Background: Following the establishment of Economic Community of West African States Medicines Regulatory Harmonization (ECOWAS-MRH) initiative in 2017, it was considered timely to carry out an evaluation of the current status of the initiative’s operating model by the pharmaceutical industry users. This study examined the challenges being encountered and identified strategies that would strengthen the ECOWAS-MRH initiative moving forward.Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from manufacturers who have submitted applications to the joint assessment procedure and had identified recommendations for improving the performance of the ECOWAS-MRH initiative.Results: Ten pharmaceutical manufacturer participants  all reported that harmonisation of registration requirements was a major benefit, allowing submission of the same dossier to multiple countries, reducing the application burden and saving time and resources. Additionally, receipt of the same list of questions from several countries enables the compilation of a single response package, resulting in shorter timelines for approvals compared to the individualised country responses. Another benefit of a harmonised registration process was the simultaneous accessibility of medicines in various markets. Key challenges included a lack of centralised submission and tracking, differences in regulatory performance of the national medical regulatory authorities, a lack of detailed information for applicants and a low motivation to use the ECOWAS-MRH route with a preference for other regulatory pathways in the ECOWAS member states.Conclusion: This study identified several approaches to increase the effectiveness of this initiative: the implementation of risk-based approaches such as use of reliance pathways; establishment of a robust information technology systems, building assessor capacity to facilitate processing and monitoring applications; and priority review of ECOWAS-MRH products. It is the responsibility of every country to establish an effective and efficient medicine regulatory system in order to ensure timely patients’ access to high-quality, safe and efficacious medicines . Vogel .The active engagement and co-operation of manufacturers with regulators in the medicine regulatory system is vital to the success of a national health system. Presently, there are multiple national jurisdictions that manufacturers have to contend with in order to obtain the requisite raw or starting materials, intermediate or semi-finished products, and where applicable, packaging materials from one country into another so as to manufacture a finished pharmaceutical product or vaccine. Furthermore, there are multinational pharmaceutical companies who conduct activities such as contract manufacturing across multiple countries worldwide, which underlines the complex nature of manufacturing of medicines and vaccines. The ideal regulatory environment that would benefit applicants would be one that multiple countries subscribe to under an umbrella of harmonisation. Furthermore, there is evidence to show that pharmaceutical applicants have a selective bias with regard to regulatory systems that provide transparency, accountability and predictability .There are various regulatory mechanisms available at this time that correspond to these parameters, such as the well-established centralised authorisation procedure of the European Union. In this procedure, applicants apply for a single centralised marketing authorisation for a product, which is valid throughout the European Union member states as well as Iceland, Liechtenstein and Norway . SimilarPresently, various diseases such as malaria and tuberculosis occur predominantly in Africa, with the WHO stating that in 2017, 92% of the 219 million cases of malaria reported worldwide were from Africa ; therefoThe challenges to the assessment of applications for marketing authorisation for new chemical entities and vaccines in Africa have been identified . Moran aMedicine regulatory harmonisation appears to be an effective mechanism for deploying technical, human and financial resources efficiently for the benefit of the population. According to the WHO, applicants who participate in the WHO prequalification programme enjoy various benefits such as increased sales or market access, improved image or brand, reduced manufacturing costs and increased capacity/skills. By extrapolation, applicants who participate in similar harmonisation initiatives like the ECOWAS-MRH can also experience their share of these benefits by having access to patients in all the 15 member states of ECOWAS, making this a win-win situation for both the applicants and patients .Started in 2017 by the West African Health Organization (WAHO), the ECOWAS-MRH initiative seeks to enhanced accessibility of high-quality, safe and effective medicines and vaccines in the ECOWAS . By the About a decade ago, Narsai and colleagues reported that there was inadequate information in the literature detailing the views of pharmaceutical manufacturers about the regulatory systems in Africa . This siAs a result of completing an earlier study aimed to assess the effectiveness and efficiency of the current operating model of the ECOWAS-MRH initiative by the national medical regulatory authorities (NMRAs) in the member countries , this prThe objectives of this study were to obtain the views of the pharmaceutical applicants or their local representatives of the ECOWAS-MRH initiative about the performance of the programme to date, identify the challenges experienced by the applicants throughout the life cycle of the ECOWAS-MRH initiative, determine the strengths and weaknesses of the initiative, identify the ways of improving the performance of the work-sharing programme and envisaging the strategy for moving forward.All ten pharmaceutical manufacturers who have submitted marketing authorisation applications for assessment of medicines at the regional level since the beginning of the ECOWAS-MRH initiative participated in the study. The study participants were classified as Innovator, Generics (foreign) -manufacturer outside ECOWAS and Generics - manufacturer within ECOWAS.Data for the study were obtained through completion of the Process Effectiveness and Efficiency Rating (PEER) questionnaire  by appliThe questionnaire consists of five sections namely; demographics, the benefits and challenges of the ECOWAS-MRH initiative, improving the performance (effectiveness and efficiency) of the work-sharing programme and envisaging the strategy for moving forward.Semi-structured interviews with a checklist were conducted with each manufacturer in order to validate and elaborate their responses in the PEER questionnaire. This also provided the study participants with an opportunity to discuss any difficulty they faced in responding to some of the sections of the questionnaire. In addition, this post-completion of the questionnaire was designed for the applicants to reflect both their experience of the initiative and that of the ECOWAS-MRH through a dialogue.For the purpose of clarity, the results of the study are presented in five parts: 1) Demographics; 2) Benefits of the ECOWAS-MRH initiative; 3) Challenges of the ECOWAS-MRH initiative; 4) Improving the performance (effectiveness and efficiency) of the work-sharing programme; and 5) Envisaging the strategy for moving forward.The respondents were mostly regulatory affairs managers, with varying years of regulatory experience ranging from 3 to 30. A summary of the manufacturers and their product categories is provided in Eight out of the 20 submissions have been issued with recommendation letters. The remaining submissions have either been deferred or are still in the screening phase for various reasons.Both the innovator and foreign generics are available in almost all the ECOWAS member states with the exception of Guinea Bissau; however, local generics are mostly available in Nigeria and Ghana . The assHalf of the number of manufacturers  keep a separate record of applications submitted for assessment under the ECOWAS-MRH initiative to facilitate tracking and adherence to deadlines.The benefits of the ECOWAS-MRH initiative that were identified by most of the applicants were the harmonisation of registration requirements across the region (80%), information sharing among regulators (50%) and capacity building (40%) for assessments. However, the benefits of leadership commitment/governance structure (30%) and shorter timelines for approval (30%) were identified by a few of the respondents .The strengths of the ECOWAS-MRH process for recommending the registration of products were identified as priority review of ECOWAS-MRH products, regular committee meetings enabling timely finalisation of products after ECOWAS-MRH recommendation, separate register and tracking of ECOWAS-MRH products and products approved under ECOWAS-MRH made available on each country’s website. Medicines and vaccines eligible for the ECOWAS-MRH joint assessment are those included in the WHO Essential Medicine list, HIV/AIDS, malaria, tuberculosis, reproductive health, neglected tropical diseases, antibiotics, for public health emergencies, registered by stringent regulatory authorities, prequalified by WHO, registered under Swissmedic procedure for scientific advice and Marketing Authorisation for Global Health Products (MAGHP), granted a scientific opinion in line with the European Medicines Agency’s Article 58 of Regulation (EC) No 726/2004, life-saving commodities by the UN Commission on life saving medicines for women and children and other priority medicinal products as determined by the WAHO.Upon completion of the ECOWAS-MRH joint assessment for such eligible medicines and vaccines, these are then granted marketing authorisation via the national registration system in the relevant country . PrioritThe benefits of the ECOWAS-MRH initiative identified by applicants (manufacturers) included: a reduced submission burden as applicants compile one dossier (modules 2–5) for submission to multiple countries; savings in time and resources as applicants receive same list of questions from multiple countries, enabling the compilation of a single response package; shorter timelines for approval compared with those for the individual countries and access to various markets at the same time. A better understanding of the individual country requirements was stated as an additional benefit of the ECOWAS-MRH initiative to applicants .Increased availability of medicines and quicker access to quality assured medicines were reported as benefits of the ECOWAS-MRH initiative to patients in the individual or in the ECOWAS region by the applicants.The lack of ability to mandate central registration; differences in the regulatory performance of the countries; dependence on the countries’ processes for communication with applicants; absence of centralised submission and tracking and lack of detailed information on the process for applicants were identified as challenges of the ECOWAS-MRH initiative.Other challenges were also cited namely, lack of identified NMRA processes for movement from regional to local approval in the ECOWAS countries, no clear process for approval and lack of NMRA responsiveness in communicating updates of application status .Additional challenges identified by manufacturers submitting applications to the ECOWAS-MRH initiative included: low motivation and appeal to use the ECOWAS-MRH route as there are few success stories available or publicised; lack of clarity about the process for submission and follow-up in each country; differing labelling requirements in participating countries and low motivation to use the ECOWAS-MRH route because other review routes such as reliance on approvals from stringent regulatory authority or other ECOWAS countries now being used by individual countries are faster; failure by countries to adhere to promised timelines; the risk of losing access to all member states once a product is rejected by ECOWAS-MRH ; a lack of information on country and ECOWAS-MRH websites about the process, milestones or timelines; the absence of lists of pending and approved products; the perception that the ECOWAS-MRH process is more stringent than some country processes; and differences in time to implementation of ECOWAS-MRH recommendations by partner states .• Lack of enough personnel• Absence of proper knowledge of review process• Unharmonised system of review• Lack of information on country and the ECOWAS-MRH websites about the process, milestones and timelines for pending and approved products• Each member country has different requirements for Module 1 and applicants having to fulfil all countries’ requirements• There is no clear process to follow once approval has been received from the ECOWAS- MRH procedure• Having to bring all the member countries regulators together in a timely manner to review the dossiers/applications• Delay in response time between applicants and reviewersComments by applicants to the challenges faced by the NMRAs in reviewing the ECOWAS-MRH applications were related to personnel and resources as well as the application and review process as below:Suggestions from applicants to improve the effectiveness of the ECOWAS-MRH initiative  were to The applicants suggested the following ways to improve the efficiency of the ECOWAS-MRH initiative: improved central tracking of ECOWAS-MRH products; specific and clear requirements made easily available to applicants; use of robust information technology (IT) systems; a centralised system for submission of applications and communication with applicants; compliance with target timelines by measuring and monitoring each milestone in the review process; and transparency in metrics and statistics such as percentage of reviews completed within timelines; and increased resources such as the number of assessors .Regarding possible strategies for moving forward, the applicants proposed that the establishment of a regional administrative body to centrally receive and track ECOWAS-MRH applications which would be responsible for allocating work, apportioning the applicable fees to countries, tracking of applications and communication with applicants was the most effective strategy to improve efficiency of the ECOWAS-MRH initiative. On the other hand, continuing with the current operation of the model without any changes was considered the least effective strategy to improve efficiency of the ECOWAS-MRH initiative. Seventy percent (70%) of the respondents agreed that the establishment of an ECOWAS regional medicines agency, if legally possible, will be the best strategy for improved performance going forward.• Implement a one-time payment process by ECOWAS, eliminating individual NMRA separate statutory registration fees• Harmonise labelling across all ECOWAS countries, eliminating individual country-specific labelling• Standardise and harmonise Module 1 dossier requirement across the ECOWAS countries to expedite the registration process• Require one Certificate of Pharmaceutical Product (CPP) for any of the member countries or for countries where commercialisation is being planned rather than separate CPPs for each country• Allow applicants to market their products across ECOWAS countries after ECOWAS-MRH approval to expedite the availability of medicines• Provide an online ECOWAS-MRH portal application system to expedite application submissions, tracking and evaluation• Ensure effective follow-up process and prompt communication to applicants• Confirm that a link to the application process is available on all country NMRA websites• Create a clear ECOWAS-MRH process pathway for applicants to follow• Include a drastic reduction in country good manufacturing process (GMP) fees for sites already evaluated through the process• Discourage the need for a new set of GMP fees for each NMRA, as this will have great impact on the ability to progress the application in each ECOWAS country• Concentrate the ECOWAS-MRH initiative solely on the quality and efficacy of the products, as decisions on products’ commercial presentation should be left to individual countries for effective cost management• Improve communication of the multiple benefits of the ECOWAS-MRH initiative as it is presently poorly communicated among participating companies• Strengthen the regulatory function and inspection• Respond quickly to submitted documents, especially dossiers from applicantsFinally, the respondents provided strategies that could be considered in strengthening the ECOWAS-MRH initiative going forward.This study obtained the views of the both generic and innovator pharmaceutical applicants about the performance of the programme to date, identified the challenges experienced throughout the life cycle of the ECOWAS-MRH initiative, determined the strengths and weaknesses of the initiative, identified the ways of improving the performance of the work-sharing programme and envisaged the strategy for moving forward. The applicants expressed their views on all aspects of the ECOWAS-MRH initiative and offered very valuable suggestions for its improvement.The important benefit of harmonisation of registration requirements across the region was identified by almost all the applicants at this time. It is noted that in a similar study of the ECOWAS-MRH initiative by the authors , the benThe medicines regulatory harmonisation initiative in West Africa (ECOWAS-MRH) aims to improve the registration timelines without compromising the quality of regulatory decisions submitted for marketing authorisation. The joint assessment procedure, which is patronised by the NMRAs in the West African region and pharmaceutical manufacturers in other parts of the world is a classic example of this harmonisation initiative .As noted by the applicants, the strength of the ECOWAS-MRH initiative to prioritise the review of ECOWAS-MRH products for subsequent registration in the member states can be maximised to help make such medicines and vaccines available for public health use in a timely manner. The clearly identified benefits to applicants derived from the ECOWAS-MRH initiative  resultinSome of the challenges of the ECOWAS-MRH initiative namely, lack of centralised submission and tracking which were identified by the applicants in the study were also identified by the NMRAs in the previous study . SimilarThe challenges faced by manufacturers submitting applications to the ECOWAS-MRH initiative such as low motivation to use the ECOWAS-MRH route and preference for other regulatory pathways in the ECOWAS member states is reflected in the low number of applicants who have accessed the ECOWAS-MRH initiative to date . Other cSuggestions to improve the effectiveness of the ECOWAS-MRH initiative provided by the applicants were previously offered by the NMRAs, such as making publicly available any information that might help applicants in managing their submissions such as document templates, lists of questions and answers, timelines and milestones, decision-making transparency aids such as publishing Public Assessment Reports, consistency in application of guidelines and decisions, engagement and interaction with stakeholders, minimising the need for country-specific documents and publishing of pending and approved products. Use of risk-based approaches for example, reliance pathways was also suggested as another way that could be explored to improve the effectiveness of the ECOWAS-MRH initiative. The WHO Prequalification Programme success stories should be examined and piloted in the ECOWAS region .The suggestions presented by the applicants to improve the efficiency of the ECOWAS-MRH initiative, were also previously provided by the NMRAs, such as implementing robust IT systems and building capacity of assessors to facilitate processing and monitoring milestones of applications should also be explored . SimilarThe views of the NMRAs from the previous study  have beeProvide incentives to applicants in ECOWAS through fast-track processing of applications and reducing GMP inspection fees to encourage more submissions from applicants to the ECOWAS-MRH initiative.• Engage with the WHO Prequalification Programme to create a facilitated regulatory pathway for medicines and vaccines that have been issued with recommendation letters following successful completion of the ECOWAS-MRH joint assessment procedure.• Provide eligibility for international procurement agencies to source medicines and vaccines with recommendation letters for public health use in situations where there are no prequalified alternatives• Encourage training for applicants to develop their skills, knowledge, and competence• Convene stakeholder meetings on a biannual basis to engage with manufacturers and update them on requirements to ensure compliance with regulations• The authors’ key recommendations for improving the ECOWAS-MRH initiative for both generic and innovator applicants are.This study identified the benefits and challenges of the ECOWAS-MRH initiative as experienced by the applicants as well as strategies available to improve its effectiveness and efficiency. If implemented by both generic and innovator applicants, the key recommendations that have been proposed should further strengthen this initiative to enable it to fulfil its mandate in the ECOWAS region.


