Pituitary metastasis accounts for a very low percentage of cases of brain metastasis from lung cancer, and there are uncertainties and challenges in diagnosis and treatment. We hope to shed some light on the diagnosis and treatment by reporting a case of ALK fusion mutation-positive lung cancer pituitary metastasis.We report a 48-year-old female patient with an initial diagnosis of stage IVB lung adenocarcinoma with ALK fusion. The patient developed headache, dizziness, hypopituitarism and hyperprolactinemia one year after treatment with crizotinib. Later, the patient underwent neurosurgical resection of the pituitary tumor and then symptomatic relief. Postoperative pathology suggested pituitary metastasis, and the next-generation gene sequencing conducted on the pituitary metastasis indicated that secondary drug resistance mutation ALK-I1171s occurred after the ALK fusion gene.In this article, we present a patient with suspected pituitary metastases with lung cancer. The progression to pituitary mass resection and next-generation gene sequencing of the pituitary metastasis are suggestive for further diagnosis and treatment. According to available reports, pituitary metastases from lung cancer are very rare, especially when compared with metastases to other endocrine glands, such as the adrenal gland and thyroid gland . Lung ca18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed a soft tissue density shadow in the right lower lobe with a size of 3.4*2.4 cm; enlarged bilateral supraclavicular and mediastinal lymph nodes, thickened bilateral pleura and increased pericardial effusion were metabolism increased; the metabolism in thoracic vertebrae T4, lumbar vertebrae L1, L5, and right ilium were also increased The incidence of pituitary metastases accounts for 1% of the total incidence of pituitary lesions , making The ALK gene has been identified in a variety of solid tumors and is a potent oncogenic driver gene . ALK proPituitary metastasis from lung cancer is very rare, and surgical treatment could be a positive option. Although crizotinib was chosen for financial reasons in this patient, alectinib has been shown to have longer PFS than crizotinib in multiple phase III clinical trials, and alectinib is now widely used as first-line therapy, especially in brain metastasis. This patient developed pituitary metastasis after crizotinib resistance, and next-generation sequencing suggested the presence of the ALK I1171S mutation. The ALK I1171S mutation has been shown to result in secondary resistance to crizotinib, and ceritinib has proved effective when patients develop the secondary ALK 1171S mutation.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SF and DH had the original idea for the article and guided the treatment and management of the patient. DH and KZ wrote the article incorporating the comments from LZ. All authors reviewed and approved the final draft of the article. All authors contributed to the article and approved the submitted version.This work was funded by the National Natural Science Foundation of China (82002825 to DH).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Conventional zeolite manufacturing processes are highly energy-intensive and come along with a significant carbon dioxide footprint. Here, we discuss the main energy consumers and potential alternatives toward a more sustainable production of zeolites: from simple optimization efforts on existing unit operations to new and novel manufacturing concepts such as the continuous crystallization and solidothermal route toward zeolites and their industrial applicability. These efforts contribute to the global effort into transitioning manufacturing of chemicals and catalysts to a net-zero environment by cutting greenhouse gas emissions to as close to zero as possible. Zeolites continue being one of the most relevant classes of catalysts for both chemical and petrochemical industries. Their intrinsic properties in terms of variable framework geometries, tunable compositions, and accessible pore structure of molecular dimensions enabled their use as catalysts or adsorbents in many industrial relevant processes , and the2 footprint of large industrially relevant applications and playing an important role in environmental catalysis reducing harmful NOx emissions from diesel cars and trucks and stationary sources; there is a strong incentive toward a more sustainable zeolite manufacturing process.Zeolite manufacturing in general is a highly energy-intensive process, with the steps 2 + 4 + 5: crystallization, drying, and calcination, respectively, as the major energy consumers due to the need for elevated temperatures over extended periods of time for these particular unit operations. Even though zeolite-based catalysts during their lifetime significantly contribute to more efficient chemical processes, in turn reducing the overall CO• Space time yield of the recipe: mostly expressed as kilogram product, per volume of the synthesis reactor and time. This gives an indication of the synthesis yield, with lower values indicating long synthesis time (high energy consumption) or lower reactant yields (high volumes of wastewater).2 footprint in zeolite manufacturing; although, they would not be a direct emitter in the process itself.• Raw material selection: some syntheses involve expensive and complicated organic structure-directing agents, which would require complex synthesis procedures with high amounts of waste/high energy consumption. Sometimes, mineralizing agents such as fluorides or other inorganics are used which present issues in terms of EHS and off-gas/wastewater handling. Raw materials could be an important source of the CO• Energy of synthesis gels is often an overlooked aspect in academia: this refers to the stability of the raw materials during hydrothermal synthesis and the risk of thermal/catalytic decomposition, resulting in increased pressure or runaway reactions.Driven mostly by academic research, around 246 of the zeolite framework topologies were synthesized, not including the intergrowth structures. These materials could be produced in various compositions, and additionally over 20,000 structures are known, hypothetically. Despite this, less than 15–20 zeolite structures made their way into industrial applications. In addition to the potential lack of applications, the transfer of zeolite recipes from an early-stage academic environment into an industrial setup is not trivial. Some of the aspects that are mostly overlooked in academia, but are industrially relevant, are as follows:In this paper, we address concepts that could improve the sustainability directed toward zeolite manufacturing steps such as synthesis, drying, and calcination.via a secondary heating loop powered by steam or natural gas firing, which in turn can be translated into the generation of CO2. The CO2 footprint per kilogram of zeolite depends strongly on the gel composition and the conduct of crystallization; quite often well above 1 kg CO2/kg of the zeolite product. These constraints are nicely captured within the concept of space-time-yield, which describes the amount of zeolite produced in a given crystallization time per volume of the corresponding reactor. The higher the solid content in the gel, the shorter the crystallization time, and the higher the space-time-yield. As the amount of energy required to heat up and maintain the crystallization at the target temperature is more or less independent from the gel composition, a higher space-time-yield not only means a higher efficiency in the utilization of the given equipment but also a huge lever to reduce the energy consumption per kilogram of the zeolite.The conventional crystallization process involves heating up the synthesis gel to elevated temperatures (120–200°C) over an extended period of time (20–100 h) to allow the crystallization of the desired zeolite framework. The heating of the autoclaves typically occurs indirectly ex situ by taking samples for the determination of the degree of crystallization and in situ by implementing the speed of sound sensors to follow the progression of the particle size distribution  comes with heat-up and