Gaps

GAP
  • 文章类型: Journal Article
    背景:检测葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症是治疗疟疾的重要考虑因素。G6PD缺乏可能导致疟疾治疗期间的溶血性贫血,因此,确定G6PD缺乏症在疟疾治疗策略中非常重要。
    方法:本报告提供了范围审查的结果以及证据和差距图,供G6PD近患者试验指南开发小组考虑,以支持间日疟原虫的根治。本范围审查调查了G6PD缺乏症的常见诊断测试以及决策的重要背景和其他因素。这些因素包括世界卫生组织(世卫组织)指南制定手册建议的六个考虑因素,这些因素对确定建议的方向和力度很重要,并包括“可接受性”,\'可行性,\'\'权益,结果的\'\'估值,\'\'性别\'和\'人权\'。本范围审查的目的是为未来的系统审查和证据综合提供指导,这可以更好地为制定世卫组织关于将G6PD缺乏症检测作为疟疾治疗战略一部分的建议提供信息。
    结果:进行了全面搜索,包括出版,任何文章的同行评审文献,研究G6PD诊断测试和“可接受性”因素的任何研究设计和方法,\'可行性,\'\'权益,结果的\'\'估值,\'\'性别\'和\'人权\'。从搜索中确定了1152项研究,其中14人被确定有资格纳入本次审查。这些研究包含来自21个独特国家的数据,这些国家将G6PD诊断测试视为疟疾治疗策略的一部分。上下文和附加因素之间的关系,G6PD缺乏症的诊断测试和研究方法在总体证据和差距中提出,这表明大多数证据是诊断测试的背景因素,和标准G6PD(SD生物传感器)测试。
    结论:本范围审查产生了动态证据和差距图,对G6PD诊断测试领域内的新兴证据具有反应性。证据和差距图提供了所有可用文献的全面描述,这些文献涉及对决策重要的背景和其他因素,关于特定的G6PD诊断测试。调查感兴趣的背景因素的大多数可用数据与定量G6PD诊断测试有关。虽然可以对这些数据进行正式的定性综合,作为系统审查的一部分,数据可能太异,这是不合适的。这些结果现在可用于为世卫组织G6PD指导发展小组的未来方向提供信息,以支持间日疟原虫的根治。
    BACKGROUND: Testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important consideration regarding treatment for malaria. G6PD deficiency may lead to haemolytic anaemia during malaria treatment and, therefore, determining G6PD deficiency in malaria treatment strategies is extremely important.
    METHODS: This report presents the results of a scoping review and evidence and gap map for consideration by the Guideline Development Group for G6PD near patient tests to support radical cure of Plasmodium vivax. This scoping review has investigated common diagnostic tests for G6PD deficiency and important contextual and additional factors for decision-making. These factors include six of the considerations recommended by the World Health Organization (WHO) handbook for guideline development as important to determining the direction and strength of a recommendation, and included \'acceptability\', \'feasibility,\' \'equity,\' \'valuation of outcomes,\' \'gender\' and \'human rights\'. The aim of this scoping review is to inform the direction of future systematic reviews and evidence syntheses, which can then better inform the development of WHO recommendations regarding the use of G6PD deficiency testing as part of malaria treatment strategies.
    RESULTS: A comprehensive search was performed, including published, peer-reviewed literature for any article, of any study design and methodology that investigated G6PD diagnostic tests and the factors of \'acceptability\', \'feasibility,\' \'equity,\' \'valuation of outcomes,\' \'gender\' and \'human rights\'. There were 1152 studies identified from the search, of which 14 were determined to be eligible for inclusion into this review. The studies contained data from over 21 unique countries that had considered G6PD diagnostic testing as part of a malaria treatment strategy. The relationship between contextual and additional factors, diagnostic tests for G6PD deficiency and study methodology is presented in an overall evidence and gap, which showed that majority of the evidence was for the contextual factors for diagnostic tests, and the \'Standard G6PD (SD Biosensor)\' test.
    CONCLUSIONS: This scoping review has produced a dynamic evidence and gap map that is reactive to emerging evidence within the field of G6PD diagnostic testing. The evidence and gap map has provided a comprehensive depiction of all the available literature that address the contextual and additional factors important for decision-making, regarding specific G6PD diagnostic tests. The majority of data available investigating the contextual factors of interest relates to quantitative G6PD diagnostic tests. While a formal qualitative synthesis of this data as part of a systematic review is possible, the data may be too heterogenous for this to be appropriate. These results can now be used to inform future direction of WHO Guideline Development Groups for G6PD near patient tests to support radical cure of P. vivax malaria.