The authors were not able to provide the raw data and the Editor-in-Chief and editorial board no longer have confidence in the reported results. The article is therefore retracted.Materials.This retraction was approved by the Editor-in-Chief of the journal The authors did not agree to this retraction.


Cultural intelligence can affect the cross-cultural adaptation of international students in China, but the mechanism of its influence is still unclear. This study examines the mediating effect of the psychological resilience of international students in China in the process of cultural intelligence affecting cross-cultural adaptation. We used the cultural intelligence scale, psychological resilience scale, and cross-cultural adaptation scale to measure 624 foreign students in China.(1) There is a significant positive correlation between the cultural intelligence, psychological resilience, and cross-cultural adaptation of international students in China. (2) Resilience plays a mediating effect in the influence of the cultural intelligence of international students in China on cross-cultural adaptation.The cultural intelligence of international students in China can directly affect their cross-cultural adaptation and can also affect their cross-cultural adaptation through the mediating effect of psychological resilience. As increasing numbers of foreign students choose to study and live in China, under the influence of foreign cultures, international students in China will suffer from maladjustment  to assess cultural intelligence. The CQS has 20 questions, including four dimensions: metacognition, cognition, motivation, and behavior  to explore the mechanism of cultural intelligence affecting cross-cultural adaptation, and the maximum likelihood method is used to estimate and test it. The results are as follows: χThe purpose of this study was to explore the influence mechanism of cultural intelligence on the cross-cultural adaptation of international students in China. The results of this study show that the overall level of cross-cultural adaptation of international students in China is low, and there is a positive correlation between cultural intelligence and cross-cultural adaptation among international students in China, which is consistent with the previous study (Lin et al., The study also found that cultural intelligence has an impact on cross-cultural adaptation through the mediating effect of psychological resilience. This is consistent with previous research results Kumpfer, . Some stIn terms of theory, this study reveals the mechanism of cultural intelligence on cross-cultural adaptation and the applicability of the psychological resilience model supported by empirical evidence in explaining the relationship between cultural intelligence and cross-cultural adaptation. The results of this study also have a certain application value. This study has found that cultural intelligence can improve the psychological resilience of international students in China and promote their cross-cultural adaptation.However, this study has the following limitations: first, the study has highlighted that the micro-intervention model based on cultural intelligence can effectively improve cultural intelligence (Reichard et al., The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Academic Committee of Guangxi Science and Technology Normal University. The participants provided their written informed consent to participate in this study.KC is responsible for questionnaire distribution and data processing and paper writing. FZ is responsible for revising project management papers. Both authors contributed to the article and approved the submitted version.


