracted from eligible studies., Results: Ten studies finally included in the systematic review. The results of quality assessment of the study showed that a reasonable quality of all studies. Incremental QALYs were in favor of dapagliflozin plus SCT treatment regimen. In all the studies, the incremental costs per QALY was below the willingness-to-pay (WTP) threshold with the exception of one study in United Kingdom which the ICER and WTP were $83,650 and $50,000. All the studies determined the National Health Care perspective. The highest and lowest ICERs were $83,650 and $1991 per QALY in United Kingdom and Thailand, respectively., Conclusion: Results of cost-effectiveness analyses showed that adjunct dapagliflozin plus SCT is cost-effective compared to SCT alone despite the additional costs of the drug. Finally it can be concluded that dapagliflozin is a worldwide cost-effective as an adjunct medicine in HFrEF management., (© 2022. The Author(s).)

Distyly, a floral dimorphism associated with heteromorphic self-incompatibility and controlled by the S-locus supergene, evolved independently multiple times. Comparative analyses of the first transcriptome atlas for the main distyly model, Primula veris, with other distylous species produced the following findings. A set of 53 constitutively expressed genes in P. veris did not include any of the housekeeping genes commonly used to normalize gene expression in qPCR experiments. The S-locus gene CYP T acquired its role in controlling style elongation via a change in expression profile. Comparison of genes differentially expressed between floral morphs revealed that brassinosteroids and auxin are the main hormones controlling style elongation in P. veris and Fagopyrum esculentum, respectively. Furthermore, shared biochemical pathways might underlie the expression of distyly in the distantly related P. veris, F. esculentum and Turnera subulata, suggesting a degree of correspondence between evolutionary convergence at phenotypic and molecular levels. Finally, we provide the first evidence supporting the previously proposed hypothesis that distyly supergenes of distantly related species evolved via the recruitment of genes related to the phytochrome-interacting factor (PIF) signaling network. To conclude, this is the first study that discovered homologous genes involved in the control of distyly in distantly related taxa., (© 2022. The Author(s).)

The use of sanctions as a policy tool to affect change in the political behavior of target states has increased over the past 30 years, along with a concern about their impact on civilian health. Some researchers have proposed that targeting sanctions can avoid their moral costs, yet others have challenged this claim. This systematic mixed-studies review explored the debate about targeted sanctions by appraising their health effects as reported in the medical and public health literature, with a global focus and through the COVID-19 era.We searched three electronic databases without temporal or geographical restrictions and identified 50 studies spanning three decades (1992-2021) meeting our inclusion criteria. Using a piloted form, we extracted quotations addressing our research questions and identified themes that we grouped according to the effects of sanctions on health or its determinants, generating frequency distributions to assess the strength of support for each theme. While no study posited a causal relationship between sanctions and health, or engaged the morality of sanctions, most implied that when sanctions were present, health was inevitably impacted, even for sanctions ostensibly targeted to minimize civilian harm. Our findings suggest that given the integrated nature of the global economy, it is all but impossible to design sanctions that will achieve their stated goals without inflicting significant harm on civilians. We conclude that the use of sanctions as a policy tool threatens global health and human rights, especially in times of crises.

