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Abstract Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Lack of appropriate early diagnostic tools for drug-resistant tuberculosis (DR-TB) and their incomplete drug susceptibility testing (DST) profiling is concerning for TB disease control. Existing methods, such as phenotypic DST (pDST), are time-consuming, while Xpert MTB/RIF (Xpert) and line probe assay (LPA) are limited to detecting resistance to few drugs. Targeted next-generation sequencing (tNGS) has been recently approved by WHO as an alternative approach for rapid and comprehensive DST. We aimed to investigate the performance and feasibility of tNGS for detecting DR-TB directly from clinical samples in Bangladesh. pDST, LPA and tNGS were performed among 264 sputum samples, either rifampicin-resistant (RR) or rifampicin-sensitive (RS) TB cases confirmed by Xpert assay. Resistotypes of tNGS were compared with pDST, LPA and composite reference standard (CRS, resistant if either pDST or LPA showed a resistant result). tNGS results revealed higher sensitivities for rifampicin (RIF) (99.3%), isoniazid (INH) (96.3%), fluoroquinolones (FQs) (94.4%), and aminoglycosides (AMGs) (100%) but comparatively lower for ethambutol (76.6%), streptomycin (68.7%), ethionamide (56.0%) and pyrazinamide (50.7%) when compared with pDST. The sensitivities of tNGS for INH, RIF, FQs and AMGs were 93.0%, 96.6%, 90.9%, and 100%, respectively and the specificities ranged from 91.3 to 100% when compared with CRS. This proof of concept study, conducted in a high-burden setting demonstrated that tNGS is a valuable tool for identifying DR-TB directly from the clinical specimens. Its feasibility in our laboratory suggests potential implementation and moving tNGS from research settings into clinical settings.

Type 2 Diabetes Mellitus (T2DM) is a chronic condition that requires ongoing self-management and education. In recent years, there has been a growing interest in utilizing mobile serious games as a tool for patient education and engagement. This article presents the development of DiaPo, a mobile serious game designed to improve self-management education for patients with T2DM. DiaPo integrates gamification techniques to increase patient engagement and motivation while providing essential information about disease management. The development of DiaPo followed a structured design process, utilizing the Analysis, Design, Development, Implementation, and Evaluation (ADDIE) educational system. This systematic approach allowed for the integration of best practices in educational game design and diabetes care. The development team consisted of experts in medical informatics, game design, and diabetes care, ensuring a multidisciplinary approach to the game's creation. The game's narrative focuses on a T2DM patient who earns positive points for making healthy lifestyle choices and negative points for poor ones. This gamified approach aims to reinforce positive behaviors and provide immediate feedback on negative ones. Interactive animations confirm or deny options selected by the player, further enhancing the learning experience. DiaPo offers a flexible and adaptable platform suitable for diverse audiences, promoting inclusiveness and accessibility in T2DM education. DiaPo represents a novel approach to self-management education for patients with T2DM, utilizing gamification techniques and a multidisciplinary design process to create an engaging and informative mobile serious game. By promoting inclusiveness and accessibility, DiaPo has the potential to empower patients with T2DM to take an active role in their disease management. As the field of mobile serious games continues to evolve, DiaPo stands as a promising tool for improving T2DM education and patient outcomes.