cool-down times of at least a couple of hours each, while the minimum residence time for crystallization amounts from hours to days. The thermal lag results in heterogeneities in terms of heat distribution within the synthesis reactors, which could influence the nucleation and crystal growth process of zeolite synthesis -free synthesis. OSDAs mostly consisting of quaternary ammonium or phosphonium salts are generally applied in the synthesis of high Si or specialty zeolites. Although highly effective toward the synthesis of target zeolite structures and compositions, these organic molecules are often costly and require special handling (EHS issues). Since they are mostly burned during the zeolite calcination, special off-gas treatment is required to handle the COx, NOx, and other emissions. In this sense, minimizing the amount of such OSDAs in the synthesis gel and applying simple and less toxic molecules are preferred for industrial synthesis . A compl2 storage and gas-purification.New synthesis routes to frameworks that generally require the use of an OSDA, such as BEA and high silica CHA SSZ-13, were reported without the need of an OSDA . Using aspace-time-yields under the avoidance of emissions to both wastewater and air.The synthesis mechanism behind the zeolite OSDA-free synthesis was studied by different research groups. Particularly, the role and proper selection of the seed crystal and the composition of the synthesis gel were found critical for the success of this synthesis route . The preUse of waste as a raw material for zeolite synthesis is another approach to increase the sustainability of zeolite crystallization. Quite often untransformed raw materials, OSDAs, or Si/Al species, for example, are separated and recycled into the synthesis gels, rather than being disposed. In addition, waste streams from other chemical manufacturing processes could be used as raw materials for zeolite synthesis. An example in this sense is the use of silicon waste coming from the production of solar panels. This source of Si was shown to be used in the synthesis of high-value MFI zeolites, such as TS-1  Figure .Moving toward sustainability and net-zero in the industrial manufacturing of zeolites requires researchers in academia and the industry to consider energy consumption and generation of emissions already during the very early research phase when developing new materials or recipes. Proper selection of the crystallization method and the respective equipment and raw materials and the corresponding structure directing agents is critical on this path.In addition to crystallization, the drying step, typically conducted in spin flash or spray dryers , and thex, and CO emissions and the overall simplification of the post-treatment process. Furthermore, as the calcination process puts thermal stress on the integrity of the framework, potentially leading to dealumination or even partial collapse of the porous framework, the avoidance of such a step can also improve the overall quality of the zeolite powder and in turn furbish a catalyst with enhanced catalytic activity, e.g., via higher preservation of active sites in the framework.Typical temperatures applied during calcination are in the range between 500 and 650°C under oxidizing conditions to burn off the organic structure inside the zeolite framework . Heat reAnother interesting approach for the case, the addition of OSDAs to the synthesis gel cannot be circumvented, is the merging of the drying and calcination steps into one single process step. This is achievable by applying the concept of flash calcination . The wetThe new learnings in terms of drying and calcination of zeolites have the potential to apply less energetically intensive processes with less thermal stress on the zeolite framework.There exist multiple pathways toward a more sustainable zeolite production, reducing the overall environmental footprint for this industrially highly relevant class of materials. Electrification allows the simple conversion of existing unit operations without major changes to the already present zeolite production processes. Moving toward the OSDA-free zeolite synthesis can likewise make use of the existing production infrastructure, while fully eliminating the need for a highly energy-intensive calcination step and also dramatically decreasing wastewater generation and other emissions. Applying new concepts such as the continuous zeolite synthesis in a tube reactor or the solidothermal zeolite crystallization does face a higher barrier toward the realization being put into steel and iron. The intensifying push toward carbon dioxide neutrality by both the society and customers is, however, a strong driving force not only for academia but also for the relevant zeolite manufacturers to explore alternative and novel concepts to produce zeolites that during their lifetime not only act as catalysts contributing to the reduction of the environmental impact but also result from a low and green energy consumption-based production process.


The prevalence of heart failure (HF) is increasing in the ageing world population, and its burden on the medical and health economic fields is enormous. Rehabilitation is an essential component of the nonpharmacological treatment of patients with HF; however, its efficacy and cost-effectiveness for patients with acute HF remain unclear. A trial assessed the cost-effectiveness of acute cardiac rehabilitation among older adults. Herein, we discussed strategies for the cost-effectiveness analysis of acute cardiac rehabilitation using the rehabilitation therapy in older acute heart failure patients trial. Heart failure (HF) is a major public health issue, and its global burden on the medical and health economic sectors is enormous. The annual healthcare budget for HF is high, accounting for 1–2% of the total annual healthcare budget in Europe and the United States (US). In addition, the total health expenditure for HF in the US is expected to increase by 127% between 2012 and 2030 [Exercise-based rehabilitation is a nonpharmacological method of HF treatment. A clinical guideline has reported that cardiac rehabilitation is useful for clinically stable patients with HF . In contOne important clinical trial involving older acute HF patients was conducted in the U.S., and subsequently the cost-effectiveness analysis (CEA) was published . CEA is The first point is the patient population in the trial. The REHAB-HF trial included approximately 55% of frail older adults, but excluded approximately 98% of patients with acute HF due to the following reasons: dementia, dependent on activities of daily living, planned discharge to a nursing home, and difficulties complying with trial requirements . This coThe second point is the comparator in the trial. According to the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure, it is recommended that such patients in the REHAB-HF trial should receive care from multidisciplinary teams as a nonpharmacological intervention . To ensuThe third point is the cost related to caregiver burden. Both the patients and their caregivers should be considered in CEAs of trials including older adults who need some assistance in their activities of daily life. The Second Panel on Cost-effectiveness in Health and Medicine recommends using not only payer’s perspective, but also societal perspective, which considers the effect of the intervention on the patients, caregivers, and social resources in a CEA with a long-time horizon . CaregivFinally, there are two issues in the modelling for CEA. The time horizon used in the CEA of the REHAB-HF trial was lifetime. The time horizon must be long enough that the intended and unintended benefits and harms are captured . In contWe discussed the strategy for the CEA of acute cardiac rehabilitation in older adults with HF using the REHAB-HF trial. Considering more frail older people (who can be a key population in HF in the ageing world) and the cost related to caregiver burden, and modelling with an appropriate time horizon and more accurate data may be useful in the future analysis of the cost-effectiveness of acute cardiac rehabilitation in older adults.