Beta-lactam allergies (BLA) pose a challenge to the optimization of antibiotic therapy as some of these are not true allergies, are minor reactions, or instead may be adverse effects. This issue is further complicated by the fact that traditional methods of challenging allergies can be costly or time-consuming. The purpose of this study was to evaluate the safety of a protocol which directly challenges patients with a BLA via full dose administration of the challenge antibiotic based on the risk of cross-reactivity.This retrospective, observational, case-control study compared the incidence of hypersensitivity reactions following the administration of a beta-lactam antibiotic in patients with a reported BLA to that of those without a reported BLA. It included adults in the community hospital setting who received a beta-lactam antibiotic for any indication during an inpatient admission between March 2018 and October 2022. The treatment groups were separated by the presence or absence of a documented BLA. The primary outcome was the occurrence of a hypersensitivity reaction following the administration of a beta-lactam antibiotic.A total of 910 out of 1000 patients were eligible for evaluation, and 116 of those patients had a history of a BLA documented on the chart whereas 794 did not. The primary outcome of an IgE-mediated hypersensitivity reaction occurred in 1 out of 116 in the BLA group and 4 out of 794 in the non-BLA group  (see table).ResultsNo significant increase in the incidence of IgE-mediated allergic reactions was noted in the patients with a history of a BLA, however, the study was not powered to detect a difference due to the rarity of IgE-mediated reactions. Despite a trend towards an increased risk of reactions in patients with a history of a BLA, the majority of the few reactions that occurred were non-severe in nature. The benefits of challenging a BLA outweigh the risks in this setting.All Authors: No reported disclosures


The use of cannabidiol (CBD) has received growing attention, and cannabis-based medicines are being explored as analgesics. In 2021, a task force, initiated by the International Association for the Study on Pain (IASP), published a series of narrative and systematic reviews and meta-analyses covering multiple aspects of pre-clinical and clinical pain research examining the efficacy and safety of cannabinoids as analgesics. It was concluded that the available evidence does not support the use of cannabinoids as analgesics on either safety or efficacy grounds.The Lancet Regional Health—Europe, Pramhas et al.,In the current issue of The primary result from the study by Pramhas et al.,,An important exploratory outcome from the study by Pramhas et al.,The strength of the study by Pramhas et al.,Chronic musculoskeletal pain is complex and multiple factors are generally associated with high levels of clinical pain, such as poor quality of sleep, inflammation, psychological factors and sensitization of the nervous system.Kristian K-S Petersen received the invitation to write this commentary and wrote the first draft of the manuscript. Lars Arendt-Nielsen and Andrew SC Rice have completed a series of systematic reviews, meta-analyses and recommendations within the area of cannabis-based medicine and provide critical feedback to the manuscript. All authors agreed to submit the final manuscript.Kristian K-S Petersen chairs the Special Interest Group for Musculoskeletal Pain under the International Association for the study of Pain (IASP). Lars Arendt-Nielsen was the president for the IASP and initiated the IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia and Andrew SC Rice chaired the Task Force.


Suicide represents one of the most discussed mental health issues in the world today and health challenges for the future. The burden of suicide is calculated in very high numbers (800 thousand people per year) by the WHO (2014), ranking it among the other most frequent causes of death. The key criteria to determine suicidal or non-suicidal behavior is the presence of intentional self-injurious behavior, in which the individual intentionally attempts to harm himself.Objectives: Aim of the study: was to make a presentation and evaluation of the demographic and clinical factors of suicidal self-injurious behavior in patients hospitalizedPatients’ data were obtained from the archived clinical files of the Psychiatric Emergency Department and other wards at “Xhavit Gjata” Tirana Psychiatric Hospital. The method used is a descriptive retrospective study of patients admitted during period of January-May 2019. About 75 archived clinical files were thoroughly studied and analyzed, on various demographic and clinical variables.Albanian women remain more at risk for suicide attempts, while male suicide mortality is higher, as in the world. Higher determination and the use of more lethal methods ranked among the factors contributing to the higher mortality of men. The 29-49 age group is the most affected in our study according to suicide attempts and self-harming behavior. The most pronounced accompanying diagnoses of suicide attempts are major depressive disorders, but not leaving behind psychotic disorders. The average length of stay in the hospital is 18.4 days.The deepening of knowledge on the etiology, on the factors influencing suicide and on the methods of treatment are only some of the issues facing public health today. Identification of self-injurious behaviors pave the way for treatment and assistance for anyone considering suicide.None Declared


Cost Effectiveness and Resource Allocation (2023) 21:2110.1186/s12962-023-00430-2Following publication of the original article, the authors flagged the respective given and family names of the authors had been erroneously swapped. The author list has been corrected in the published article and the corrected names can be seen in the author list of this erratum.The publisher thanks you for reading this erratum and apologizes for any inconvenience caused.


Many artificial intelligence (AI) algorithms have been developed for medical practice, but few have led to clinically used products. The recent hype of ChatGPT shows us that simple, user-friendly interfaces are one major factor in the applications’ popularity. The majority of AI-based applications in clinical practice are still far from simple-to-use applications with user-friendly interfaces. Therefore, simplifying operations is one key to AI-based medical applications’ success. Many AI algorithms have been developed for medicine, but only a few have led to clinically used products and tools , 2. The The first drive of Karl Benz in his Motorwagen on Ring Street of Mannheim (Germany) in 1886 counts as the first drive of an engine-powered car on public roads after years of innovation . In the When the Xerox Palo Alto Research Center designed an experimental personal computer to investigate how small and cost-effective a personal computer could be, no one would have thought of the mass use of computers and other computer-related applications decades later . FurtherChatGPT  is an AI chatbot introduced recently . Almost History and the present show us that simplicity of operation is one major key to the success of new technological applications. Improving the simplicity of operation would help accelerate the broad implementation of AI-based applications in clinical practice.


In recent years, there has been a growing interest in the development of eco-friendly solutions to control pests and promote soil health. One promising approach is the use of microbe-pesticide interactions to achieve smart-soil bioremediation  and Hansschlegelia zhihuaiae S113 to remediate soils contaminated with the herbicide bensulfuron-methyl. The researchers found that the combined use of AMF and H. zhihuaiae S113 was more effective in reducing bensulfuron-methyl residues in soil compared to the use of either organism alone. The study also showed that the combination treatment improved soil nutrient availability and microbial activity, which may have contributed to the enhanced biodegradation of bensulfuron-methyl. In another study, Kumar et al. suggested that the use of environment-restoring microbes isolated from the rhizosphere of horticultural crops under subtropics may provide a promising approach for the bioremediation of chlorpyrifos-contaminated soils. Sharma et al. identified the rhizospheric bacteria for the removal of the carbendazim in soil. They showed the inhibitory effect of carbendazim in isolated bacterial strain. They showed carbendazim  decreases the concentration of indole acetic acid, ACC deaminase and siderophore production in bacterial cells.Li et al. suggest that the L1 microbial consortium has the potential to be used for the bioremediation of chlorimuron-ethyl-contaminated soils. However, further research is needed to optimize the conditions for the degradation process and to assess the long-term effectiveness and safety of this approach. The findings of this study may also have implications for the development of microbial consortia for the bioremediation of other herbicides and pollutants. The identification and characterization of the novel dmdA gene and its product may also have implications for the development of new herbicide-resistant crops and the biotechnological production of valuable compounds from dicamba. Zong et al. reported on the novel pyrethroid degrading enzyme SGNH esterase Est882, which can degrade diverse pyrethroids significantly.Singh and Saxena discussed the recent findings on the pesticide-microbe interaction and showed the relationship among environmental factors at various trophic levels. He et al. discovered the cypermethrin-degrading binary consortium of the genus Rhodococcus and Comamonas. The developed consortium was effective for the elimination of pyrethroids from the environment. Wahla et al. reported that biochar-immobilized bacteria enhanced metribuzin degradation in the environment. Similarly, Pan et al. observed that immobilized bacteria can accelerate atrazine degradation in soil. Zhao et al. suggested development of the solid agents can facilitate the soil microbial degradation of pesticides.Baazeem et al. reported Bacillus subtilis and other bacterial strains identified in their study can be used as an alternative to chemical pesticides for the control of Aphis punicae and Aphis illinoisensis. However, further research is needed to evaluate the efficacy of these bacterial strains under field conditions and to assess their long-term impact on the environment. Siddique et al. highlight the importance of insect gut microbiota in the degradation of pesticides. The gut microbiota of insects can play a critical role in detoxifying pesticides and reducing the accumulation of pesticide residues in the environment. The gut microbiota can also modify the physicochemical properties of pesticides, making them more susceptible to degradation. The composition of gut microbiota in insects can be influenced by several factors, including diet, host genetics, and environmental conditions. Therefore, the gut microbiota of insects can adapt to the presence of pesticides, leading to the development of pesticide-resistant gut microbiota. Astaykina et al. reported the impact of three pesticides on the gut microbiota of a earthworm Lumbricus terrestris. Pathak et al. discussed the negative impacts of pesticides on the environment, and living systems. They suggested the adoption of more sustainable and eco-friendly management strategies using microbial technology.Jaffer et al. described the the gut microbiota in insect physiology and the biodegradation of pesticides, and suggests that this knowledge could be leveraged for the development of more sustainable and eco-friendly approaches to pest management.The articles published on this Research Topic advanced our understanding of pesticide-microbe interactions in soil and other environments. The Research Topic focuses on the degradation of pesticides using various bacterial and fungal strains. In addition, the Research Topic gives insights into the impact of pesticides on the gut microbiota. Further work is needed to meet the major challenges in the field of microbe-pesticide interaction. Advances in 'omics technologies will promote discoveries of novel methods and future applications capable of cleaning large-scale polluted sites in an eco-friendly manner.The editorial draft was written by PB, SC, and CM. All authors contributed to the revision and improvements and approved the final version for submission. All the editors collaborated well for the successful completion of the Research Topic.