Cancer, being one of the deadliest diseases, poses significant challenges despite the existence of traditional treatment approaches. This has led to a growing demand for innovative pharmaceutical agents that specifically target cancer cells for effective treatment. In recent years, the use of metal nanoparticles (NPs) as a promising alternative to conventional therapies has gained prominence in cancer research. Metal NPs exhibit unique properties that hold tremendous potential for various applications in cancer treatment. Studies have demonstrated that certain metals possess inherent or acquired anticancer capabilities through their surfaces. These properties make metal NPs an attractive focus for therapeutic development. In this review, we will investigate the applicability of several distinct classes of metal NPs for tumor targeting in cancer treatment. These classes may include gold, silver, iron oxide, and other metals with unique properties that can be exploited for therapeutic purposes. Additionally, we will provide a comprehensive summary of the risk factors associated with the therapeutic application of metal NPs. Understanding and addressing these factors will be crucial for successful clinical translation and to mitigate any potential challenges or failures in the translation of metal NP-based therapies. By exploring the therapeutic potential of metal NPs and identifying the associated risk factors, this review aims to contribute to the advancement of cancer treatment strategies. The anticipated outcome of this review is to provide valuable insights and pave the way for the advancement of effective and targeted therapies utilizing metal NPs specifically for cancer patients.

Abstract Urban gas pipelines pose significant risks to public safety and infrastructure integrity, necessitating thorough risk assessment methodologies to mitigate potential hazards. This study investigates the dynamics of population distribution, demographic characteristics, and building structures to assess the risk associated with gas pipelines. Using geospatial analysis techniques, we analyze population distribution patterns during both day and night periods. Additionally, we conduct an in-depth vulnerability assessment considering multiple criteria maps, highlighting areas of heightened vulnerability in proximity to gas pipelines and older buildings. This study incorporated the concept of individual risk and the intrinsic parameters of gas pipelines to develop a hazard map. Hazard analysis identifies areas with elevated risks, particularly around main pipeline intersections and high-pressure zones. Integrating hazard and vulnerability assessments, we generate risk maps for both day and night periods, providing valuable insights into spatial risk distribution dynamics. The findings underscore the importance of considering temporal variations in risk assessment and integrating demographic and structural factors into hazard analysis for informed decision-making in pipeline management and safety measures.

Tuberculosis is a respiratory disease that is treatable with antibiotics. An increasing prevalence of resistance means that to ensure a good treatment outcome it is desirable to test the susceptibility of each infection to different antibiotics. Conventionally, this is done by culturing a clinical sample and then exposing aliquots to a panel of antibiotics, each being present at a pre-determined concentration, thereby determining if the sample isresistant or susceptible to each sample. The minimum inhibitory concentration (MIC) of a drug is the lowestconcentration that inhibits growth and is a more useful quantity but requires each sample to be tested at a range ofconcentrations for each drug. Using 96-well broth micro dilution plates with each well containing a lyophilised pre-determined amount of an antibiotic is a convenient and cost-effective way to measure the MICs of several drugs at once for a clinical sample. Although accurate, this is still an expensive and slow process that requires highly-skilled and experienced laboratory scientists. Here we show that, through the BashTheBug project hosted on the Zooniverse citizen science platform, a crowd of volunteers can reproducibly and accurately determine the MICs for 13 drugs and that simply taking the median or mode of 11-17 independent classifications is sufficient. There is therefore a potential role for crowds to support (but not supplant) the role of experts in antibiotic susceptibility testing.

BackgroundMolecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.MethodsA candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.Findings15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.InterpretationThis first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.FundingUNITAID, Wellcome, MRC, BMGF.

Abstract Background The war in Ukraine has led to significant migration to neighboring countries, raising public health concerns. Notable tuberculosis (TB) incidence rates in Ukraine emphasize the immediate requirement to prioritize approaches that interrupt the spread and prevent new infections. Methods We conducted a prospective genomic surveillance study to assess migration's impact on TB epidemiology in the Czech Republic and Slovakia. Mycobacterium tuberculosis isolates from Ukrainian war refugees and migrants, collected from September 2021 to December 2022 were analyzed alongside 1574 isolates obtained from Ukraine, the Czech Republic, and Slovakia. Results Our study revealed alarming results, with historically the highest number of Ukrainian tuberculosis patients detected in the host countries. The increasing number of cases of multidrug-resistant TB, significantly linked with Beijing lineage 2.2.1 (p