Objective: The problem of medication errors (MEs) has constantly been receiving considerable attention worldwide due to their health impact and costly consequences. MEs occur in all phases of prescription, preparation, administration, distribution and delivery to the patient; however, dispensing errors are more common in this study, we have attempted to identify various MEs that occurred by pharmacists and calculate their financial and physical harm costs., Design: This was a 8-year retrospective study., Setting: This study evaluated the costs of MEs in the Iranian health system caused by dispensing mistakes from 2012 to 2019. We retrieved documents and reports from the Tehran Medical Council Archive. Then, we extracted dispensing error data from ME record forms and analyzed them using SPSS software., Main Outcome Measures: Cost of dispensing errors., Results: Among 3000 available MEs documents, only 2.6% of cases were dispensing errors. Errors included dispensing of wrong medication (75.6%), delivering expired medicines (11.5%), wrong medication order (9%), wrong medicine compounding (2.6%) and wrong dose of medication (1.3%). The most common cause of dispensing errors was physicians' poor handwriting (23.1%). Legal reactions, due to MEs, occurred in a range of actions from written reprimand in the professional records to some months of deprivation from professional activities., Conclusion: The analysis of the MEs that lead to the legal prosecution in the Iranian Medical Council shows that most cases, according to the severity of harm, were dispensing wrong medicines which caused temporary patients harm., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Diabetes mellitus (DM), as one of the most common metabolic diseases, is the ninth leading cause of death globally and imposes heavy costs on the health systems including both costs of treatment and management of secondary complications. This study intended to investigate the cost-effectiveness of dulaglutide compared with liraglutide in the management of patients with type 2 DM in Iran., Method: We conducted a cost-utility analysis using a 5-state Markov model from the health system perspective, over a 10-year time horizon, in 2018 in Iran. Sensitivity of the model has been evaluated through tornado diagram and using one-way sensitivity analysis. In addition, probabilistic sensitivity analysis has been accomplished using Monte Carlo simulation., Results: The average costs of treatment of patients with type 2 DM using the dulaglutide and liraglutide treatment regimens are 17 577.09 and 18 517.54 US dollars per patient, respectively, over a 10-year time horizon. In terms of effectiveness, the average discounted quality-adjusted life-year rates are estimated at 5.560 and 5.403 for the dulaglutide and liraglutide treatment regimens, respectively. The model is mostly sensitive to the price of dulaglutide and liraglutide, the hemoglobin A1c reduction of liraglutide, and the utility resulting from less injection frequency of dulaglutide, respectively., Conclusion: Dulaglutide, in addition to being more effective, providing 0.156 more quality-adjusted life-years for the patients, reduces costs by 940.45 US dollars per patient over a 10-year time horizon. Therefore, due to the greater effectiveness and lower cost, it is concludable that dulaglutide is the cost-effective (incremental cost-effectiveness ratio = -6028.52) treatment alternative from the health system perspective., (Copyright © 2022 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Foetal Alcohol Spectrum Disorder (FASD) has emerged as a significant public health issue, in Canada and elsewhere. Health experts increasingly acknowledge that the disproportionate impact of FASD on indigenous people is driven by social and historical contexts, especially in settler colonial states like Canada. However, they generally frame FASD as preventable through abstinence and the effects of FASD as manageable through provision of appropriate medical and legal protection to affected offspring. Drawing from Marxist, anticolonial and anti-imperial theories and applying a Critical Discourse Analysis approach, we identify the (re) production of colonial and capitalist dominance in the expert literature. We show that dominant narratives depoliticize FASD by conceptualizing settler colonialism as a past event, ignoring ongoing, contemporary forms of settler colonial dispossession and resituating FASD within an expert language that locates solutions to FASD within affected individuals and communities. In so doing, these narratives legitimize, and contribute to perpetuating, existing disease inequities, prevent the formulation of policies that address the very real and as yet unmet needs of FASD affected individuals, families and communities and erase from the public discourse discussions about changes that could truly address FASD inequities at their root. We conclude by elaborating on the implication of these narratives for policy, practice and equity, in Canada and other settler colonial states.