Mental disorders are increasingly recognized as leading contributors to the global disease burden, and of the years lived with disability . TF-CBT is the first line of treatment for patients with PTSD and uses stabilization techniques before the confrontation. The authors reported that in patients without concurrent somatoform disorders, integrating pranayama into TF-CBT might reduce their post-traumatic symptoms and increase their mental quality of life more efficiently than TF-CBT alone. However, the authors also emphasized the preliminary nature of the findings and the need to replicate the results by intention-to-treat analyses. These findings are relevant given the reported flare-up of post-traumatic stress symptoms (96.2%) as mental health consequences of COVID-19 . The article by Shidhaye et al., addressed maternal mental health outcomes  in pregnant women from rural settings of India, representing a marginalized sector of the population with enhanced vulnerability during the pandemic (Busch-Hallen et al., Another clinical trial of this Research Topic by Inbaraj et al., the authors presented the design and method of a randomized clinical trial, wherein they aimed to study the Impact of integrated yoga therapy on cognitive impairment and cardiac dysfunction regarding the quality of life in breast cancer patients undergoing chemotherapy. These subtle adverse effects, particularly changes in memory or cognition, remain unattended in many women, affecting their memory, and the ability to think clearly during and after chemotherapy (Vitali et al., In the study protocol by This research compendium also included an interesting state-of-the-art narrative review article on the coexisting condition of irritable bowel syndrome and fibromyalgia. These two health conditions share common pathophysiological mechanisms; sensitization of peripheral and central pain pathways and autonomic dysfunction. The conjuncture of these two conditions led to increased symptom severity, mental health comorbidities, and decreased quality of life. On an individual basis, mind-body interventions have been reported to benefit both the conditions and influence central pain syndromes and autonomic dysregulation. The authors evaluated the current evidence on the role of mind-body therapies in the coexisting state. They reported the limited availability of data in co-diagnosed patients. They also warranted the need for high-quality trials to tailor the programs individually.Given the wide diversity in psychological morbidities and scarcity of data, it becomes imperative to conduct studies to address the gaps in the area, ranging from epidemiology to intervention research.VM: manuscript writing. NM: review of manuscript. All authors contributed to the article and approved the submitted version.


Background Free tissue transfer is considered the gold standard option for the reconstruction of distal leg defects. Free tissue transfer using recipient vessels in the contralateral leg (cross-leg bridge) is a potential option to supply the flap if there are no suitable recipient vessels in the injured leg. Most studies have described this technique using end-to-end anastomosis which sacrifices the main vessel in the uninjured leg. This study evaluated the use of a cross-leg free latissimus dorsi muscle flap for the reconstruction of defects in single-vessel legs, using end-to-side anastomosis to recipient vessels in the contralateral leg without sacrificing any vessel in the uninjured leg.Methods This is a retrospective study that included 22 consecutive patients with soft tissue defects over the lower leg. All the reconstructed legs had a single artery as documented by CT angiography. All patients underwent cross-leg free latissimus dorsi muscle flap using end-to-side anastomosis to the posterior tibial vessels of the contralateral leg.Results The age at surgery ranged from 12 to 31 years and the mean defect size was 86 cm2. Complete flap survival occurred in 20 cases (91%). One patient had total flap ischemia. Another patient had distal flap ischemia.Conclusion Cross-leg free latissimus dorsi muscle flap is a reliable and safe technique for the reconstruction and salvage of mutilating leg injuries, especially in cases of leg injuries with a single artery. As far as preservation of the donor limb circulation is concerned, end-to-side anastomosis is a reasonable option as it maintains the continuity of the donor leg vessels. Reconstruction of defects in the middle and lower thirds of the leg is challenging and requires innovative solutions. Microsurgical reconstruction with free tissue transfer has been considered the gold standard option for treating such defects, and this necessitates the presence of adequate recipient leg vessels.If there are no reliable recipient blood vessels, the use of the contralateral leg vasculature is a potential option to supply the transferred tissues. Using cross-leg bridge free tissue transfer was first described by Taylor et al in 1979, and the principal concept of this technique is to anastomose the flap to intact vessels in the contralateral noninjured leg. This temporary vascular anastomosis supports the flap until it forms sufficient vascular connections with its edges and bed in the injured leg, then separation is performed.A number of studies have reported successful reconstruction of leg defects with cross-leg free tissue transfer, utilizing muscle/musculocutaneous flaps such as latissimus dorsi, rectus abdominis, gracilis, and vastus lateralis musclesY- orT-shape fashion and suturing it to the recipient vessel in a flow-through anastomosis fashion.Most of these previous studies used end-to-end anastomoses to the recipient vessel in the contralateral uninjured leg. The major drawback of end-to-end anastomoses is scarifying one of the main blood vessels of the uninjured limb. Therefore, several new reconstructive techniques have been introduced in order to maintain and preserve the integrity of the recipient arterial system of the uninjured leg. These techniques include redirecting the artery of the flap to the distal end of the recipient vessel after pedicle divisionAlthough there are many studies which demonstrated the use of free tissue transfer with end-to-side anastomoses to recipient vessels in the same injured leg with the aim of preserving distal perfusion in patients with impaired vasculature,The purpose of this study is to present the outcomes of the use of cross-leg free latissimus dorsi muscle flap for reconstruction of defects in single-vessel legs, using end-to-side microvascular anastomosis to recipient vessels in the contralateral leg without sacrificing any of its vessels.We retrospectively reviewed 22 consecutive patients with traumatic soft tissue defects, in legs with a single artery as documented by CT angiography, who underwent cross-leg free latissimus dorsi muscle flap with end-to-side microvascular anastomosis to the posterior tibial artery of the contralateral leg. After the ethical approval of the study protocol, patients' data were collected from the patients' registry. The patients' demographic and clinical data included sex, age, type of injury, location of the injury, defect size, vascular status of injured legs, associated comorbidities, and time of flap separation, postoperative complications, and revision procedures.Under general anesthesia, sharp debridement is performed removing all necrotic or scarred tissues until reaching a healthy bleeding tissue bed. In the contralateral noninjured leg, the posterior tibial artery and one of its venae comitantes are dissected and prepared as recipient vessels. An inferiorly based skin flap, approximately 4 cm in width and length, is elevated to form the base of the bridge and protect the vascular anastomosis.With the patient in the lateral position, latissimus dorsi muscle flap is harvested with the dominant thoracodorsal pedicle. A small skin island is included with the muscle to facilitate flap monitoring. The muscle is then sutured to the healthy edges of the defect in the injured leg allowing maximal interface between the flap and the recipient site. The inferiorly based skin flap previously raised on the uninjured limb is turned and sutured to the opposing edge of the muscle flap to form the bridge .The two legs are fixed together using an external fixator. End-to-side microvascular anastomosis is then performed between the thoracodorsal vessels and the posterior tibial artery and one of its venae comitantes on the contralateral uninjured leg. Patients are maintained on low-molecular weight heparin from the time of surgery till the patient is completely mobilized to protect against deep venous thrombosis. All patients stayed hospitalized until flap separation for monitoring of the flap and adequate wound care. The muscle is covered by a split-thickness skin graft either before the time of flap separation or during the flap separation procedure.After 3 weeks postoperatively, the free flap pedicle was occluded with noncrushing clamps at the bedside and the flap vascularity status was assessed clinically using a needle prick test. If there is bright red blood bleeding in the distal part of the flap and no signs of insufficient flap circulation noted, we then conduct the second stage of flap separation and divide it from the recipient extremity. If flap circulation seems insufficient, we wait further 4 or 5 days and repeat that. After the removal of the external fixator and separation of the two legs, physiotherapy is started immediately to prevent joint stiffness.2(mean 86 cm2). Follow-up ranged from 12 to 18 months, with an average of 15 months. The patients' demographic, clinical data, and vascular status of each patient are summarized inThe mean age at surgery was 21 years with a range from 12 to 31 years. Of the 22 patients, 19 were males and 3 were females. All defects were located in the leg. The defect was on the right leg in 14 patients and the left leg in 8 patients. The defect size ranged from 35 to 280 cmAll injured extremities were reconstructed with latissimus dorsi cross-leg free flaps as described in the surgical technique section. End-to-side anastomosis was performed to the contralateral posterior tibial artery in all cases to maintain distal blood flow. The second stage procedures were performed between 3 and 6 weeks.Complete flap survival was reported in 20 cases (91%). One patient had total flap ischemia which was managed by debridement and negative pressure wound therapy for 3 weeks until the wound was clean with healthy granulation tissue, then a split-thickness skin graft was applied. Another patient had distal marginal flap ischemia that was managed by debridement, antibiotics, and wound care until healing by secondary intention occurred. Infection in the recipient site occurred in three patients and was treated conservatively by antibiotics and repeated wound dressings. Mild seroma in the flap donor site occurred in two patients and was managed by syringe aspiration for one time with no recurrence. All wounds in the contralateral leg healed uneventfully without complications apart from the anticipated scarring. Five patients needed regrafting of residual small exposed parts of the muscle flap due to partial skin graft loss . AlthouTransposition of local tissue flaps (fasciocutaneous or muscle), if available, is the first choice to reconstruct defects of the leg. When there are no available local tissues for transposition, distant flaps and free flaps play a major role in these occasions.Pedicled cross-leg flaps have been widely used for the reconstruction of leg and foot defects since 1854.The continuous improvement of the outcomes of microsurgical interventions has made free flap reconstruction a routine option in lower extremity reconstructive surgery.Haddock et al described using the perforator-to-perforator anastomoses as another solution to avoid scarifying of the ipsilateral limb recipient vessel.Therefore, it is necessary to use alternative options when there are no adjacent vessels available near the soft tissue limb defect and to perform the microvascular anastomosis outside the zone of injury. These include the use of vein graftsThe use of cross-leg bridge free flaps is a relatively old surgical technique, firstly described by Taylor et al in 1979 to solve the problem of lack of vessels in the recipient leg using cross-leg free DCIA flap to reconstruct bony and soft tissue defect in the leg.Cross-leg free flaps allow the transfer of the needed tissues including skin and muscle with or without bone using microvascular anastomoses performed away from the zone of injury to reconstruct challenging tissue defects with healthy vascularized tissue.Yamada et al applied the same technique in six patients using free rectus abdominis muscle flap anastomosed to vessels of the contralateral noninjured leg with a good outcome.Latissimus dorsi flap has many advantages as a cross-leg free flap in the reconstruction of complex leg defects as it can provide a sizable flap with a long pedicle and good vessel caliber.The use of the posterior tibial vessels as cross-leg bridge recipient vessels has often been described in the literature as an end-to-end anastomosis as this allows easy positioning and safe anastomosis.This problem has led to design several innovative techniques to maintain the integrity of the recipient arterial system. Akyurek et al described a new technique to restore the continuity of the recipient artery in cross-leg free latissimus dorsi flap procedure after end-to-end anastomoses. They reestablished the continuity of the posterior tibial artery at the time of flap separation by dissecting the thoracodorsal artery till its bifurcation in the muscle flap, transecting it, and reanastomosed to the distal ligated end of the posterior tibial artery.Yu et al suggested an alternative option to preserve integrity of the recipient vessel which is an end-to-side anastomoses to the contralateral limb in order to maintain continuity of the distal blood flow, although they performed the microvascular anastomoses of their cross-leg bridge free flaps series in an end-to-end fashion.In the present study, we performed an end-to-side anastomosis of the thoracodorsal vascular pedicle of the free latissimus dorsi flap to the contralateral recipient posterior tibial artery while preserving the single vessel of the injured leg untouched and at the same time preserving the recipient vessels of the uninjured limb undisturbed after separation of the flap. This is the first case series which reported cross-leg free flap reconstruction using an end-to-side anastomosis to the posterior tibial vessels of the contralateral leg. We found that the use of this technique in 22 consecutive cases has resulted in an overall success rate of 91% which is comparable to the results of other previous studies describing cross-leg free flap using end-to-end or flow-through anastomosis. Furthermore, we believe that the end-to-side anastomosis technique, described in this study, have distinct advantages. The most obvious advantage is the prevention of reduction of the blood flow to the recipient extremity and protecting the continuity of the posterior tibial vessels of the noninjured leg while maintaining efficient free flap perfusion. This technique has also obviated the need to use long vein grafts or to prepare bifurcated thoracodorsal arterial pedicle that cannot be easily available for flow-through anastomosis. In addition, it seems that end-to-end anastomosis to a major artery causes problems such as temporary congestion or severe swelling of the free flaps which are induced by excessive inflow. These may be other advantages of using end-to-side anastomosis.These findings suggest that cross-leg free flap using end-to-side anastomosis is an efficient and safe alternative for reconstruction of mutilating leg injuries with compromised vasculature, without sacrificing any vessel in the donor leg.The limitation of this study is its retrospective design and being a case series without prospective data or a comparison control group using end-to-end or flow-through anastomosis which preserves the integrity of the contralateral recipient vessel. However, this series demonstrates that the end-to-side anastomosis to the contralateral recipient vessel is a viable option in cross-leg free flaps reconstruction supported by the high rate of flap survival and low complication rate.In conclusion, cross-leg free latissimus dorsi muscle flap is a reliable and safe technique for the reconstruction and salvage of complex leg defects in mutilating leg injuries. It can provide a good reconstructive solution, especially in cases of leg injuries with a single artery, without increasing the risk of complications. As far as preservation of the donor limb circulation is concerned, cross-leg end-to-side anastomoses are a reasonable alternative as it maintains the continuity of the donor leg vessels for any possible future need.