Pathogenicity, or the ability of a microorganism to cause disease, depends on several factors, among which the immune status of the host and the microbial species involved in the exposure play a key role. Microbial pathogenicity is a complex, multifactorial process, governed by genetic and molecular features associated with virulence and/or resistance determinants involved in critical steps of pathogenesis . An estiPathogens, titled "New Insights into Bacterial Pathogenesis," aims to collect recent findings regarding the relationship between virulence and resistance that allows pathogenic bacteria to colonize and invade human tissues. In this Special Issue, readers will find contributions  that provide information on various aspects concerning bacterial pathogenicity, such as mechanisms of pathogenicity, antibiotic resistance, strategies to maintain elements essential for bacterial growth and survival, and the application of molecular techniques for the identification of various pathogens.This Special Issue of Porphyromonas gingivalis [The original manuscript by Swietnicki and colleagues is the first report in the literature to analyze in detail the O-type antigen biosynthetic pathway of a human oral pathogen involved in dental tissue destruction, ngivalis . They foAliarcobacter butzleri, an emerging enteropathogen that shows high genetic diversity [Another original study conducted by Bonifácio et al. analyzed the natural transformation capacity of iversity . The autS. aureus [S. aureus infections by limiting, during the colonization phase of the host by this microorganism, the availability of zinc, a metal that plays a key role in many metabolic processes . The authors demonstrated how zinc deprivation in vitro affects growth, biofilm formation, and the hemolytic activity of S. aureus. These findings may be a potential supportive approach to contain topical MRSA infections. Elhakim et al. are the authors of a pilot study that investigated the role of zinc-metal ions in the pathogenesis of . aureus . This woEscherichia coli (EHEC) [Another manuscript by Hirakawa et al. investigated the role of major members of the outer membrane protein family OmpA, OmpW, and OmpX in the type III secretion system (T3SS)-mediated virulence of enterohemorrhagic i (EHEC) . The autMycoplasma bovis (M. bovis) secretome [M. bovis is an important bovine pathogen responsible for huge economic losses in the dairy and beef industries worldwide. Previous studies have shown that the IL-8/neutrophil axis plays an important role in the pathogenesis of mycoplasma. The manuscript produced by Lu et al. shows that MbovP0145 induces the upregulation of IL-8 expression by interacting with beta-actin in the cytoplasm and contributing to activation of the MAPK signaling pathway. Thus, the increased expression of IL-8 is a crucial factor in the activation and migration of neutrophils from blood to the site of M. bovis infection. This Special Issue also features a manuscript on the function of the MbovP0145, a protein present in the ecretome . M. boviE. coli pathogenesis, namely, the factors involved in the transition from intestinal commensal E. coli to invasive E. coli that causes bloodstream infections [E. coli from intestinal epithelial cells is dependent on the presence of an IncFII plasmid carrying the gene encoding for the protein modulating hemolysin expression (Hha). In addition, these authors showed that the transfer of the resistance plasmid IncFII, identified through an innovative survey approach that compares and analyzes clonal E. coli isolates from rectal swabs and blood cultures of the same individuals, contributes to the transition of commensal to invasive E. coli strains in vivo. This Special Issue also features another manuscript that investigated a different aspect of fections . The worThis Special Issue also presents a review manuscript on the different functional aspects of Zur proteins found in various bacterial species . The manFinally, to conclude this series, this Special Issue includes two review manuscripts dealing with the global problem of bacterial resistance to antibiotics and the advantages and limitations of molecular methods applied to the diagnosis of bacterial infections. The main mechanisms of antibiotic resistance in ESKAPE pathogens and a detailed description of the most commonly used classes of antibacterial drugs against these pathogens are critically reported in . In the last review, Gerace et al. addressed the important issue of recent advances in the use of molecular methods for the diagnosis of bacterial infections and provided an overview of the possible range of applications of these methods . The autOverall, this Special Issue highlights the complexity of pathogenetic mechanisms actuated by different bacterial species in the context of microbe–host interactions that impact both pathology and disease outcome. Understanding the pathogenetic mechanisms of these clinically well-documented phenomena is a priority for the development of novel and effective therapeutic approaches for disease prevention. The knowledge gained from the articles discussed here could contribute to the development of pathogen-specific strategies and significantly accelerate vaccine development.We would like to thank all the authors who participated in this Special Issue and the reviewers for their helpful comments.