The present study aimed to investigate the mechanisms of resistance to tigecycline and to determine sequence types of Acinetobacter baumannii isolates recovered from children, using the Multilocus Sequence Typing (MLST). A total of 74 A. baumannii isolates were recovered from patients at one of the children's hospital in Tehran, Iran. Antimicrobial susceptibility testing of the isolates was performed for different classes of antibiotics and minimum inhibitory concentrations of colistin and tigecycline were determined using broth microdilution method and E-test strips, respectively. The presence of ISAba1, AbaR, tet(39), and tetX and the expressions of adeB, adeG, and adeJ efflux pump genes were measured using Polymerase Chain Reaction (PCR) and quantitative real-time PCR (RT-PCR), respectively. The diversity of mutations across the regulatory genes of RND efflux pumps (adeRS, adeL, and adeN) and trm gene were determined using their PCR amplification and DNA sequencing in tigecycline-resistant isolates. In addition, STs of tigecycline-resistant isolates were determined using MLST method. Three A. baumannii isolates were resistant to tigecycline. Several amino acid substitutions were identified in AdeRS, AdeN, and Trm but no alteration was found in AdeL. Nevertheless, adeB, adeG, and adeJ overexpression were observed in 1, 2, and 1 isolates, respectively. The tigecycline-resistant isolates belonged to ST1720 and ST2285. This is the first study reporting on ST2285 in A. baumannii populations. Among 74 isolates, two tigecycline susceptible isolates carried tet(39) gene but no tetX gene was detected. We concluded that mutations in regulatory genes of RND efflux pumps and the trm gene may play some important role in A. baumannii resistance to tigecycline., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, we introduce an interpretable graph-based deep learning prediction model, AttentionSiteDTI, which utilizes protein binding sites along with a self-attention mechanism to address the problem of drug-target interaction prediction. Our proposed model is inspired by sentence classification models in the field of Natural Language Processing, where the drug-target complex is treated as a sentence with relational meaning between its biochemical entities a.k.a. protein pockets and drug molecule. AttentionSiteDTI enables interpretability by identifying the protein binding sites that contribute the most toward the drug-target interaction. Results on three benchmark datasets show improved performance compared with the current state-of-the-art models. More significantly, unlike previous studies, our model shows superior performance, when tested on new proteins (i.e. high generalizability). Through multidisciplinary collaboration, we further experimentally evaluate the practical potential of our proposed approach. To achieve this, we first computationally predict the binding interactions between some candidate compounds and a target protein, then experimentally validate the binding interactions for these pairs in the laboratory. The high agreement between the computationally predicted and experimentally observed (measured) drug-target interactions illustrates the potential of our method as an effective pre-screening tool in drug repurposing applications., (© The Author(s) 2022. Published by Oxford University Press.)

Drug-target interaction (DTI) prediction through in vitro methods is expensive and time-consuming. On the other hand, computational methods can save time and money while enhancing drug discovery efficiency. Most of the computational methods frame DTI prediction as a binary classification task. One important challenge is that the number of negative interactions in all DTI-related datasets is far greater than the number of positive interactions, leading to the class imbalance problem. As a result, a classifier is trained biased towards the majority class (negative class), whereas the minority class (interacting pairs) is of interest. This class imbalance problem is not widely taken into account in DTI prediction studies, and the few previous studies considering balancing in DTI do not focus on the imbalance issue itself. Additionally, they do not benefit from deep learning models and experimental validation. In this study, we propose a computational framework along with experimental validations to predict drug-target interaction using an ensemble of deep learning models to address the class imbalance problem in the DTI domain. The objective of this paper is to mitigate the bias in the prediction of DTI by focusing on the impact of balancing and maintaining other involved parameters at a constant value. Our analysis shows that the proposed model outperforms unbalanced models with the same architecture trained on the BindingDB both computationally and experimentally. These findings demonstrate the significance of balancing, which reduces the bias towards the negative class and leads to better performance. It is important to note that leaning on computational results without experimentally validating them and by relying solely on AUROC and AUPRC metrics is not credible, particularly when the testing set remains unbalanced.