In an era of electronical medical records, rapidly expanding publication rates of medical knowledge, and large-scale registries, orthopaedics is in a dire need of innovative approaches to facilitate the adoption of the latest knowledge in clinical practice. While machine learning (ML) has been heralded as one solution to many research tasks hampered by previous technological limitations , there iText classification – Categorisation and clustering of scientific articles based on level of evidence and/or sub-topics, detected using abstract screening for relevant terms.Information extraction – Identification of information related to patients, interventions, comparisons, and outcome variables (PICO elements) [lements)  from eleQuestion answering – Automated responses to frequently asked questions with a custom medical knowledge base used to generate conversational layers.Sentiment analysis – Assessment of the emotions and opinions of patients about a medical service based on analysis of the affective qualities of written reviews [ reviews .Summarization – Abstraction of a large volume of medical evidence to generate a short summary with essential and easy to understand information for patients.Natural language processing is a ML-based tool that involves quantitative encoding of information derived from human language. Data generated from speech- and text-processing NLP algorithms can be used to solve a variety of tasks with broad applications in medical practice and research. Due to limited examples of NLP-based research in orthopaedics , 15, comF1 score  are key metrics used in the evaluation and interpretation of NLP models.Understanding of the inner workings and performance of ML models are key steps in identifying applications for NLP in orthopaedic research . AccuracWhile there is no shortage of available data for orthopaedic research, a major barrier to the accessibility of data is due to its storage as unstructured text. A previously published editorial outlined the discrepancy between the publication rate of primary research articles and the synthesis of up-to-date evidence in the form of systematic reviews and meta-analyses . ConsequThe use of standardized knowledge bases is essential for the design and implementation of NLP algorithms designed for specific research purposes. We believe the next step towards solving the challenges associated with information extraction is to establish comprehensive knowledge-base of annotated disease- or injury-specific medical text. This idea rests on the principle that an NLP model is more likely to perform well when trained on a body of domain-specific information, with expert-level annotation and abstraction of the key element in the text, even if it has been pre-trained for general language understanding. A recent study of biomedical image analysis determined that improvements in labelling instructions have an immense impact on the interrater variability in the quality and consistency of annotations, and consequently, on the performance of the final algorithm . SimilarOver the recent year, large language models (LLMs), such as GPT-4 , Med-PaLWe believe the adoption of NLP frameworks to be one of the key steps in the evolution of medical data extraction and evidence-synthesis. There is currently a need for innovative solutions to obtain meaningful information from the growing availability of structured and unstructured medical text, with the goal to improve the quality of patient care. Considering the immense potential in the clinical and research setting, there is a growing need for the dedicated training of healthcare professionals in the fundamental concepts and applications of AI. The annotation of condition-specific training data and design of efficient NLP pipelines are complex tasks, which require close collaboration between the healthcare and technology sectors to establish high-quality and scalable systems despite existing disparities across the global healthcare sector. Rather than solely being the end-users of AI systems, healthcare professionals should take a more active role in the development of frameworks for specific aspects of orthopaedic research and clinical care. Finally, expert consensus is required to integrated labelled and unlabelled orthopaedic datasets to train LLMs and GAI models to perform domain-specific tasks, such as clinical concept extraction, medical relation extraction, and medical question answering, with high efficiency, accuracy and reliability.