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  • 文章类型: Journal Article
    近年来,各种聚(ADP-核糖)聚合酶(PARP)抑制剂(PARP)已被批准用于治疗几种癌症,以靶向同源重组(HR)缺陷的脆弱性(例如,由于BRCA1/2功能障碍)。在这篇综述中,我们分析了在使用PARPis治疗BRCA1/2缺陷型癌症方面正在进行的辩论和最近的突破。并置“双链断裂(DSB)”和“单链DNA(ssDNA)缺口”模型的PARPis诱导的合成致死性。我们关注这种互动的复杂性,强调关于DNA聚合酶θ(POLθ)和ssDNA缺口在塑造治疗反应中的作用的新兴研究。我们仔细研究了这些发现的临床后果,特别是关于PARPi的功效和抗性机制,强调了BRCA突变肿瘤的异质性以及迫切需要先进的研究来弥合实验室模型和患者预后之间的差距.
    In recent years, various poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been approved for the treatment of several cancers to target the vulnerability of homologous recombination (HR) deficiency (e.g., due to BRCA1/2 dysfunction). In this review we analyze the ongoing debates and recent breakthroughs in the use of PARPis for BRCA1/2-deficient cancers, juxtaposing the \'double-strand break (DSB)\' and \'single-stranded DNA (ssDNA) gap\' models of synthetic lethality induced by PARPis. We spotlight the complexity of this interaction, highlighting emerging research on the role of DNA polymerase theta (POLθ) and ssDNA gaps in shaping therapy responses. We scrutinize the clinical ramifications of these findings, especially concerning PARPi efficacy and resistance mechanisms, underscoring the heterogeneity of BRCA-mutated tumors and the urgent need for advanced research to bridge the gap between laboratory models and patient outcomes.
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  • 文章类型: Journal Article
    近几十年来,极端天气事件导致了广泛的产量损失和重大的全球经济损失。非洲农业由于其恶劣的环境和有限的适应能力而特别脆弱。这篇系统的综述分析了来自WebofScience的96篇文章,科学直接,和谷歌学者,专注于非洲和世界各地与玉米相关的生物物理研究。我们调查了非洲观测到的和预测的极端天气事件,它们对玉米生产的影响,以及评估这些影响的方法。我们的分析表明,干旱,热浪,洪水是非洲玉米生产的主要威胁,影响产量,适宜的种植面积,和农民的生计。虽然研究采用了各种方法,包括现场实验,统计模型,和基于过程的建模,非洲的研究往往受到数据差距和技术限制的限制。我们发现了三个主要差距:(I)缺乏可靠的长期实验和经验数据,(ii)获得先进的气候变化适应技术的机会有限,(iii)对特定极端天气模式及其与管理制度的相互作用的知识不足。这篇综述强调了迫切需要在非洲开展有针对性的研究,以提高对极端天气影响的认识,并制定有效的适应战略。我们提倡集中研究数据收集,技术转让,并将当地知识与新技术相结合,以增强非洲的玉米抗灾能力和粮食安全。
    Extreme weather events have led to widespread yield losses and significant global economic damage in recent decades. African agriculture is particularly vulnerable due to its harsh environments and limited adaptation capacity. This systematic review analyzes 96 articles from Web of Science, Science Direct, and Google Scholar, focusing on biophysical studies related to maize in Africa and worldwide. We investigated the observed and projected extreme weather events in Africa, their impacts on maize production, and the approaches used to assess these effects. Our analysis reveals that drought, heatwaves, and floods are major threats to African maize production, impacting yields, suitable cultivation areas, and farmers\' livelihoods. While studies have employed various methods, including field experiments, statistical models, and process-based modeling, African research is often limited by data gaps and technological constraints. We identify three main gaps: (i) lack of reliable long-term experimental and empirical data, (ii) limited access to advanced climate change adaptation technologies, and (iii) insufficient knowledge about specific extreme weather patterns and their interactions with management regimes. This review highlights the urgent need for targeted research in Africa to improve understanding of extreme weather impacts and formulate effective adaptation strategies. We advocate for focused research on data collection, technology transfer, and integration of local knowledge with new technologies to bolster maize resilience and food security in Africa.