This study aims to investigate the influence of psychological biases on the investment decision of Chinese individual investors after the pandemic of COVID-19 with a moderating role of information availability. A cross-sectional method with a quantitative research approach was employed to investigate the hypothesized relationships among variables. The snowball sampling technique was applied to collect the data through a survey questionnaire from individual investors investing in the Chinese stock market. Smart-PLS statistical software was used to analyze the data and for the estimation of hypotheses. Results indicated that overconfidence, representative bias, and anchoring bias have a significant and positive influence on investment decisions during the post-Covid-19 pandemic; however, the availability bias has insignificant and negative effects on the investment decision during the post-COVID-19 pandemic. Moreover, findings indicated that information availability has a significant moderating role in the relationship of psychological biases with the investment decision during the post-COVID-19 pandemic. This study contributes to the body of knowledge regarding behavior finance, psychological biases, and investment decision in emerging stock markets. The findings of the present study improve the understanding that how investors’ psychology affects their investment decisions. At the start of January 2020, the spread of coronavirus (COVID-19) in China not only resulted in a huge loss of lives but also continued to influence the economy all over the globe negatively . All couSocial norms due to the pandemic’s severe effects and the potential threat of disease . The anxIn the literature, a large number of researchers studied the consequences of calamities, including terrorism attacks, aircraft crashes, and earthquakes, on the financial decisions of investors and firms. In addition, In their book “Behavioral Finance,” Cognitive bias refers to the individual’s overestimation of their capabilities, cognitive aptitudes, and accuracy of knowledge  toward aHypothesis 1: There is a significant association between overconfidence and investment decision of Chinese individual investors in the post-Covid-19 pandemic.Another name for this particular bias is “familiarity bias”. In the situation of lack of information or weak knowledge, neural processes use shortcuts to process this insufficient information to attain desired targets. Normally, information is evaluated on a previous experience basis. For instance, while purchasing a house, an individual will evaluate and compare prices of similar houses in that particular locality for understanding the property risk and future value of the asset. Representativeness refers to similar situations and occurrences in the population . AccordiTherefore, the following hypothesis based on the extensive literature review is proposed.Hypothesis 2: There is a significant association between representative bias and investment decisions of Chinese individual investors during the post-COVID-19 pandemic.This bias is concerned with the irrelevant comparison of stock price levels during the decision-making process. Investors with anchoring bias tentatively decide the price based on previous information while selling and buying shares. In this way, the timing of an investor’s decision may be wrong where he/she may sell stock at the time of decreased prices or may sell stocks at the time of increased prices. In addition, investors may lose good opportunities as their decided price for buying or selling may not be reached sometimes. This bias is also linked with the representative bias because the previous experience of investors is a common factor for both. Investors are commonly found optimistic about rising prices and are pessimistic about declining prices . InvestoHypothesis 3: There is a significant association between anchoring bias and investment decisions of Chinese individual investors during the post-COVID-19 pandemic.Availability bias refers to the decision-making of an investor by relying on readily available information and ignoring other substitutes . When deHypothesis 4: There is a significant association between availability bias and investment decisions of Chinese individual investors during the post-COVID-19 pandemic.Literature on information searching endorses that the trading attitudes of investors are influenced by the accessibility of information. Similarly, studies of behavioral finance also concluded investment behaviors of individuals are influenced by their various cognitive skills. These deviations in investment behaviors need to be explained with new dimensions because they do not yet explain how information accessibility influences investment decisions in stock markets. Hypothesis 5: Information availability has a significant moderation role in the association of overconfidence with the investment decision of Chinese individual investors during the post-COVID-19 pandemic.Hypothesis 6: Information availability has a significant moderation role in the association representative bias with the investment decision of Chinese individual investors during the post-COVID-19 pandemic.Hypothesis 7: Information availability has a significant moderation role in the association anchoring bias with the investment decision of Chinese individual investors during the post-COVID-19 pandemic.Hypothesis 8: Information availability has a significant moderation role on the association availability bias with the investment decision of Chinese individual investors during the post-COVID-19 pandemic.The objective of this study is to investigate the influence of psychological biases on the investment decision of Chinese individual investors after the pandemic of COVID-19 with a moderating role of information availability. To attain the objective, a quantitative approach to research with a survey questionnaire is a suitable research technique . The surConvergent validity (CV) and discriminant validity were investigated by using a measurement model. Convergent validity is used to estimate the degree that how different items measure the same concept. According to the suggestions of In In For the examination of the hypothesis, this research opted for the bootstrap method to test the association among independent, dependent, mediating, and moderating variables . The hypt = 3.782) and representativeness bias also positively and significantly influences the investment decision of individual investors . Moreover, anchoring bias also has a significant influence on investment decisions . Furthermore, availability bias has a significant but negative influence on investment decisions . Thus, H1, H2, H3, and H4 are supported.p = 0.016). Anchoring bias also significantly influence on the investment decision . However, the availability bias has a significant but negative effect on the investment decision . These results are in line with the study of The first objective of this study was to investigate the decision after the COVID-19 outbreak among Chanies hypotheses of the study. This study found that on investment decision of Chanies individual investors significant and positive effect on investment decision (β = 0.342, This study aimed to investigate the influence of psychological biases on the investment decision of individual investors after the COVID-19 pandemic. This study also intended to examine the role of information available on the relationship of psychological biases with the investment decision of individual investors. This a quantitative approach of research was employed to stock market. Results show that overconfidence, and positive influence on investment decisions; however, the availability bias has a significant but negative effect on the investment decision. Moreover, findings indicated that information availability has a significant moderating role in the relationship of psychological biases with the investment decision. The findings of the current study may benefit the participant of the stock market and other investors while they take the investment decision. The results of this study will contribute to the body of behavioral finance literature because it established the relevance of the prospect theory in illuminating the interaction between psychological factors, information availability, and the investment decisions of individual investors in a single model. Indirectly, this study offers a new direction in research on the predictors of investment decisions after the pandemic of COVID-19 in the context of China.This study will help financial specialists, economic institutions, and policymakers to generate better stock market strategies and make informed and rational investment decisions. This study also acknowledged the importance of various behaviors that has substantial impacts on investor investment decisions in the stock market during the post-COVID-19 pandemic. This study will assist such stock market experts and governments to know the importance of overconfidence, representativeness, anchoring, and availability biases in their investment decision. For making informed and rational investment decisions information availability for the investor is critical. However, effective legislation relating to information availability for investor is important to make significant investment decisions in the stock market. This study can also help us understand how information availability is important in identifying new investors who have not yet earned investment expertise and hence have not established investment strategy behavior during the post-COVID-19 pandemic.Even though this study is unique in its proposition, there are limitations that should be addressed in future research. First, this study used a sample of Chinese investors. Thus, the results have limited generalized ability and changing the population in future research could validate the results of this study. Furthermore, this study has limited the four psychological biases that influence individual investors’ investment decisions.Future research could investigate how the other psychological biases affect the investment decision of individual investors after the COVID-19 crisis.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients/participants or patients/participants legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.NJ presented the main idea, contributed to writing the original draft, and collected the data. JS contributed to the technique and methodology. KT performs the analysis. VJ revised and proofread the article. All authors contributed to the article and approved the submitted version.