Abstract The Mycobacterium tuberculosis complex (MTBC) includes several human- and animal-adapted pathogens. It is thought to have originated in East Africa from a recombinogenic Mycobacterium canettii-like ancestral pool. Here, we describe the discovery of a clinical tuberculosis strain isolated in Ethiopia that shares archetypal phenotypic and genomic features of M. canettii strains, but represents a phylogenetic branch much closer to the MTBC clade than to the M. canettii strains. Analysis of genomic traces of horizontal gene transfer in this isolate and previously identified M. canettii strains indicates a persistent albeit decreased recombinogenic lifestyle near the emergence of the MTBC. Our findings support that the MTBC emergence from its putative free-living M. canettii-like progenitor is evolutionarily very recent, and suggest the existence of a continuum of further extant derivatives from ancestral stages, close to the root of the MTBC, along the Great Rift Valley.

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

As the age increases, the power and ability of the elderly to recognise architectural spaces and related internal or external areas decreases. This initially increases their dependence on others, and in the next stages they may lose the ability to find their way. The purpose of this research is to provide an understanding of the elements that play a role in the mental dimensions of aging. The present article was formed in order to answer these questions: ‘how does the perception and cognition of the elderly take place with a focus on environmental and human approaches’, and ‘what are the influential indicators in the perception and cognition of the elderly’. For this purpose, Kahrizak elderly home was chosen. Using the 'Space Syntax’ method, this article examines the behavioural and cognitive responses of the elderly regarding the spatial characteristics of the elderly home. The research method includes two cognitive and spatial parts. In the cognitive section, after interviewing the elderly and receiving cognitive maps, the findings from the cognitive maps were compiled. Space configuration was evaluated through depth map software and Space Syntax parameters. In this analysis, spatial parameters such as connection value, connectivity, selection, depth of access and resolution have been examined and compared with cognitive maps. The analyses show that the maximum correlation is 7.3 and its average is 3.5, the maximum and average correlation parameters are 20 and 8.6, respectively. The maximum and average selection parameters are equal to 67 and 11.06, respectively. The maximum and average access depth parameters are 257 and 138.7, respectively. The analysis shows that Space Syntax modelling can be effective for understanding the perceptibility of space by the elderly, but for a correct understanding of the same space, other methods such as cognitive maps are needed. The results show that multiple objective and subjective factors are effective in the elderly's perception and their knowledge of space, together and sometimes with priorities over each other.

Abstract Background The emergence of carbapenem-resistant Enterobacterales (CRE) continues to threaten public health due to limited therapeutic options. In the current study the incidence of carbapenem resistance among the 104 clinical isolates of Escherichia coli and the genomic features of carbapenem resistant isolates were investigated. Methods The susceptibility to imipenem, tigecycline and colistin was tested by broth dilution method. Susceptibility to other classes of antimicrobials was examined by disk diffusion test. The presence of bla OXA-48, bla KPC, bla NDM, and bla VIM carbapenemase genes was examined by PCR. Molecular characteristics of carbapenem resistant isolates were further investigated by whole-genome sequencing (WGS) using Illumina and Nanopore platforms. Results Four isolates (3.8%) revealed imipenem MIC of ≥32 mg/L and positive results for modified carbapenem inactivation method and categorized as carbapenem resistant E. coli (CREC). Colistin, nitrofurantoin, fosfomycin, and tigecycline were the most active agents against all isolates (total susceptibility rate of 99, 99, 96 and 95.2% respectively) with the last three compounds being found as the most active antimicrobials for carbapenem resistant isolates (susceptibility rate of 100%). According to Multilocus Sequence Type (MLST) analysis the 4 CREC isolates belonged to ST167 (n = 2), ST361 (n = 1) and ST648 (n = 1). NDM was detected in all CREC isolates (NDM-1 (n = 1) and NMD-5 (n = 3)) among which one isolate co-harbored NDM-5 and OXA-181 carbapenemases. WGS further detected bla CTX-M-15, bla CMY-145, bla CMY-42 and bla TEM-1 (with different frequencies) among CREC isolates. Co-occurrence of NDM-type carbapenemase and 16S rRNA methyltransferase RmtB and RmtC was found in two isolates belonging to ST167 and ST648. A colistin-carbapenem resistant isolate which was mcr-negative, revealed various amino acid substitutions in PmrB, PmrD and PhoPQ proteins. Conclusion About 1.9% of E. coli isolates studied here were resistant to imipenem, colistin and/or amikacin which raises the concern about the outbreaks of difficult-to-treat infection by these emerging superbugs in the future.