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  • 文章类型: Journal Article
    目的:家族性高胆固醇血症(FH)导致低密度脂蛋白胆固醇水平升高,这增加了过早发生动脉粥样硬化性心血管疾病(ASCVD)的风险。由于动脉壁的首次功能和形态变化发生在儿童时期,治疗应在儿童早期开始,以减轻ASCVD的升高风险.儿科医生在FH患儿的检测和护理中起着重要作用。在这项研究中,我们的目标是探索荷兰儿科医生在FH护理方面的潜在差距,以提高他们对FH患儿的认识和认识。
    方法:匿名在线调查,使用GoogleForms部署,荷兰儿科学协会通过通讯分发了26个关于儿童FH护理的封闭式和半封闭式问题,大多数荷兰执业儿科医生都订阅了该通讯。此外,我们要求荷兰所有荷兰医院的儿科部门在其雇用的儿科医生中亲自分发这项调查。受访者被指示在没有任何帮助或使用在线资源的情况下回答问题。
    结果:9月1日之间,2023年和11月1日,2023年,158名(估计11%的反应率)荷兰儿科医生完成了调查。他们报告的儿科医生经验中位数(IQR)为15.0(6.0-22.0)年,34人(21.5%)在学术医院工作。大多数(76.6%)的儿科医生正确地确定了典型的FH血脂谱,但68(43.0%)低估了FH的真实患病率(1:300)。有37.3%和25.9%的儿科医生报告了对FH患者ASCVD风险增加的低估和认识,分别。尽管70.9%的儿科医生正确定义了FH,只有67例(42.4%)选择他汀类药物和依泽替米贝治疗重度高胆固醇血症.
    结论:这项研究的结果表明,荷兰儿科医生对儿童FH的知识和认识存在显著差距。需要通过教育和培训举措来改善儿童的FH护理,以减轻早期ASCVD的终身风险。
    背景:•家族性高胆固醇血症(FH)导致LDL-胆固醇水平升高,这增加了过早发生动脉粥样硬化性心血管疾病(ASCVD)的风险。•动脉粥样硬化的过程始于儿童期•儿科医生在FH儿童的检测和治疗中发挥重要作用。
    背景:我们的研究结果突出了儿科医生在FH患儿护理方面的巨大差距,这可能导致检测和治疗欠佳。•儿童的FH护理需要通过教育举措来改善,以最终预防成年后的ASCVD。
    OBJECTIVE: Familial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH.
    METHODS: An anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources.
    RESULTS: Between September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0-22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia.
    CONCLUSIONS: The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life.
    BACKGROUND: • Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). • The process of atherosclerosis starts in childhood • Pediatricians play an important role in the detection and treatment of children with FH.
    BACKGROUND: • Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment. • FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood.
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  • 文章类型: Journal Article
    背景:技术的进步增强了教育,培训,以及在医疗保健中的应用。然而,围绕仿真技术的可访问性和使用存在限制(例如,模拟器)用于健康专业教育。提高非营利组织在大学研究中心开发的技术的可及性(非营利组织;例如,医院)有可能造福全球人口的健康。这种技术的一个例子是3D打印模拟器。
    目的:本范围审查旨在确定使用开源数据库分发用于3D打印的模拟器设计如何促进可靠的医疗保健培训解决方案,同时最大程度地降低商业化的风险。
    方法:此范围审查将遵循Arksey和O\'Malley方法框架以及JoannaBriggsInstitute关于范围审查的指导。OvidMEDLINE,CINAHL,WebofScience,和PsycINFO将以2012年至2022年的应用时间框架进行搜索。此外,灰色文献将与参考列表搜索一起搜索。将包括探索在学术环境和医疗保健部门中使用开源数据库来分发模拟器设计的论文。将对标题和摘要进行两步筛选,然后全文,建立纸质资格。论文的筛选和数据提取将由2名审稿人(MS和SS)完成,以确保质量。范围审查将报告有关通过开源数据库分发3D打印模拟器设计的便利信息。
    结果:本次审查的结果将确定与非营利组织和基于大学的研究中心形成伙伴关系以共享模拟器设计的差距。范围审查将于2024年12月启动。
    结论:所收集的信息将对医疗保健提供者等利益相关者具有相关性和有用性。研究人员,和非营利组织,以克服有关仿真技术的使用和分布的研究空白。范围审查尚未进行。因此,目前没有可报告的调查结果。
    PRR1-10.2196/53167。
    BACKGROUND: Advancements in technology have enhanced education, training, and application in health care. However, limitations are present surrounding the accessibility and use of simulation technology (eg, simulators) for health profession education. Improving the accessibility of technology developed in university-based research centers by nonprofit organizations (NPOs; eg, hospitals) has the potential to benefit the health of populations worldwide. One example of such technology is 3D-printed simulators.