Background: Uncertainty in real-world product profiles is the main barrier to pharmaceutical market access. Managed entry agreements (MEAs) are the formal arrangements to overcome these uncertainties. Despite the extensive experience of developed countries in implementing such agreements, the experience of developing countries is minimal. As health decision-makers in Iran have moved towards implementing MEAs since 2020, seeking stakeholders' insights is crucial for filling this experience gap and facilitating the optimal implementation of these new policies., Methods: Our research was done in three phases: (1) Focus group interviews to disclose the main objectives of implementing MEAs in Iran, (2) the AHP approach to prioritize uncertainties, and (3) individual semi-structured interviews to carry out strengths, weaknesses, opportunities, and threats (SWOT) analysis., Results: Based on our stakeholders' views, increasing flexibility in improving patients' access to innovative and expensive drugs and responding to budget impact uncertainty seems highly prioritized for conducting MEAs in Iran. The SWOT analysis showed that although MEAs have the chance for success due to their strengths and opportunities, such as providing early and assured access, allocating resources efficiently, and enhancing the efficiency of post-marketing studies, policymakers should consider the weaknesses and threats such as difficulty in defining outcomes, high transaction cost, and lack of suitable infrastructure to increase the success rate., Conclusions: Efficient implementation of MEAs depends on the weaknesses and threats and considering the views of relevant stakeholders. Constructive interaction among all stakeholders is essential for adequately executing MEAs., Competing Interests: Conflict of Interests: The authors have no competing interests to declare., (Copyright © 2022, Author(s).)

Introduction: This study aimed to evaluate chronic pain and fatigue in patients 12 months after hospitalization for Covid-19., Methods: We studied the COVID-19 patients discharged from Hospital, March 10 and April 20, 2020., Results: A total of 157 patients were included in this study. Forty-three patients (27.4%) complained of chronic fatigue and muscle weakness in the last six months. The visual analog fatigue scale (VAFS) score of 3.84 ± 1.48 was obtained. Forty patients (25.5%) were suspected of Chronic Fatigue Syndrome (CFS).Twenty-four patients (15.3%) had severe chronic pain or exacerbation of previous chronic pain, most of which were reported in the lower back (70.8%) and lower extremities (66.7%). Pain intensity had a mean score of 2.33 ± 0.87 and was mainly described as "muscle cramps," "persistent dull pain," and "boring and numbing." In women, chronic pain and fatigue, extended hospital stays, ICU admission, and depressed mood were common than in men.For these pain and fatigue, 37% used nonsteroidal anti-inflammatory drugs, and 16.3% used antidepressants. Only one person had applied for physiotherapy, and none of the patients had received psychotherapy., Conclusion: Fatigue and chronic pain in patients recovering from COVID-19 are common complications, even after 12 months of illness., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pharmaceutical advertising is not only considered a key factor in the successful launch of pharmaceutical products, but is also an important source of public health information with a significant impact on consumer choice and behavior. Nowadays, advertising has become the broadest dissemination channel for various products, including medicines, which may ultimately lead to the generalization of self-treatment or mistreatment. Improper drug promotion can exacerbate unhealthy outcomes by making false or misleading claims, using inferior references, and failing to meet international standards. This study aimed to examine the requirements for pharmaceutical advertising from regulatory perspective and the compliance of Iranian pharmaceutical advertisements to related standards and guidelines. It is limited to print advertisements in Iranian national medical journals and magazines., Method: The present study is a descriptive-analytical study using bibliometric methods. As a first step, a comprehensive review of the national and international regulations on drug advertising was conducted and a comparison of different regulations was provided. In the second step, a checklist was created to evaluate the compliance of drug advertising with the extracted regulations., Result: The results of the present study show that the claims made in Iranian drug advertisements are 29.10% valid, 27.67% exaggerated, 23.10% controversial, 12.62% misleading, and 6.8% invalid. In general, we found that most medical advertisements in Iranian journals and magazines comply with national laws and regulations. However, many international requirements are not met in these advertisements., Conclusions: Although we found that printed medical advertisements in Iran are roughly compliant with national regulations, there is still a long way to achieve full compliance. Monitoring processes should be improved and clearly defined penalties should be set to avoid misleading claims and their likely health consequences. It is very important in Iran to update the existing rules and regulations for medical advertisements according to international guidelines. More careful monitoring of the content of advertising and the accuracy of claims are also needed., (© 2022. The Author(s).)