Digital technologies and advances in computational methods have become key drivers of innovation in many medical fields. In precision psychiatry, accurate and reliable measures of mental health are critical for informing patient care and clinical research. There has been growing concern over the limitations of traditional mental health assessments that are typically grounded in nosology defined by the DSM and are based on interviewer-led assessments or patient self-report questionnaires. Whereas such gold-standard clinical assessments can be cost-prohibitive, insensitive to change, and prone to subjective biases, the use of digital technologies provides an opportunity to improve the practical feasibility as well as the inter-rater and test-retest reliability of repeated mental health assessments. The key promise of this approach is to unlock the clinical potential of digital technologies in ways that foster research of high clinical relevance and impact on clinical care. I will discuss these promises and challenges for the future use of machine learning approaches for predicting and monitoring post-traumatic stress and resilience.None Declared


The transannular patch repair of tetralogy of Fallot never seems to go out of style, despite the availability of other valve function-preserving techniques. I read with great interest the current article from the highly credible and experienced team at Fuwai Hospital  . As ackn


Silicosis still represents a major occupational Research Topic worldwide. The enforcement of strict safety standards and worker protection measures have lowered the level of occupational exposure and decreased the incidence of related lung diseases, in some countries. However, this success is mainly limited to high-income countries and new occupational and/or environmental hazard may arise from new materials or emerging pollutants (EP), as well-illustrated by the cases of accelerated silicosis from artificial stone (AS) dusts or the risk posed by natural occurrences of asbestos and asbestos-like minerals (NOA) , mainly in the form of ls (NOA) . In factls (NOA) . Diseasels (NOA) . Fibrousls (NOA) . The patls (NOA) ; ii) thels (NOA) . The comTo design an integrated occupational and environmental strategy for hazard assessment and control, the toxicity paradigms for airborne toxic particles have to be extended to the whole realm of inorganic dusts also in non-conventional exposure scenarios. To tackle this challenge, we must advance our knowledge on the complex interplay established by inorganic particles and biological environments. In parallel, new exposure scenarios of well-known or still poorly-described inorganic dusts, e.g., quartz , asbestoTo cover promising, recent, and novel research trends in all the above mentioned aspects of toxic or potentially toxic inorganic particles and fibres, we challenged the scientific community to advance the development of mineral particle eco-exposome, which represents the Frontier for assessing the effects of multiple exposures to chemicals. This challenging task translates, for inorganic particles and fibres, in the design of integrated investigation strategies that will bridge minero-chemical properties to hazard assessment.The contributions collected spanned from the definition of the geological occurrence of a well-known carcinogenic fibre to the description of the molecular interactions taking place at the bio-inorganic interface of silica and silicates.Patel et al. reviewed almost 200 references to define the new state-of-the-art in the geolocalization of the occurrence of erionite worldwide. Erionite is a fibrous zeolite which has been recognized as the causal agent to lung cancer and malignant mesothelioma. The extensive analysis of the literature provides more than 100 global locations where erionite has been reported. In addition to reporting the geological setting of host rocks and the paragenetic sequence of erionite formation, the paper includes a description of the fiber morphological and mineralogical properties and an overview of the techniques to identify and characterize the mineral. With an analytical perspective, the work by Avataneo et al. dealt with the emerging concern of the presence of asbestos fibres in water. To compensate for the limited attention that has been dedicated to waterborne asbestos, this experimental work mimicked a Scanning Electron Microscopy analysis of waterborne chrysotile from stream water and tested the reliability of the method with a multi-instrument, multi-operator double check of samples. Good practices to perform reliable analyses on surface water samples containing asbestos were proposed. To investigate the overlooked presence of emerging contaminants such as naturally occurring fibre-like particles (FLP), Talbot et al. performed a re-examination of several particulate matter filters from three sites across Auckland (NZ) that were collected during a 20-year long air monitoring campaign. The analysis confirmed the occasional presence of erionite in the re-analysed filters. A micro-dispenser method to prepare depositions of asbestos fibres for toxicological tests in vitro is reported by Della Ventura et al. This novel approach deposit micro-sized droplets from a suspension of fibres and allows control of some key parameters including the deposition area, the deposition time, and the uniformity and volume of the deposited liquid. Advances on the description of the molecular interactions taking place between inorganic particles and model membranes are reported in the collective Research Topic. Moving from the interaction paradigm proved to occur between cellular membranes and a specific population of weakly interacting silanols exposed at quartz surfaces, the nearly free silanols , Pavan et al. expanded their interaction model to the other crystalline silica polymorphs and paved the way to a comprehensive understanding of the structure-activity relationship between nearly free silanols and membranolytic activity of crystalline silica. With a complementary approach focussed on membrane chemistry, Sydor et al. showed that an increase in the cholesterol content of membranes can attenuate the silica-induced membrane alterations, ultimately suggesting that the selective manipulation of lysosomal cholesterol may be a way of mitigating silica-induced lysosomal disruption and preventing chronic inflammatory disease progression.The work by Overall, this Research Topic has put together some novel and relevant research that can pave the way for a more integrated comprehension of how inorganic chemistry, analytical approaches and toxicological investigations can be integrated to develop an eco-exposome approach to particle and fibre hazard assessment.


We aimed to investigate partnership-working across sectors through the example of the Wales Physical Activity Partnership (WPAP). Three national organisations specialising in sport, environment and public health formed a strategic alliance under the Welsh Government’s direction to support the long-term innovative legislation of the Wellbeing of Future Generations  Act 2015 (WBFGA).We completed in-depth semi-structured interviews with WPAP members  involved in the leadership, management and work-stream levels of the partnership. The leadership group members were interviewed twice, with 12 months between interviews, to follow-up progress of the partnership and changes in strategic direction. The interviews were transcribed and analysed in NVivo using Braun & Clarke’s (2014) thematic analysis.The participants had experiences of operating in leadership, management and working group roles within the partnership, each representing their organisation. The major themes were related to the partners sudden change in short-term priorities and the efforts to maintain momentum in line with the long-term direction of their alliance. The Covid-19 pandemic was felt to accentuate underlying issues, by limiting capacity and halting momentum in the developing the partners’ shared agenda. The leadership group remained confident of the added value to their organisations by connecting sport, environment and public health and recognised the shared responsibility of their organisation in supporting the Welsh Government to increase physical activity across Wales. The working group members felt that the governance structure and division of work-streams diluted the potential of the three partners, and often felt “compartmentalised” and there was limited communication between work-streams.The impact from the Covid-19 pandemic was a barrier to building and maintaining momentum in this partnership between sport environment and public health. Wales is the first country to impose that public organisations bear a legislative duty to evidence their contribution towards the long-term strategy to improve physical activity, health and wellbeing via the WBFGA. Innovative legislation has provided a foundation for organisations in diverse sectors to shift their agendas to evidence long-term contributions but short-term pressures, such as the Covid-19 pandemic, may dilute the commitment and strategic intent.


Hfq is required by many Gram-negative bacteria to chaperone the interaction between small non-coding RNA (sRNA) and mRNA to facilitate annealing. Conversely and despite the presence of Hfq in many Gram-positive bacteria, sRNAs in Gram-positive bacteria bind the mRNA target independent of Hfq. Details provided by the Hfq structures from both Gram-negative and Gram-positive bacteria have demonstrated that despite a conserved global structure of the protein, variations of residues on the binding surfaces of Hfq results in the recognition of different RNA sequences as well as the ability of Hfq to facilitate the annealing of the sRNA to the mRNA target. Additionally, a subset of Gram-negative bacteria has an extended C-terminal Domain (CTD) that has been shown to affect the stability of the Hfq hexamer and increase the rate of release of the annealed sRNA-mRNA product. Here we review the structures of Hfq and biochemical data that have defined the interactions of the Gram-negative and Gram-positive homologues to highlight the similarities and differences in the interactions with RNA. These interactions provided a deeper understanding of the how Hfq functions to facilitate the annealing of sRNA-mRNA, the selectivity of the interactions with RNA, and the role of the CTD of Hfq in the interactions with sRNA. Small non-coding RNAs (sRNA) have been shown to regulate a variety of different responses in bacteria by acting as a posttranscriptional regulator of translation and are often associated with adaptive stress response, including antibiotic resistance . The mosEscherichia coli (Ec) as an essential Host factor for the replication of bacteriophage Qβ RNA (Takada99).Hfq was first identified in e Qβ RNA , and is e Qβ RNA . Hfq is e Qβ RNA . One funcis-encoded and trans-encoded sRNAs  and Bacillus subtilis (Bs) residue F42, Staphylococcus aureus (St) Y42). Hfq residues make a base specific contact through a conserved Q8 that recognizes an O2 of uridine or O6 of adenine, a conserved K56 residue and an amine group at position 41 . A conserved H57 (Ec and Sa numbering) interaction with O2’ of the ribose likely ensures a preference for RNA over DNA binding. The proximal side binding site appears to be a general binding site of all Hfq homologues and binds to single strand A/U rich RNA sequences and may participate in the rearrangement of secondary structures of the RNA  to an (A-L) recognition not only alters the specificity of the sequence bound on the distal side, but also reduces the maximum number of bases bound from 18 nucleotides by Gram-negative Hfq to 12 by the Gram-positive Hfq.Similar to Gram-negative bacteria, Gram-positive bacteria have six binding sites, with each binding site located at the interface of two subunits of Hfq. However, an inserted amino acid in the loop between β-strands 3 and 4 and a small number of seemingly conservative variations, particularly I30 to an aromatic , in Gram-positive Hfq results in a slight shifting of the first A-site and a loss of the second A-site . These cThe difference in the electrostatic surface potential of the lateral rim of Hfq between Gram-negative and Gram-positive homologues plays a significant role in the difference in the annealing function of Hfq homologues . The surE. coli numbering) is also highly conserved but has been shown to pack against the lateral edge of the core (The CTD of Hfq varies greatly not just between the Gram-positive bacteria where it is largely absent or severely truncated, but also within different species of Gram-negative bacteria in which the length of the CTD varies greatly . While tthe core . The midthe core .Two models of the Hfq facilitated sRNA-mRNA annealing in Gram-negative bacteria have been proposed based on the differences observed in the sRNA that is involved in the interactions with Hfq. Two different classes of sRNA, Class I and Class II, have been identified based on these differences in the interaction with Hfq and the recognition sequence of the sRNA . Both clClass II sRNA binds with the same binding motif to the proximal side of Hfq as Class I but the second binding site of the sRNA is on the distal side of Hfq with an AAN motif, as opposed to the rim. The mRNA targets of Class II sRNAs are unable to bind to the distal side of Hfq even if they contain an AAN motif and must therefore bind to the rim of Hfq at the UU binding site. The formation of the sRNA-Hfq-mRNA complex again results in the annealing of the sRNA with the mRNA sequence. However, in the case of Class II sRNA, the mRNA is degraded, but the sRNA often remains bound to Hfq for multiple rounds of mRNA binding . As a coAn additional consequence of the difference in the interaction between Class I and Class II sRNAs is the role of the CTD of the Hfq in the regulation of the process. Early work into the role function of the CTD appeared conflicting, with some work indicating that the CTD played no role in the Hfq interaction with sRNA, while other work indicates that the CTD is required for the proper binding and annealing of sRNA to the mRNA target . While dThe facilitation of annealing of Hfq for Class I and Class II sRNA in Ec is initiated by the sRNA and mRNA binding to Hfq. Both RNAs potentially undergo a rearrangement of stem regions exposing the seed sequence at the lateral rim region of Hfq. The exposure of the single strand seed sequence of the sRNA and mRNA following the rearrangement of the stem regions allows the annealing of the sRNA-mRNA at the rim of Hfq . Class IThe CTD also plays an important role in discriminating between Class I and Class II binding of Hfq. In the presence of the CTD, Class II sRNAs bind preferentially to Hfq over Class I. However, the removal of the CTD removes the preference for Class II sRNA . It has Recent studies examining the stability of the Hfq using mass spectroscopy combined with the observations described above has led to a more comprehensive model of the chaperone activity of Hfq . The CTDcis-encoded that are perfectly or highly complementary to the mRNA target. Gram-negative bacteria contain more trans-encoded sRNAs that have limited complementarity to the mRNA target (trans-encoded sRNAs (cis and trans-encoded sRNAs to support this hypothesis.There are multiple differences in the binding surfaces of Hfq between Gram-positive bacteria compared to Gram-negative bacteria. The difference in the requirement of Hfq between the two classes of bacteria likely results in the origins of the sRNA in the different bacteria. The sRNA identified in Gram-positive bacteria are predominantly A target . Therefoed sRNAs . The co-DA: Writing – review & editing. DW: Writing – original draft.