Tendons are essential components of the musculoskeletal system that links the skeletal muscle to the skeleton. This dense connective tissue exhibits great plasticity. Therefore, research on the influence of types of exercise, including acute and long-term training, on the structural and mechanical properties of tendons in athletic and sedentary populations is of critical importance in the design of scientific-based exercise plans and effective tendinopathy treatment. Here, we review recent studies on the relationship between exercise and tendon health and tendinopathy repair to provide a general understanding of how exercise may reshape tendons. Tendon injury, especially patellar and Achilles tendon injuries, exhibits a high prevalence in professional athletes and impacts sports performance . In sedeTo better monitor and reflect the situation of tendons, many methodologies have been developed and utilized. The mechanical properties of the tendon including stiffness, tensile strength, cross-sectional area (CSA), slack length, and elasticity are assessed by protocols based on ultrasound . In noniDifferent exercise styles often affect the rehabilitation care of patients with tendon injury. Previous studies have shown that patients with tendon injury usually progress from low-intensity exercise to high-intensity exercise, with increasing tendon load that patients must endure before fully resuming high-demand activities . While tBefore investigating the relationship between exercise and tendon tissue, a comprehensive understanding of the physiology and pathology of tendons is necessary . LocatedLinking the skeletal muscle to the bone, the tendon transmits the mechanical force from the skeletal muscle to the bone, enabling locomotion. Similar to the structure of the skeletal muscle, the fibrils in tendons have a hierarchical relationship. The fibrils composed of type I collagen in a triple-helical form fibre, then fascicles, and finally the tendon . To formAway from the middle part of the tendon, the heterogeneity increases given the formation of junctions that link the tendon to the skeletal muscle and the skeleton, namely, the myotendinous junction and osteotendinous junction, respectively. Between the muscle and the tendon, the myotendinous junction receives stress during contractile force transmission, where the fibre from the tendon inserts into the muscle body to increase the stability of the structure. The fibrocartilaginous tissue that connects the tendon and the skeleton is also called an enthesis. A large amount of type II collagen produced by chondrocyte-like cells in this area shapes the different mechanical properties and pathogenesis of enthesis and tendon, although injuries occurring in both areas are not easily repaired completely.Although the situations are not all the same in all the tendons in the body, generally, the tendons are relatively poorly vascularized with more dependency on synovial fluid diffusion to provide nutrition. The myotendinous junction, enthesis, and surrounding connective tissue such as the paratenon serve as the origin of blood supply for the tendon . Blood vMature tendons are composed of dense connective tissue that is hypocellular, with most of the cells in the tissue being active and being highly proliferative and fibroblast-like tenoblasts and terminally differentiated tenocytes. The tenocytes are spindle-shaped flat cells lying in rows between collagen fibres, forming an exquisite three-dimensional network in the ECM to maintain cell–cell communication . The higTDSCs were first isolated from human hamstring and mouse patellar tendons in 2007, after which TDSCs were identified in many other animals including rats and rabbits. TDSCs express various markers, including octamer-binding transcription factor-4 (Oct-4), Nanog, nucleostemin (NS), stage-specific embryonic antigen (SSEA)-4, c-Myc, and SRY-box transcription factor (Sox) 2 . Here, wMacroscopically, exercise stimulates the tendon mechanistically. Upon activation of molecular signalling pathways, mechanical stimulation signals are conveyed by the ECM deep into the cell and converted to intracellular biological signals by mechanosensitive receptors in the cell plasma membrane. Investigations of the response of tendon cells to mechanical stimulation and the underlying mechanism are of significance for guiding exercise interference in tendon remodelling and tendinopathy treatment. Conversely, the observation and summary of the adaptation of tendons to mechanical loading would enlighten research on the pathogenesis of tendinopathy. With the development of different modes of mechanical stimulation including compression and tension and bioengineering methods to construct cultured tendon tissue, an increasing number of molecules and related signalling pathways involved in the mechanical regulation of the tendon have been reported.β) in the SMAD2/3 signalling pathway are reported to regulate the expression of Scx [β signalling functions in ECM organization induced tenocyte morphogenesis and the formation of myotendinous junctions [Composed of tendon cells, strong collagen fibre, and diverse noncollagen ECM, tendons are dynamic responders to frequent mechanical loads. ECM remodelling during this process influences cell function. The secretion and degradation of the ECM in tendons change sensitively after mechanical stimulation to adapt to the environment and maintain homeostasis. Appropriate mechanical force from the structures around the tendon is necessary for the development and maturation of the tendon. Among the molecules that participate in the regulation of tendon dynamics, scleraxis (Scx) has been studied most. This transcription factor is expressed specifically in progenitors and cells in all tendons. Scx deficiency in mice results in limited use of all paws and back muscles and a complete inability to move the tail . Fibrobln of Scx , 26. Durn of Scx . The uprn of Scx . Fibrobln of Scx . TGFβ siunctions , 30. In unctions , 32. FurThe immediate effect of a certain mode of exercise on tendons is worthy of exploration for several reasons. Acute exercise with excessive dose and intensity may expose the tendon on the risk of strain injury, partial to complete rupture, and structural destruction of the myotendinous junction , 34. MeaThe stiffness of the Achilles tendon is reduced after maximal voluntary contractions , 36. HowIn addition to morphological analysis, for in-depth knowledge of the alterations in tendons after acute exercise, protein synthesis was examined in tendons. To assess protein synthesis in human subjects, isotope labelling through intravenous injection was employed, and the labelling of target proteins was quantified by gas chromatography–mass spectrometry for quantification. The study showed a rapid increase in collagen synthesis in the patellar tendon after strenuous exercise in the young male volunteers, and the levels peaked at 24 hours post exercise . AnotherIn an observation of calf Achilles tendon, isolated eccentric and concentric loading with the addition of 20% body weight of the Achilles tendon was exerted by the two limbs separately. Sonograms collected 3-24 hours after exercise showed that both loading conditions resulted in decreased normalized Achilles tendon thickness, whereas eccentric loading induced a significantly greater Achilles tendon thickness than concentric loading. However, the transient change after the two modes of exercise completely recovered during a similar time course . An expeStretching is also necessary to adjust the state of skeletal muscle and tendons before and after exercise. Dissection of the function of stretching in tendon movement is important to obtain a proper warm-up effect before and after relaxation of concentrated mechanical loading. A study with 14 participants (7 men and 7 women) showed that the range of motion and maximum voluntary contraction increased after 5 rounds of 60 seconds of static stretching, whereas the muscle-tendon stiffness decreased immediately but not at 5 or 10 minutes poststretching. The mechanical changes in the muscle-tendon junction were attributed to changes in muscle elongation instead of changes in tendon morphology .Although experimental and clinical data have continued to accumulate since the scientific management of the musculoskeletal system attracted the attention