ABSTRACT: Objectives: The increase in multidrug-resistant bacteria has reached an alarming rate globally, making it necessary to understand the underlying mechanisms mediating resistance in order to discover new therapeutics. Tigecycline (TGC) is a last-resort antimicrobial agent for the treatment of serious infections caused by extensively drug-resistant Enterobacteriaceae. Methods: The TGC-resistant Escherichia coli mutants were obtained by exposing three different TGC-susceptible isolates belonging to ST131 (n = 2) and ST405 (n = 1) to increasing concentrations of TGC. The genetic alterations associated with reduced susceptibility to TGC were identified using whole genome sequencing. The fitness cost of TGC resistance acquisition, as well as incidence of cross-resistance, was also investigated. Results: The TGC minimum inhibitory concentrations (MICs) of in vitro selected mutants were elevated 8 to 32 times compared with ancestral strains. Inactivating mutations (frameshift and nonsense) or amino acid substitutions were identified in genes encoding proteins with diverse functions, including AcrAB efflux pump or its regulators (lon and marR), Lipopolysaccharides (LPS) inner core biosynthesis enzymes (waaQ and eptB), ribosomal S9 protein (rpsI), and RNA polymerase β subunit. In most cases (but not all), acquisition of TGC resistance was associated with a fitness cost. While TGC resistance development was associated with cross-resistance to other members of the tetracycline family and chloramphenicol, hypersensitivity to nitrofurantoin was identified among heptose III-less LPS mutants. Conclusion: TGC resistance among the studied mutants was found to be multifactorial with extrusion by efflux transports being the most common mechanism. The LPS inner core biosynthesis pathway, as well as ribosomal S9 protein, could be additional targets for TGC resistance.

Dentists have always sought to harmonize the shapes of the teeth with the entire face based on parameters such as gender, personality, and age. The Visagism concept helps dentists to be able to create a smile that is not only for esthetics but also in harmony with all the psychological characteristics of the patient. The aim of this study was to investigate the match between smile design and personality traits of patients applying for smile design.Materials & Methods:This is a descriptive-analytical study. Standard photographs in three different modes of rest, gentle smile, and full smile were taken from 104 patients aged 30-18 years referred to the School of Dentistry of the Islamic Azad University of Isfahan in 2016 for smile design. Patients were given a questionnaire about temperament and an interview questionnaire for understanding their dental needs. The photos were checked by one professional observer and classified according to the Visagism concept and the photos were analyzed with the results of the questionnaire and the interview form. The Data were analyzed by Chi-square and One-Way ANOVA test (p value < 0.05).Results:Consistency percentage between personality and smile was 71.1% (p value < 0.0001). The most consistent in these 2 factors was Phlegmatic temperament (81.1%).Conclusion:Since there is a significant relationship between smile design and personality, it is recommended that in reconstructing a smile dentists should not limit themselves to aesthetic aspects from a dental point of view, but by creating a patient's psychological evaluation, create an esthetic smile plan in harmony with patients' psychological characteristics.