Coronary revascularization is one of the most studied treatment modalities in cardiology; however, there is no consensus among experts about its indications in patients with stable coronary artery disease (SCAD). Contemporary data regarding the role of revascularization in SCAD are in clear conflict with the current European guidelines. This article discusses the main statements of the most significant American and European Guidelines on myocardial revascularization of the last decade and also analyzes the appropriateness of revascularization to improve the prognosis and symptoms in SCAD in the light of new research data, primarily the ISCHEMIA study (NCT01471522) and the ACC/AHA 2021 Revascularization Guidelines based on them. Data on the revascularization in SCAD obtained after the completion of ISCHEMIA  and their potential significance are discussed. The results of ISCHEMIA sub-analyses in the most important “controversial” subgroups  are reviewed, as are the results of the ISCHEMIA-CKD substudy in patients with severe chronic kidney disease (CKD). A record number of studies have been conducted on myocardial revascularization in SCAD , but desIn this article, we analyze the appropriateness of myocardial revascularization to improve prognosis and symptoms in SCAD and compare the statements of the current Guidelines with the new research data.The most significant recommendations on which clinical decision-making in practice has been based in the last decade were the European Guidelines on Myocardial Revascularization , the ESCThe indications for revascularization available in the listed sources are summarized below  and textEuropean revascularization Guidelines  are veryHowever, the ESC Guidelines on CCS  state inAlthough these guidelines have been the basis of clinical decision-making for a long time, they are controversial. Also, statements on the prognostic benefit of coronary artery bypass grafting (CABG) in individuals with high-risk coronary lesions and reduced EF are based on observational data from the 1980s and 1990s, conducted before the era of modern optimal medical therapy (OMT) . Neverthn = 5179) comparing an invasive and conservative strategy in patients with SCAD receiving contemporary medical therapy and PCI/CABG performed by contemporary approaches ) . RevascuAn additional follow-up of ISCHEMIA participants (ISCHEMIA-EXTEND) up to 7 years confirmed the conclusion of the main study that there was no benefit of the invasive strategy in terms of overall mortality. This resulted from the opposite effects of a statistically significant decrease in cardiovascular mortality found in the invasive group (probably as a result of a decrease in the frequency of spontaneous AMI observed in the early period of follow-up) and a parallel unexpected increase in non-cardiac, apparently oncological, mortality. The significance of these data has yet to be assessed.Based on the results of ISCHEMIA, the American Cardiology Societies issued the new Clinical Guidelines , where oAt the same time, revascularization by CABG in patients with 3-vessel disease and preserved EF received a Class IIb recommendation. In this regard, the European Association for Cardio-Thoracic Surgery, the American Association for Thoracic Surgery, and the Society of Thoracic Surgeons issued statements disagreeing with this conclusion. As an argument, they indicate that this conclusion in the Guidelines is based on a subgroup analysis of the RCT, which itself is not randomized. Moreover, a separate analysis of the predictive value of revascularization depending on its type was not published at the time of publication of the Guidelines ,36. It cThe ISCHEMIA study generally demonstrated no prognostic benefit of a primary invasive strategy for individuals with SCAD and a moderate-to-high-risk stress test receiving current OMT on the cumulative cardiovascular endpoint. No advantage of revascularization regarding all-cause mortality was confirmed in the ISCHEMIA-EXTEND 7-year interim analysis. Also, revascularization was of no benefit in SCAD patients with advanced CKD. It can be concluded that a conservative strategy may be the primary choice for the majority of patients with SCAD who meet the ISCHEMIA eligibility criteria and do not have limiting symptoms. For other SCAD patients not meeting the ISCHEMIA eligibility criteria, the tailored strategy choice is advisable.The ISCHEMIA findings conflicted with the current European guidelines, and given the size of the study and the high quality of the data, a revision of the recommendations seemed inevitable. However, the new ACC/AHA guidelines for revascularization based on the results of ISCHEMIA were not supported by the cardiac surgery communities regarding the appropriateness of surgical treatment of multivessel lesions. Indeed, conclusions about the insufficient prognostic effect of revascularization in patients with high-risk coronary anatomy in the main trial are based on secondary analysis. On the other hand, while the cardiovascular mortality benefit of invasive strategy in MVD patients was shown in the secondary analysis of ISCHEMIA EXTEND, it was offset by the unexpected rise of non-cardiovascular mortality. In this regard, the appropriateness of an invasive approach for patients with MVD should be specifically addressed and the conduct of an RCT with a direct comparison of invasive and conservative strategies in this category of patients looks justified and substantiated by the results obtained in ISCHEMIA and ISCHEMIA EXTEND. The same applies to patients with reduced EF and LMCA lesions, which were underrepresented or not represented in ISCHEMIA. These much-needed data will be able to complete the most up-to-date SCAD treatment strategy algorithm.


The energy of sunlight is converted into chemical energy during photosynthesis in plants. The blue and red spectral regimens are absorbed in the chloroplasts, and their energy ensures the production of NADPH and ATP by the use of water. Subsequently, atmospheric carbon dioxide is incorporated into ribulose 1,5-bisphosphate using NADPH and ATP, from which further carbohydrates will be synthesized. These carbohydrates will be used as the precursors of further compounds or for the production of energy for various metabolic processes during respiration. Besides ensuring energy for the various biochemical and physiological processes, light is also involved in the modulation of these processes. Plants have specific photoreceptors to perceive light signals from the sun including red- and far-red light-absorbing phytochromes (Phy), the blue and green light-perceiving cryptochromes (Cry), the blue light-sensing phototropins (PHOT), and the UV-B-absorbing UVR8 photoreceptor. These photoreceptors, in interaction with specific transcription factors, adjust the metabolic processes to daily and seasonal fluctuations of light intensity and spectrum.Under high light intensity, the excess energy can lead to greater production of reactive oxygen species (ROS) in the chloroplasts, which results in oxidative stress. While a moderate increase in the ROS levels may activate various adaptive processes, their great production is toxic for the cells due to the damage of proteins, lipids, and nucleic acids. The amount of ROS is controlled by the redox system consisting of non-enzymatic  and enzymatic  compounds. ROS and antioxidants regulate the redox environment in the cells, tissues, and organs of plants, which affects the activity of various proteins.International Journal of Molecular Sciences entitled “Light-Dependent Control of Metabolism in Plants” consists of five original articles and one review. Although the influence of light conditions on metabolism has been studied earlier in several research groups, the valuable contributions of this issue give much new information in this field and indicate the unsolved problems worthy of future research.This Special Issue of the Light can control metabolism at transcriptional, post-transcriptional, and post-translational levels. Eprintsev et al.  investigThe light quality-dependent transcriptional control of basic metabolic processes such as nitrate, sulfate reduction, and maintenance of redox homeostasis was shown by Balogh et al.  in barleThe transcriptional control of the various biochemical processes by supplemental far-red light was also shown in Chinese kale in the work of Li et al. . Far-redBrassicaceae family, and some of them have antioxidant functions, which may contribute to their efficient use against cancer. UV-A also increased the total flavonoid content, which could further increase the antioxidant capacity of this species. In addition, it also improved the growth of kale through the increase in chlorophyll content and its quality due to the elevation of protein and sugar levels. These observations give further evidence for the importance of the determination of optimal spectral conditions for indoor farming.Supplemental UV-A light also modified the metabolism in kale grown under red and blue illumination as described by Jiang et al. . It induMicroalgae by Rani and Maróti [The modulation of metabolism by changing the light conditions could also be useful for the removal of pollutants from the environment as it was observed for nitrate in green d Maróti . CompariAll five research articles demonstrated the transcriptional regulation of the metabolism by light and two of them ,4 showedThis Special Issue encompassed a very broad range of the light-dependent control of metabolism from the DNA-methylation through the transcription until the enzyme activation. It included both basic research questions (gene regulation) and applied research (waste management). Although this issue introduced several new aspects of the regulation of plant metabolism by intensity and spectrum of light, these investigations were carried out in various organs or tissues. The study of the metabolic changes at subcellular levels would be an interesting future research direction and it could contribute to the understanding of the fine-tuning of metabolism by light intensity and spectrum.