    OBJECTIVE: This scoping review aims to identify how the use of open-source databases for the distribution of simulator designs used for 3D printing can promote credible solutions for health care training while minimizing the risks of commercialization of designs for profit.
    METHODS: This scoping review will follow the Arksey and O\'Malley methodological framework and the Joanna Briggs Institute guidance for scoping reviews. Ovid MEDLINE, CINAHL, Web of Science, and PsycINFO will be searched with an applied time frame of 2012 to 2022. Additionally, gray literature will be searched along with reference list searching. Papers that explore the use of open-source databases in academic settings and the health care sector for the distribution of simulator designs will be included. A 2-step screening process will be administered to titles and abstracts, then full texts, to establish paper eligibility. Screening and data extraction of the papers will be completed by 2 reviewers (MS and SS) for quality assurance. The scoping review will report information on the facilitation of distributing 3D-printed simulator designs through open-source databases.
    RESULTS: The results of this review will identify gaps in forming partnerships with NPOs and university-based research centers to share simulator designs. The scoping review will be initiated in December 2024.
    CONCLUSIONS: The information collected will be relevant and useful for stakeholders such as health care providers, researchers, and NPOs for the purpose of overcoming the gaps in research regarding the use and distribution of simulation technology. The scoping review has not been conducted yet. Therefore, there are currently no findings to report on.
    UNASSIGNED: PRR1-10.2196/53167.
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  • 文章类型: Journal Article
    肺癌是全球发病率和癌症相关死亡率最高的癌症。在葡萄牙,它是第四常见的癌症,每年诊断出近6000例新病例。肺癌是男性癌症相关死亡的主要原因,是女性癌症相关死亡的第三大原因。尽管全球公认的指南和建议是肺癌患者的理想路径,在世界各地的实际临床管理中出现了一些挑战.建议强调对高危人士进行充分筛查的重要性,精确的肿瘤活检,和准确的最终诊断,以确认结节的肿瘤性质。肺肿瘤类型的详细组织学分类和全面的分子表征对于选择有效且针对患者的治疗方法至关重要。然而,在葡萄牙临床组织和国家医疗保健系统的背景下,肺癌患者的理想途径仍然存在一些差距,涉及从缺乏国家肺癌筛查计划到组织学诊断和分子表征方面的困难到治疗方法的挑战。在这份手稿中,我们解决了最相关的弱点,提出了一些改善肺癌患者管理的潜在解决方案的建议,有助于决定性地提高他们的整体生存率和生活质量。
    Lung cancer has the highest incidence and cancer-related mortality worldwide. In Portugal, it ranks as the fourth most common cancer, with nearly 6000 new cases being diagnosed every year. Lung cancer is the main cause of cancer-related death among males and the third cause of cancer-related death in females. Despite the globally accepted guidelines and recommendations for what would be the ideal path for a lung cancer patient, several challenges occur in real clinical management across the world. The recommendations emphasize the importance of adequate screening of high-risk individuals, a precise tumour biopsy, and an accurate final diagnosis to confirm the neoplastic nature of the nodule. A detailed histological classification of the lung tumour type and a comprehensive molecular characterization are of utmost importance for the selection of an efficacious and patient-directed therapeutic approach. However, in the context of the Portuguese clinical organization and the national healthcare system, there are still several gaps in the ideal pathway for a lung cancer patient, involving aspects ranging from the absence of a national lung cancer screening programme through difficulties in histological diagnosis and molecular characterization to challenges in therapeutic approaches. In this manuscript, we address the most relevant weaknesses, presenting several proposals for potential solutions to improve the management of lung cancer patients, helping to decisively improve their overall survival and quality of life.