BackgroundInflammatory Bowel Disease (IBD) affects the quality of life. Patient education and support needs are crucial components of comprehensive chronic illness care. The main purposes of this review were to (i) explore the informational and supportive needs of these patients to improve the quality of life in the existing literature and (ii) identify the gaps related to the needs of the patients in articles.MethodsThe scoping review is based on the Daudt methodological framework, a modified version of Arksey and O'Malley. Electronic databases were extensively searched from January 01, 2000 to April 30, 2022. Four electronic databases (PubMed/Medline, CINAHL, APA PsycInfo, Psychology and Behavioral Sciences Collection, APA PsycArticles, and ProQuest) were searched using controlled vocabulary, and specific keywords. The searched terms were matched to each database. We manually searched two key journals, namely the Journal of Inflammatory Bowel Disease and the Journal of Crohn's and Colitis.ResultsIn the review, 75 studies on the assessment of the information and support needs of patients with IBD were reviewed. In this regard, 62 and 53 studies were regarding information needs and support needs, respectively. Most of the information needs of patients with IBD reported in the studies were related to diet needs, and educational needs were the most essential support needs.ConclusionsHealth policymakers and managers can develop care and educational programs related to this disease in health centers according to the needs of the patients. Health professionals, especially gastroenterologists, are the primary referral sources for information on patients. Therefore, gastroenterologists can take the lead in planning and educating the patients and sharing their decisions.Systematic review registrationOSF, https://doi.org/10.17605/OSF.IO/3MWGJ.

Introduction: The rapid growth of population, agriculture, urban and industries has led to increasing water demand and competition for its consumptions. The promotion of agricultural water productivity has the main effect on improving water consumption. Water delivery and scheduling methods are important to increase the flexibility of irrigation systems. Among different available methods, the on-request water delivery has higher flexibility than the rotational one and doesn’t need the high cost of automatic systems. The appropriate adjustment of the structures and their operational instructions between successive requests is a function of discharge variation, time interval between operations, coincidence of different request, physical condition of canal and structures and hydrodynamic behavior of the flow, which is a complex task. To obtain the performance of the recently utilized method, i.e., FSL (Fuzzy SARSA Learning), it is necessary to compare it to a traditional method like Artificial Neural Network (ANN). In this research, data from the east Aghili canal was trained for programming water delivery and distribution using MLP (Multi-Layer Perceptron) and RBF (Radial Basis Function) networks of ANN with the on-request method. Finally, the results of the FSL and ANN models were compared.Material and methods: In this research, the MLP (Multi-Layer Perceptron) and RBF (Radial Basis Function) networks of ANN were used to determine the procedure for exploiting the operational instructions of the on-request method in the east Aghili canal, in Khuzestan Province, using its flow and gate opening data. In this research, 70%, 15%, and 15% of data were used to train, test, and validate the model, respectively. The correlation coefficient and root mean square error were used for determining the better method. Modeling of the canal was done using the Irrigation Canal Conveyance System (ICSS) hydrodynamic model. To evaluate the MLP, RBF, and FSL outputs, maximum and average errors of water depth, adequacy, efficiency, equity, and dependability were used.Results and discussion: The operational instructions were determined using the MLP in March 2017 in the east Aghili canal, and were compared to the corresponding determined operational instructions using FSL. According to the obtained results, it was observed that the MPA index in the ANN method in the first and second block of this channel, respectively were 0.952 and 0.919 and in the case of using the FSL method, these values were equal to 0.996 and 1. Also, the MPF index in the simulation using the ANN in both blocks were equal to 1 and in the case of FSL, these values were equal to 0.999 and 0.971. The maximum error of MAE of water level in the first and second block of the study, respectively were equal to 9.2 and 3.8 % and in the case of using the FSL method, these were equal to 5.5 and 7.4 %. The results showed that the MLP was better than the RBF to determine the operational instructions. The MAE and IAE indicators were minimum, and the water delivery indicators were close to their desired values according to the Molden and Gates (1990) criteria. Aldo, it was revealed that the FSL was better than the MLP, however, the MLP results were valid and can be used in practice.Conclusion: In this research, the ANN model was used for determining operational instructions using MATLAB. The training was done using the MLP and RBF using the east Aghili canal data. The ICSS was used for simulating the canal. The results showed that the MLP was better than RBF, and the FSL model was better than the MLP as well. However, both of them can be used in practice.