This finding corroborates previous studies that have demonstrated low quality-of-life scores among patients with cataracts We read with interest the letter to the editor by Fazzi and colleagues who report a negative correlation between anxiety (measured with the IDATE) and quality of life (measured with the WHO-QOL-BREF) in 52 patients with cataracts.We would like to clarify that the cited paper did not assess quality of life in patients with cataracts and hence did not demonstrate low quality-of-life scores among patients with cataracts.


Functional magnetic resonance imaging (fMRI) has been used to identify the neural activity of both youth and adults diagnosed with major depressive disorder (MDD) in comparison to healthy age-matched controls. Previously reported abnormalities in depressed youth appear to mostly align with those found in depressed adults; however, some of the reported aberrant brain activity in youth has not been consistent with what is observed in adults, and to our knowledge there has not yet been a formal, quantitative comparison of these two groups. In addition, it is not known whether these observed differences between youth and adults with depression are attributable to developmental age or length-of-illness.The aim of this study is to elucidate the similarities and differences in patterns of abnormal neural activity between adults and youth diagnosed with MDD and to then determine whether these observed differences are due to either developmental age or length-of-illness.We used multilevel kernel density analysis (MKDA) with ensemble thresholding and triple subtraction to separately determine neural abnormalities throughout the whole brain in primary studies of depressed youth and depressed adults and then directly compare the observed abnormalities between each of those age groups. We then conducted further comparisons between multiple subgroups to control for age and length-of-illness and thereby determine the source of the observed differences between youth and adults with depression.Adults and youth diagnosed with MDD demonstrated reliable, differential patterns of abnormal activation in various brain regions throughout the cerebral cortex that are statistically significant . In addition, several of these brain regions that exhibited differential patterns of neural activation between the two age groups can be reliably attributed to either developmental age or length-of-illness.These findings indicate that there are common and disparate patterns of brain activity between youth and adults with MDD, several of which can be reliably attributed to developmental age or length-of-illness. These results expand our understanding of the neural basis of depression across development and course of illness and may be used to inform the development of new, age-specific clinical treatments as well as prevention strategies for this disorder.None Declared


In the published article, there was an error. The stated number of protocols needed to be corrected. These errors were identified after an audit conducted by the CONIS  of Costa Rica.A correction has been made to the Ethics Statement. This statement previously stated:The studies involving human participants were reviewed and approved by Ethics Committee of Hospital San Juan de Dios, Caja Costarricense de Seguro Social (CLOBI-HSJD #014- 2015) and the University of Costa Rica (837-B5-304). The patients/participants provided their written informed consent to participate in this study.The corrected statement appears below:The studies involving human participants were reviewed and approved by the Ethics Committee of the University of Costa Rica . The patients/participants provided their written informed consent to participate in this study.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Although we agree that this statement potentially reflects the reality, it is only an inference; it cannot be proved because the studies used different databases and methodologies .As reported at the conclusion of our article, we believe that the short-term consequences of the pandemic are already apparent, and they could be greater in low- and middle-income countries. The potential long-term impact of the COVID-19 pandemic on disease staging at diagnosis will remain an important question for years to come; we take the opportunity to highlight the continued need for interventions aiming at promoting equity of access to health care in Brazil—including screening tests and effective treatments.


High-flow nasal therapy (HFNT) was introduced into clinical practice in the early 2000s as a form of noninvasive respiratory support (NIRS). During the last 20 years, a growing body of evidence has shown the value of this intervention in the management of acute and chronic respiratory failure. Indeed, HFNT has transformed the landscape of research on and the clinical management of respiratory failure; according to a report released by NEJM in 2015 [2 from anatomical dead space, generating a slight positive end-expiratory pressure effect that provides alveolar recruitment, and determines a reduction in inspiratory effort as well as an improvement in oxygenation with the delivery of a stable fraction of inspired oxygen that lowers the metabolic cost of ventilation [HFNT provides the delivery of humidified gas flow that meets or overcomes a patient’s peak inspiratory flow, assures a continuous washout of COtilation , in seleThe beneficial effects of HFNT have mainly been demonstrated in patients with acute hypoxemic respiratory failure (AHRF), and clinical practice guidelines ,5 recommDespite the lack of evidence supporting the use of NIRS in pandemic viral illnesses , HFNT ha2 reduction in mild-to-moderate AECOPD during a short-term follow-up [HFNT could also play a role in the management of hypercapnic respiratory failure in patients with acute exacerbation of COPD  (AECOPD)ollow-up ; howeverollow-up , highligollow-up  as an alThe evidence for HFNT use in chronic respiratory failure has largely been focused on patients with COPD and bronchiectasis, suggesting that its use may influence exacerbations. HFNT prolonged the time to first exacerbation in a mixed population of COPD and bronchiectasis . AnotherJournal of Clinical Medicine seeks to collect high-quality research to explore its further potential clinical applications and to strengthen the evidence of its current indications.In the current era of personalized care, there is an exciting and bright future ahead of HFNT in both acute and chronic settings. The current Special Issue of the


Radiotherapy iss an important method of local-regional treatment of malignancies and has witnessed impressive advancements in recent years. The main aim of radiotherapy is to increase the outcome of patients while minimizing side effects. The emergence of a new cutting-edge hybrid technology - Magnetic Resonance Image-guided Linear Accelerators (MR-Linac) - is a revolutionary breakthrough technology in the field. This new technology combines real-time MR imaging of “the anatomy of the day”, prediction of the dose distribution, online adaptive optimization of the plan if needed, and continuous automatic cine-MR tracking of the target. As this technology has a significantly different workflow compared to conventional radiotherapy, it is crucial to understand the fundamentals of utilizing MR-Linac to reach the goal to obtain optimal patient outcomes. The following topics we would like to emphasize are the major important components of MR-Linac technology;1One of the key influences of MR-Linac is the ability to integrate high-quality real-time MR imaging into the MR-guided radiotherapy workflow. Physicians must notice the implication of this feature to visualize the exact location of tumors and critical structures immediately before the treatment, recontouring or editing tumors and neighboring normal organs and structures if needed, and tracking the tumors continuously during beam-on and stop the treatment automatically if the target is out of the boundaries.2The successful implementation of a new MR-Linac workflow requires close teamwork between physicians, Radiotherapy Technologists (RTTs), and Medical Physicists. Each team member has a valuable role in the different steps of the workflow. This collaborative approach aims to synergistically exploit the capabilities of MR-Linac .3Members of the team should collaborate to develop optimal personalized treatment plans based on the “anatomy of the day” imaging where needed. A recent analysis of 50 patients with localized prostate cancer who were treated with ultra-hypofractionation using MRgRT in a total of 250 fractions has shown that in 76% (190/250 fractions) of fractions, reoptimizisation is needed due to various reasons . Second manuscript reports the dosimetric benefits of daily adaptation of SMART and the first clinical results in pancreatic tumors in 30 patients . Third manuscript assesses the quality of a new diffusion-weighted imaging (DWI) sequence implemented on an MR-Linac MRIdian system, evaluating and optimizing the acquisition parameters to explore the possibility of clinically implementing a DWI acquisition protocol in a 0.35-T MR-Linac . The fourth manuscript reported the use of MRgRT for pediatric patients over four years and describes important considerations in the selection and application of this technology in children . The fifth manuscript quantitatively characterizes the dosimetric effects of long on-couch time in prostate cancer patients treatment . Sixth manuscript reports the workflow and initial clinical experience of high-grade glioma radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow.  The seventh manuscript documented the critical steps needed for the appropriate delivery of MRgART for lung tumors safely and effectively. . The eight manuscripts reported one of the largest cohorts of patients treated with online MRgRT of liver metastases focusing on oncological outcome, toxicity, patient-reported outcome measures (PROMs), and quality of life . The ninth manuscript analyzed the role of MRgRT as a potential to become a widely utilized treatment platform and transform the radiation oncology treatment process just as earlier disruptive radiation therapy technologies have done . Tenth manuscript, aimed to optimize patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy . The eleventh manuscript reported the outcome and toxicity of the first 200 patients with prostate cancer treated with MRI-Linac .The first manuscript of this Research Topic aimed to evaluate the geometrical differences and metabolic parameters  as a tool for an individualized definition of the volume in need of dose escalation for squamous cell esophageal cancer (This editorial highlights the implications of recent research findings in this breakthrough technology. This Research Topic of the journal guide Physicians and Medical Physicists who are starting their voyage with this new technology and speed up their learning curve time in their new journey.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


The citation has now been inserted in the Introduction and should read:In the published article, Clinical Chemistry and Laboratory Medicine - A panhaemocytometric approach to COVID-19: a retrospective study on the importance of monocyte and neutrophil population data on Sysmex XN-series analysers .”The References section has been updated and renumbered accordingly.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.