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  • 文章类型: Journal Article
    霍乱流行病学中的各种建模技术已被开发并用于(1)研究其传播动力学,(2)预测和管理霍乱疫情,(3)评估各种控制和缓解措施的影响。在这项研究中,我们对用于霍乱动态建模的各种方法进行了批判性和系统的审查。此外,我们讨论了每种建模方法的优缺点。在谷歌学者中对文章进行了系统的搜索,PubMed,科学直接,泰勒和弗朗西斯。符合条件的研究是与霍乱动态有关的研究,不包括集中在动物霍乱传播模型上的研究。社会经济因素,以及遗传和分子相关研究。共有476篇同行评审的文章符合纳入标准,大约40%(32%)的研究在亚洲(非洲)进行。约52%,21%,9%,的研究,基于隔室(例如,SIRB),统计(时间序列和回归),和空间(时空聚类)模型,分别,而其余的分析研究使用了其他建模方法,如网络,机器学习和人工智能,贝叶斯,和基于代理的方法。纳入病原体媒介/家蝇传播的霍乱模型研究很少,一小部分研究人员(3.99%)考虑了关键流行病学参数的估计。在超过一半(58%)的研究中,仅使用疫苗接种平台作为控制措施。近年来,霍乱流行病学模型研究的研究生产率有所提高,但是作者使用了各种各样的模型。未来的模型应考虑纳入病原体的媒介/家蝇传播以及估计霍乱动力学传播的关键流行病学参数。
    Diverse modelling techniques in cholera epidemiology have been developed and used to (1) study its transmission dynamics, (2) predict and manage cholera outbreaks, and (3) assess the impact of various control and mitigation measures. In this study, we carry out a critical and systematic review of various approaches used for modelling the dynamics of cholera. Also, we discuss the strengths and weaknesses of each modelling approach. A systematic search of articles was conducted in Google Scholar, PubMed, Science Direct, and Taylor & Francis. Eligible studies were those concerned with the dynamics of cholera excluding studies focused on models for cholera transmission in animals, socio-economic factors, and genetic & molecular related studies. A total of 476 peer-reviewed articles met the inclusion criteria, with about 40% (32%) of the studies carried out in Asia (Africa). About 52%, 21%, and 9%, of the studies, were based on compartmental (e.g., SIRB), statistical (time series and regression), and spatial (spatiotemporal clustering) models, respectively, while the rest of the analysed studies used other modelling approaches such as network, machine learning and artificial intelligence, Bayesian, and agent-based approaches. Cholera modelling studies that incorporate vector/housefly transmission of the pathogen are scarce and a small portion of researchers (3.99%) considers the estimation of key epidemiological parameters. Vaccination only platform was utilized as a control measure in more than half (58%) of the studies. Research productivity in cholera epidemiological modelling studies have increased in recent years, but authors used diverse range of models. Future models should consider incorporating vector/housefly transmission of the pathogen and on the estimation of key epidemiological parameters for the transmission of cholera dynamics.
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  • 文章类型: Journal Article
    人类弓形虫病(HT)是全球范围内广泛存在的人畜共患传染病,特别是在热带地区流行。增强我们对弓形虫病的了解可以引起人们对这种被忽视的人畜共患病的社会经济影响和控制的更多关注。我们对有关伊朗弓形虫病的所有可用文章和官方文件进行了全面审查,以确定研究差距和控制其关键需求。这篇综述强调,尽管有许多研究探索了确定性和性腺宿主中弓形虫病的各个方面,以及人类和环境污染,该国不同地区仍然存在显著的数据缺陷和差距。这些差距涉及调查确定宿主的蠕虫负担和再感染率,开发更灵敏的方法来检测和区分弓形虫物种,并了解确定宿主动物的行为。此外,确定HT的潜在paratenic宿主并探索这些宿主中弓形虫幼虫的器官特异性亲和力和存活时间是探索的重要领域。还必须理解寄生虫在副科宿主中的sylvatic和domestic周期。此外,评估环境中的鸡蛋密度,探索潜在的新来源,如水,和确定具有弓形虫卵生存和发育的最佳气候条件的区域对于制定有效的预防和控制策略至关重要。确定风险群体,发展早期诊断技术,采用成像方法,识别人类的长期并发症也至关重要。社区卫生组织应优先对公众和专业人员进行健康教育。此外,准确估计确定的宿主种群,监视和防止他们在公共场所的活动,对宠物和流浪寄主实施定期驱虫做法,认识到感染作为健康优先事项的重要性至关重要。这种全面的理解倡导了一种整体的“一种健康”方法来控制HT。
    Human toxocariasis (HT) is a widespread zoonotic infection globally, notably prevalent in tropical areas. Enhancing our understanding of toxocariasis can lead to increased attention towards the socioeconomic impact and control of this neglected zoonosis. We conducted a comprehensive review of all available articles and official documents on toxocariasis in Iran to identify research gaps and critical needs for its control. This review highlights that despite numerous studies exploring various aspects of toxocariasis in definitive and paratenic hosts, as well as humans and environmental contamination, significant data deficiencies and gaps persist across different regions in the country. These gaps involve investigating the worm burden and reinfection rates in definitive hosts, developing more sensitive methods to detect and differentiate of Toxocara species, and understanding the behavior of definitive host animals. Additionally, identifying potential paratenic hosts for HT and exploring the organ-specific affinity and survival duration of Toxocara larvae within these hosts are essential areas for exploration. It\'s also imperative to comprehend the sylvatic and domestic cycles of the parasite in paratenic hosts. Furthermore, assessing egg density in the environment, exploring potential new sources such as water, and identifying regions with optimal climatic conditions for the survival and development of Toxocara eggs are crucial for the formulation of effective prevention and control strategies. Identifying at-risk groups, developing early diagnosis techniques, employing imaging methods, and identifying long-term complications in humans are also crucial. Community health organizations should prioritize health education for the public and professionals. Furthermore, accurately estimating definitive host populations, monitoring and preventing their movements in public places, implementing regular deworming practices for pets and stray hosts, and recognizing the infection\'s significance as a health priority are critical. This comprehensive understanding advocates for a holistic \"one health\" approach to control of HT.