of the public, studies on the relationship between acute exercise and tendon health remain blurry and controversial given variations in the methodologies and exercise modes and doses. Moreover, for exercise and nonexercise populations or young and old populations, the stimulation conditions established during the test should differ, as the tendons of these populations are manipulated in distinct manners via different mechanical properties. Regardless of the measurement used for the tendon itself, real-time, high-resolution observation and reflection of the mechanical state of the myotendinous and osteotendinous junction remain lacking. Acute stretching and shortening of the tendon also place great stress on the junction part of the tendon, and the environment is harsh for repair if rupture occurs due to the diversity and low proliferation activity of the cells. It is important to develop suggestions for injury prevention based on a basic understanding of the mechanical characteristics; moreover, knowledge on the junction is also critical.n = 10). The patellar tendon and Achilles tendon CSA are all comparable in trained and untrained women [Compared with a single bout of exercise, long-term training with a certain frequency is more likely to reshape locomotion system components. In a study involving 40 Chinese subjects 19 to 25 years old who were divided into two groups subject to frequent or infrequent exercise, the mean thickness of the Achilles tendon of subjects undergoing frequent-exercise was significantly greater than that of subjects undergoing infrequent- exercise. The same result of the CSA of the tendon was reported in the dominant ankle . Similared women .The effects of long-term training in a healthy athlete population on tendons may also result in differences in exercise performance. A study of 26 healthy recreational long-distance runners assessed alterations in tendon force and stiffness resulting from long-term resistance training and running economy . The exeAlong with other components in the musculoskeletal system, the tendon is a highly adaptive tissue with dynamic changes occurring inside after the stimulation of mechanical loading. A meta-analysis focusing on the adaptation of human tendons to mechanical loading reviewed different studies on human tendon adaptation to mechanical loading . ConclusDiverse animal models simulating human exercise were devised to investigate how exercise influences healthy or injured tendons. The horse is a large animal model used to study human tendon physiology and pathology. Research observing two groups of female horses with high or low intensity exercise training for 18 months found that the collagen fibril diameter of the superficial digital flexor tendon decreased in the high intensity group, but no change in collagen content was observed. Compared with the injury-prone equine superficial digital flexor tendon, the rarely injured common digital extensor tendon showed lower water content and higher elastic modulus after long-term, high-intensity training; however, no signs of degeneration or mechanical property changes were noted in the superficial digital flexor tendon . In one β superfamily is believed to be an essential signalling pathway that participates in the adaptation of tendons to exercise stimulation [β receptor inactivation mice provides strong evidence. Nevertheless, the spatiotemporal control of gene activation and inactivation by genetically modified mouse models is urgently needed to investigate the function of TGF-β function in adult tendons during types of loading interventions.Given its regulatory function in fibroblast proliferation and type I collagen synthesis, the TGF-mulation . Limb foA common understanding of the mechanism in tendon physiology and pathology depends on the uniformity of the criteria employed in the research methodology. A myriad factors of factors should be taken into account when reviewing different research results given that the assessment approach and resolution, the exercise dose and intensity, the race, age, and gender of the subjects and many other factors may lead to variable conclusions. It was even suggested by some scientists that conditioning exercises should be performed to standardize the load history of tendons before in vivo sonographic measurements of tendon thickness. According to their findings from 30 healthy male participants, conditioning of the Achilles tendon via resistive ankle exercise induced alterations in tendon structure that improved correlations between tendon thickness and body anthropometry . This deIn the observations of tendon adaptation to acute or habitual mechanical loading, the difference between males and females cannot be neglected. Of note, women are more susceptible to soft tissue injury, but the reason is unknown. It was reported that after a bout of acute exercise, collagen synthesis in tendons of men was upregulated but the increase in tendons of women was less profound or absent. Additionally, the patellar tendon of men increased in size after long-term training, whereas no alterations were noted in women. A lower mechanical strength and reduced rate of connective tissue formation in tendons of women were proposed to explain the increased risk noted in women . RegardiTendon pathologies can be divided into chronic injury and acute injury with partial or complete tendon rupture in different specific locations of the tendon. Tendon repair injury includes three overlapping stages of inflammation, proliferation and remodelling . During All the tendons in the body can be injured, among which the tendons that are used more often and perform more mechanical loading are injured more frequently. Triceps tendinopathy occurs frequently in throwing athletes and results from the insertion of the tendon into the olecranon. Patellar injuries, as well as Achilles injuries, are common in athletes involved in repetitive jumping, kicking, and running. Wrist extensor tendinopathy is associated with eccentric loading of the forearm muscle in throwing movements. Overload and repetitive improper employment of the musculoskeletal system and the sequential unsolved chronic inflammation, which impedes the proliferation of cells and remodelling of the tissue, together make the recovery of tendinopathy complicated .Factors, including acute tearing, oxidative damage, and accumulation of microtears, would cause structural destruction of the tendon matrix. The matrix synthesized after injury acts as a template for sequential matrix remodelling. As a result, fibrotic scars with different cell and ECM compositions compared with normal tendon tissue appear. The poor mechanical properties of the scar affect the elongation and energy storage of the tendon .The current treatments for tendon injury mainly include conservative therapy and surgery followed by allogenic transplantation. In the conservative strategies, eccentric exercise therapy and other interventions, including extracorporeal shock wave, ultrasound, and low-intensity lase treatment, are utilized  Figure .A scientifically developed exercise protocol was demonstrated to be effective in Achilles tendon rehabilitation by incrementally increasing the rate and magnitude of tendon loading. To propose guidelines on how to improve the function of tendons, 8 healthy young adults performed a series of rehabilitation exercise according to the plan. They researchers found that Achilles tendon loading increased when a set of isolated ankle movements or multijoint movements was performed . The resExtracorporeal shock wave therapy (ESWT) is a physiotherapeutic intervention utilized in tendinopathy treatment. The superiority of the effectiveness of ESWT compared with conservative treatment, such as inflammatory drugs, exercise programs alone, or the use of knee traps in patellar tendinopathy treatment, has been demonstrated . RecentlLow-level laser therapy (LLLT) has also attracted the attention of scientists in tendon injury repair. In a rat Achilles tendon injury model achieved by surgical hemi-transection of the Achilles tendon, different dosages of laser treatment were combined with running exercise for 3 weeks for injury repair. The results showed that rats receiving laser irradiation had less load-relaxation than control rats . During In recent decades, burgeoning evidence in animal models