Despite being a preventable and curable disease, tuberculosis (TB) is still a major global health threat and the second leading cause of death due to an infectious agent worldwide. All the efforts invested to end TB have resulted overall in rather slow decreases in TB incidence and mortality rates, which have been further negatively affected by the ongoing coronavirus disease 2019 (COVID-19) pandemic. While the majority of targets of the End TB Strategy remain off track, and we have not yet overcome the disruptions caused by the COVID-19 pandemic, recent conflicts such as the ongoing war in Ukraine are threatening the decrease of the burden of TB even further. To get back on track and get closer to ending TB, we need urgent, global, well-structured and committed multi-sectoral actions that go beyond national and global TB programmes with the support of deep investments in research and facilitation of equitable and rapid implementation of innovation worldwide.

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Summary: Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation.

مقدمه: ارﺗﺒﺎط و درك ﻣﺘﻘﺎﺑﻞ ارایه دﻫﻨﺪگان ﺧﺪﻣﺎت ﺳﻼﻣﺖ دﻫﺎن و مراجعه‌کنندگان، ﻣﻮرد ﺗﻮﺟﻪ ﺟﺪي ﻧﻈﺎم آﻣﻮزﺷﻲ دﻧﺪانﭘﺰﺷﻜﻲ قرار دارد. هدف از انجام پژوهش حاضر، بررسی و مقایسه میزان همدلی دندان‌پزشکان و دانشجویان دندان‌پزشکی شهر اصفهان با مراجعه‌کنندگان معتاد به مواد مخدر در سال 1397 بود. مواد و روش‌ها: جامعه آماری این مطالعه توصیفی- مقطعی را دانشجویان دندان‌پزشکی دانشگاه آزاد اسلامی واحد اصفهان (خوراسگان) و دندان‌پزشکان شاغل در کلینیک‌های دندان‌پزشکی شهر اصفهان تشکیل داد که از هر گروه 100 نفر به روش نمونه‌گیری در دسترس انتخاب شدند. داوطلبان پرسش‌نامه‌ای دو قسمتی شامل اطلاعات فردی و پرسش‌نامه استاندارد همدلی Jefferson (Jefferson Scale of Empathy یا JSE) را تکمیل کردند. داده‌ها با استفاده از آزمون‌های 2χ، Fisher's exact، Independent t، Linear regression و ضریب همبستگی Pearson مورد تجزیه و تحلیل قرار گرفت. یافته‌ها: میزان همدلی دندان‌پزشکان با افراد معتاد، به طور معنی‌داری بیشتر از دانشجویان دندان‌پزشکی بود (001/0 > P). میانگین متغیر همدلی با افراد معتاد، در هیچ‌کدام از گروه‌های دانشجویان و دندان‌پزشکان بین مردان و زنان یا افراد مجرد و متأهل اختلاف معنی‌داری را نشان نداد (050/0 < P). بین سن دانشجویان دندان‌پزشکی با متغیر همدلی آن‌ها با افراد معتاد، رابطه مستقیم و ضعیفی وجود داشت (050/0 > P، 271/0 = r)، اما در گروه دندان‌پزشکان، بین متغیر سن و میزان همدلی رابطه معنی‌داری مشاهده نشد (780/0 = P). بر اساس نتایج آزمون Linear regression، میزان همدلی دندان‌پزشکان با افراد معتاد بیشتر از دانشجویان بود (001/0 > P)، اما هیچ‌کدام از متغیرهای زمینه‌ای سن، جنسیت، سابقه شغلی و وضعیت تأهل، تأثیر معنی‌داری بر همدلی نداشت (050/0 < P). نتيجه‌گيري: اگرچه نمره همدلی دندان‌پزشکان با افراد معتاد به طور معنی‌داری بیشتر از دانشجویان دندان‌پزشکی بود، اما نمره همدلی هر دو گروه در وضعیت متوسطی قرار داشت. بنابراین، برنامه‌ريزان آموزش دندان‌پزشكي باید جهت افزايش همدلي با افراد معتاد، برنامه‌هاي هدفمند را به دوره آموزشی دندان‌پزشکی وارد کنند.