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  • 文章类型: Journal Article
    DNA中碱基的改变构成基因组不稳定性的主要来源。据信碱基改变引发碱基切除修复(BER),产生干扰DNA复制的DNA修复中间体。这里,我们显示基因组尿嘧啶,一种常见的碱基改变,诱导DNA复制应激(RS)而不被BER处理。在没有尿嘧啶DNA糖基化酶(UNG)的情况下,基因组尿嘧啶积累到高水平,DNA复制叉慢下来,PrimPol介导的再灌注增强,在新生DNA中产生单链缺口。UNG缺陷细胞中的ATR抑制阻断尿嘧啶诱导的间隙的修复,增加复制叉崩溃和细胞死亡。值得注意的是,一部分癌细胞上调UNG2以抑制基因组尿嘧啶并限制RS,这些癌细胞对ATR抑制剂和增加基因组尿嘧啶的药物共同治疗过敏。这些结果揭示了未加工的基因组尿嘧啶作为RS的意外来源和癌细胞的可靶向脆弱性。
    Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common type of base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA. ATR inhibition in UNG-deficient cells blocks the repair of uracil-induced gaps, increasing replication fork collapse and cell death. Notably, a subset of cancer cells upregulates UNG2 to suppress genomic uracil and limit RS, and these cancer cells are hypersensitive to co-treatment with ATR inhibitors and drugs increasing genomic uracil. These results reveal unprocessed genomic uracil as an unexpected source of RS and a targetable vulnerability of cancer cells.
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  • 文章类型: Journal Article
    实验是有用的科学工具,可以通过操纵感兴趣的变量来测试假设,同时控制其他可能使结果及其解释产生偏差或混淆的因素。为了确保准确性和再现性,实验必须有透明和可重复的方法。由于切碎机无脊椎动物在有机物加工中的重要性,碳循环,和营养循环,我们通过实验测试了微观世界实验中不同方法对碎纸机消耗和生存的影响。我们发现碎纸机物种,案件的存在与否,并且在微观世界中使用或不使用气泵不会影响切碎机的性能(即,消费和生存)。此外,水的类型(溪流或瓶装)不会影响切碎机的性能。另一方面,光量对碎纸机性能有负面影响,具有恒定的光(即,24h)减少碎纸机消耗和生存。我们的结果表明,使用不同的方法并不总是导致结果的变化,从而确保可比性。然而,光度是进行微观实验时值得关注的关键因素。我们的发现提供了有价值的见解,可以帮助研究人员设计来自新热带流的碎纸机的实验,并进行系统的评论和荟萃分析。
    Experiments are useful scientific tools for testing hypotheses by manipulating variables of interest while controlling for other factors that can bias or confuse the results and their interpretation. To ensures accuracy and reproducibility, experiments must have transparent and repeatable methodologies. Due to the importance of shredder invertebrates in organic matter processing, carbon cycling, and nutrient cycling, we tested experimentally the effect of different methodological approaches in microcosm experiments on the consumption and survival of shredders. We found that the shredder species, the presence or absence of the case, and the use or non-use of air-pumps in the microcosms did not affect shredder performance (i.e., consumption and survival). Furthermore, the type of water (stream or bottled) did not affect shredder performance. On the other hand, the amount of light had a negative effect on shredder performance, with constant light (i.e., 24 h) reducing shredder consumption and survival. Our results demonstrate that the use of different methodologies does not always result in changes in outcomes, thus ensuring comparability. However, luminosity is a critical factor that deserves attention when conducting microcosm experiments. Our findings provide valuable insights that can assist researchers in designing experiments with shredders from neotropical streams and conducting systematic reviews and meta-analyses.
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