Objectives: According to the world health organization (WHO), by the year 2030 diabetes will become the world's seventh leading cause of death. This study aimed to design and conduct a descriptive pharmacoepidemiological investigation of anti-diabetic drugs utilization during a ten-year period using the anatomical therapeutic classification/defined daily dose (ATC / DDD) system in Iran., Methods: Based on pharmaceutical wholesalers' sale reports, sale data, including value and volume, were retrieved from the Iranian Annual Pharma Statistics for 2009-2018. The ATC/DDD system was used to standardize the raw sales data. Anti-diabetic drug utilization was reported as DDD per 1000 person in the population per day. Expenditure was calculated as USD per DDD. Results were then analyzed descriptively., Results: During the ten-year study period, total anti-diabetic drug consumption increased by 235.53%. Insulin utilization grew by 148.65%, whereas non-insulin agents' use showed a 132.68% increase. Anti-diabetic drugs' expenditure increased by almost 9-fold, but changes were accompanied with many fluctuations. Although the absolute expenditure of almost all classes of anti-diabetic drugs were increasing, this growth was greater in biguanides, which only includes metformin in Iran. Approximately one-third of anti-diabetic drugs expenditures were related to fast-acting insulins. Imported drugs share in cost was significant, but not in consumption. The overall share of insulin consumption was less than 19%, but their share of total value reached 60% of the anti-diabetic market., Conclusions: The growing trend in both insulin and non-insulin anti-diabetic drugs utilization is a substantial issue for health authorities' policy making for sustainable access to medicine., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© Springer Nature Switzerland AG 2022.)

Supergenes are nonrecombining genomic regions ensuring the coinheritance of multiple, coadapted genes. Despite the importance of supergenes in adaptation, little is known on how they originate. A classic example of supergene is the S locus controlling heterostyly, a floral heteromorphism occurring in 28 angiosperm families. In Primula, heterostyly is characterized by the cooccurrence of two complementary, self-incompatible floral morphs and is controlled by five genes clustered in the hemizygous, ca. 300-kb S locus. Here, we present the first chromosome-scale genome assembly of any heterostylous species, that of Primula veris (cowslip). By leveraging the high contiguity of the P. veris assembly and comparative genomic analyses, we demonstrated that the S-locus evolved via multiple, asynchronous gene duplications and independent gene translocations. Furthermore, we discovered a new whole-genome duplication in Ericales that is specific to the Primula lineage. We also propose a mechanism for the origin of S-locus hemizygosity via nonhomologous recombination involving the newly discovered two pairs of CFB genes flanking the S locus. Finally, we detected only weak signatures of degeneration in the S locus, as predicted for hemizygous supergenes. The present study provides a useful resource for future research addressing key questions on the evolution of supergenes in general and the S locus in particular: How do supergenes arise? What is the role of genome architecture in the evolution of complex adaptations? Is the molecular architecture of heterostyly supergenes across angiosperms similar to that of Primula?, (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Recently, genetic engineering by various strategies to stimulate gene expression in a specific and controllable mode is a speedily growing therapeutic approach. Genetic modification of human stem or progenitor cells, such as Embryonic Stem Cells (ESCs), Neural Progenitor Cells (NPCs), Mesenchymal Stem/Stromal Cells (MSCs), and Hematopoietic Stem Cells (HSCs) for direct delivery of specific therapeutic molecules or genes has been evidenced as an opportune plan in the context of regenerative medicine due to their supported viability, proliferative features, and metabolic qualities. On the other hand, a large number of studies have investigated the efficacy of modified stem cells in cancer therapy using cells from various sources, disparate transfection means for gene delivery, different transfected yields, and wide variability of tumor models. Accordingly, cell-based gene therapy holds substantial aptitude for the treatment of human malignancy as it could relieve signs or even cure cancer succeeding expression of therapeutic or suicide transgene products; however, there exist inconsistent results in this regard. Herein, we deliver a brief overview of stem cell potential to use in cancer therapy and regenerative medicine and importantly discuss stem cells based gene delivery competencies to stimulate tissue repair and replacement in concomitant with their potential to use as an anti-cancer therapeutic strategy, focusing on the last two decades' in vivo studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)