and human clinical trials has demonstrated that stem cells derived from different tissues can be utilized in tissue injury repair. The hypocellularity and hypovascularity in the mature tendons makes their self-repair capability very limited. The ECM-enriched tissue environment gives rise to fibrosis and scar tissue with inferior mechanical properties. All these characteristics make the identification and application of TDSCs in the repair of tendon injury urgent and attractive.Multipotent mesenchymal stem cells (MSCs) are commonly used in tissue regeneration given the abundance of cell resources. The application of MSCs in tendon repair has been tested, and the cells serve to increase early tendon strength and decrease overall healing time . TDSCs aCollectively, we discuss the physiology of tendons and the pathology of tendinopathy. Although the basic anatomical structure of the tendon is well understood, a significant amount of mechanistic information remains unknown. With the exception of tendon cells and the ECM, the composition and dynamics of other cell types, including endothelial cells and pericytes of blood vessels, neurons, and immune cells, in healthy or injured tendon tissue must be further elucidated by newly developed methods, such as intravital confocal microscopy. Acute exercise may lead to transient alterations in collagen synthesis and the mechanical properties of tendons. Acute overloading increases the risk of tendon rupture, whereas proper static stretching prepares the tendon for better mechanical loading performance. The reshaping of tendons based on long-term frequent exercise increases their adaptability to mechanical load stimulation, reduces the probability for injury, and improves better locomotion economy. In investigations on effects of exercise on tendons, the modes and intensity of exercise and the gender of the subjects are all should not be ignored regardless of whether the subjects are athletic or sedentary. Distinct exercise interventions based on the characteristics of the population are recommended for tendon rupture prevention and tendinopathy treatment. Exercise, especially eccentric exercise, is regarded as effective in restoring tendon function. More exercise mode options with logical design are expected. Exercise rehabilitation combined with various technologies, including ESWT, LLLT, tissue engineering, and TDSTs, represents a powerful independent approach or follow-up treatment after surgery.


Most motion planners generate trajectories as low-level control inputs, such as joint torque or interpolation of joint angles, which cannot be deployed directly in most industrial robot control systems. Some industrial robot systems provide interfaces to execute planned trajectories by an additional control loop with low-level control inputs. However, there is a geometric and temporal deviation between the executed and the planned motions due to the inaccurate estimation of the inaccessible robot dynamic behavior and controller parameters in the planning phase. This deviation can lead to collisions or dangerous situations, especially in heavy-duty industrial robot applications where high-speed and long-distance motions are widely used. When deploying the planned robot motion, the actual robot motion needs to be iteratively checked and adjusted to avoid collisions caused by the deviation between the planned and the executed motions. This process takes a lot of time and engineering effort. Therefore, the state-of-the-art methods no longer meet the needs of today’s agile manufacturing for robotic systems that should rapidly plan and deploy new robot motions for different tasks. We present a data-driven motion planning approach using a neural network structure to simultaneously learn high-level motion commands and robot dynamics from acquired realistic collision-free trajectories. The trained neural network can generate trajectory in the form of high-level commands, such as Point-to-Point and Linear motion commands, which can be executed directly by the robot control system. The result carried out in various experimental scenarios has shown that the geometric and temporal deviation between the executed and the planned motions by the proposed approach has been significantly reduced, even if without access to the “black box” parameters of the robot. Furthermore, the proposed approach can generate new collision-free trajectories up to 10 times faster than benchmark motion planners. In the offline planning phase, the trained neural network structure can generate collision-free trajectory as high-level motion commands, such as long-distance, high-speed Point-to-Point and Linear motion. These motion commands can be converted as manufacture-specifical robot language and directly imported into any robot control system . Because(2) The neural network learns realistic robot dynamics and motion interpolation from actual robot motion execution and uses them to accurately calculate the actual robot motions executed by the robot control system. For example, at each search step in the offline planning phase, the proposed approach use learned robot dynamic behavior to interpolate the robot motion and check whether the robot collides with other obstacles. In the proposed approach, the planned robot motion deviates from the realistic robot motion slightly. Therefore, it can be guaranteed that as long as the robot motion planned offline is collision-free, the robot will also not collide with obstacles as executed by the robot control system. This feature addresses the problem described in Most state-of-the-art collision-free motion planning methods focus on improving the performance of motion planning algorithms in the offline phase, such as computation time and success rate of collision avoidance. Today’s agile manufacturing systems require not only automatic robot motion planning but also rapid deployment of robot motions. Therefore, more research is still needed to bridge the gap between offline planning and the rapid deployment of robot motions for reliable online execution. Therefore, we proposed a data-driven motion planning approach that considers deploying and deploying the planned motion already in the offline planning phase. The proposed approach overcomes the problems mentioned above:The proposed approach is evaluated on two different industrial applications. The results indicate that the proposed approach can generate high-level motion commands directly deployed to real robot systems with a reduced temporal and spatial deviation between executed and planned motions.via points, equally spaced in time. The control inputs at every via point are considered as optimization variables, such as angle, velocity and acceleration of robot joints. The collision and the kinematics limits of robot joints are modeled as constraint items. The length, smoothness and execution time of trajectory are described as cost functions that should be minimized. via points to find valid solutions in complex and high-dimensional solution spaces.Optimization-based motion planning originated in the field of optimal control and has been used for decades in robotics. The trajectories are usually discretized into In the past several decades, the sampling-based heuristic search method has been widely adopted in the field of motion planning in high-dimensional configuration space with great success. Rapidly-exploring Random Trees (RRT) , optimalMultiple informed methods explore regions with a higher probability of generating feasible paths to improve the searching efficiency in the configuration space of robots. Data-driven techniques such as supervised learning, imitation learning and deep reinforcement learning techniques are quickly becoming useful tools to improve the efficiency of informed searching in high-dimensional configuration space.ribution , learn tIn addition to the learning of sampling strategy , learn tThe aforementioned learning-based methods generate low-level control inputs, such as position, the velocity of robot joints. These low-level control inputs should be post-processed to be deployed to real robot systems.The works mentioned above focus on improving and verifying the performance of collision-free motion planning algorithms in simulation environments rather than on how to deploy the planned robot motion in real robot systems. Again, the