Farzaneh Ohadi, Soheila Rahgozar, Elaheh Sadat Ghodousi Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, IranCorrespondence: Soheila RahgozarDepartment of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jarib Street, Isfahan 81746-73441, IranTel +98 313 793 2455Fax +98 313 793 2456Email rahgozar@sci.ui.ac.irPurpose: Sal‐like protein 4 transcription factor (SALL4) is a stem cell transcription factor that plays an essential role in the maintenance and self-renewal of embryonic and hematopoietic stem cells, functioning as an oncogene in several cancers. However, the role of SALL4 in the biological behavior of childhood acute lymphoblastic leukemia and its relationship with multidrug resistance and relapse has remained largely unknown.Patients and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to characterize the expression pattern of SALL4 in the bone marrow samples of 43 patients with Philadelphia negative ALL and 18 children in the non-cancer control group. The presence of minimal residual disease was measured a year after the initial therapy using SSCP (single-strand conformation polymorphism). In addition, the correlation between the expression of SALL4 and ABCA3 in relapsed patients was analyzed statistically.Results: Results showed an overexpression of SALL4 in de novo patients compared with the control group (P=0.0001, AUC= 0.93), indicating the importance of this gene in the induction of leukemia. A significant increase in the ABCA3 expression levels was revealed in the relapsed patients, in comparison with the drug-sensitive group (P = 0.0005). The leukemogenetic effect of SALL4 can be related to the effect of this gene on the maintenance of pluripotency in cancer stem cells. Results also suggest that the expression of SALL4 can be considered as a diagnostic marker for pediatric ALL. Moreover, SALL4 expression levels in the minimal residual disease positive (mrd+) ALL group was significantly higher than those in the mrd− group (p=0.0001, AUC= 0.92).Conclusion: These data demonstrate the prognostic impact of SALL4 in childhood ALL. Our findings also indicated a direct correlation between the mRNA expression levels of SALL4 and ABCA3 transporter in the relapsed group of ALL patients (r=0.7). These results describe a possible mechanism by which SALL4 may lead to the development of multidrug resistance.Keywords: childhood acute lymphoblastic leukemia, multidrug resistance, SALL4, ABC transporters, relapse, ABCA3

Medical centers (that is, hospitals and clinics) in metropolitan areas produce substantial amounts of hazardous waste in both solid and liquid (wastewater) forms. Unless medical centers manage their waste with appropriate care, the significant hazards posed to urban residents and areas far outweigh the benefits of their services. Therefore, comprehensive environmental management programs need to be developed in order to minimize the associated impacts and improve environmental performance. In addition to identifying the environmental consequences, developing a comprehensive performance assessment program requires a deep understanding of the factors involved and their corresponding shares. Thus, the aim of this paper is to model environmental performance assessment in urban medical centers. Firstly, relevant criteria, sub-criteria and indicators were identified using the Delphi method. Next, Fuzzy Analytical Hierarchy Process (AHP) was applied to rank the factors and a balanced scoring was established to model the environmental performance assessment in medical centers. The adequate consistency index confirms Fuzzy AHP accuracy and consequently, the scores. The model was applied in Sarem Specialized Hospital in Tehran, Iran. The results indicate that the hospital has good environmental performance. The results show that the waste disinfection indicator, was rated the highest and most important index with a score of 84.The other indicators were ranked in terms of treated sewage and source separation of waste and application of mechanisms to control water consumption respectively with scores of 38, 26.5 and 25.