methods mentioned above use additional control loops to control the robot in real time to track the motion planned and interpolated in the offline phase. In contrast, the proposed approach does not require an additional control loop to track the planned motion since the proposed approach generates collision-free motions as high-level commands, which can be executed directly by robot control systems with a small deviation from the planned motion of less than .5% on average.This section describes the notations used in this work and formally defines the problem we consider.Let In contrast to the approaches described in , this woThis work considers static obstacles and dynamic obstacles whose motions are known. For example, for the multi-robot system, motions of all robots are usually planned one by one. When planning the motion of a given robot, the motions of the other robots are known. Let via point in the trajectory.In this work, a trajectory For complex environments and robot systems with high DOFs (degrees of freedom), the solution space of the motion planning problem is highly dimensional. Even if the solution space is represented implicitly using the sampling-based technique, it cannot be searched efficiently. In this work, the proposed approach focuses on learning the feasible solution space of motion planning problems from previous experience to improve search efficiency. In other words, the proposed approach first learns to perceive the environment surrounding the robot. Then the robot dynamics are learned to preciously simulate realistic robot motion. At last, the proposed approach learns which optimal high-level commands can move the robot toward to goal region with realistic dynamics in the perceived environment model at each search step.Since learning the complete solution space is very difficult and does not scale well to other problems, our approach begins with learning the local feasible solution space The locally feasible solution space consists of all feasible control policies that only consider the local system state   with fivFor the SCARA robot handling application, we randomly generate 1000 environments. Each environment contains a varying number of static cylindrical or cubic obstacles and a SCARA robot seen as a dynamic obstacle. Then we recorded a frame of the dynamic environment every 50 milliseconds. The environment in each frame is voxelized and fed into VAE to produce an environment embedding. We take ten frames of environment embedding following the current timestep as a data tuple for training the RNN encoder.For the machine tending application, 500 static environments are generated. In each environment, we select one of five different machine tools and place it randomly within the reachable workspace of the robot.A high-level motion command consists of the motion type and motion parameters. In this work we consider Point-to-Point (PTP) and Linear motion of the SCARA robot and the 6-axis robot. The motion parameters of both motion commands are the motion speed The High-level Control Policy Network contains two branches: one generates motion type (Motion Type Prediction Branch) and the other generates motion parameters (Motion Parameter Prediction Branch). These two branches take the same inputs: the goal state The Motion Type Prediction Branches for the SCARA robot handling and the machine tending applications consist of 10 and 12 fully connected hidden layers followed by a Softmax layer with a two-dimensional output, respectively. The Motion Parameter Prediction Branch is a 12-layer forward neural network for the SCARA robot handling application and a 15-layer forward neural network for the machine tending application, respectively. Unlike the network structure that generates samples at every search step in , we do nIn the environments generated in An improved RRT* approach  is used Both branches of the proposed network are trained in a supervised fashion. The loss of the first branch The loss of the second branch ptimizer  with iniHigh-Level Controlled Robot Dynamics Network has two branches, the Interpolation State Prediction Branch and Execution Time Prediction Branch, to predict the interpolation states and execution time of realistic robot motion.The Interpolation State Prediction Branches consist of 12 and 14 fully connected hidden layers for the SCARA robot handling and the machine tending applications, respectively. The Execution Time Prediction Branch consists of 10 and 11 fully connected hidden layers for the SCARA robot handling and machine tending applications, respectively. The Interpolation State Prediction Branch takes the current state The VRC Modul in Visual Components executes ten thousand motion commands of the SCARA robot and fifteen thousand motion commands of the 6-axis heavy duty robot. The execution time and the interpolation states of executed motion commands are recorded as the dataset.The first and second branches are trained by using standard L2 loss function For each application, this section evaluates the proposed approach in 100 new environments, which are not used in the training phase. In each environment, 20 pairs of start and goal were randomly generated. The performance of the RRT, the improved RRT* and the proposed approach was analyzed in terms of validity, the execution time of trajectory and computation time.For the SCARA handling application, the robot motions planned offline by different planners are only verified in Visual Components. In all scenarios of SCARA handling application, only 5.2% of the trajectories generated by our approach are invalid because the trained High-Level Controlled Robot Dynamics Network can predicate the robot motion more accurately in the planning phase. For the machine tending application, we deployed the robot motions planned offline on the real robot in different ways. The proposed approach generates high-level motion commands that can be directly uploaded to the robot control system see . BecauseIn The control inputs and actual values are recorded during the execution of robot motion controlled by the additional control loop . The addWe compared the execution times of the trajectories generated by the proposed approach, RRT and improved RRT* .via points while expanding the search tree, the execution time of the trajectories generated by it is essentially the same as the proposed approach. However, the optimization increases computation time, as seen in section 6.3. Since all scenarios of the machine tending application are simple, the execution time of the motion planned by each approach varies slightly.It is necessary to note that the trajectory’s execution time varies significantly due to different distances between the start and goal states. To compare the performance of different approaches more reasonably, we classify the planning tasks into three categories according to the distance between the start and goal states: 1. near distance , 2. middle distance  and 3. far distance (bigger as 60% of the robot’s range). It can be seen that the average execution time of the trajectories generated by the proposed approach is twenty percent faster than RRT in the SCARA robot handling application. Since improved RRT* optimizes the number of via points (a points  in the nWe compared the computation time of the proposed approach with the benchmark approach in scenarios with different complexities. As the environment becomes more complex, the advantage of our approach in terms of computation time becomes obvious . In partWe have proposed a novel deep neural network that generates collision-free trajectories as high-level motion commands. The generated trajectory can be directly deployed in the robot control system without post-processing. Furthermore, the experiment results show that the proposed approach outperforms the benchmark approaches in terms of validity, execution time of planned motion and computation time. One future direction is to extend our data collection procedure and generalize our network to handle more high-level commands for robots with higher degrees of freedom.


Antimicrobial stewardship (AMS) initiatives promote the responsible use of antimicrobials in healthcare settings as a key measure to curb the global threat of antimicrobial resistance (AMR). Defining the core elements of AMS is essential for developing and evaluating comprehensive AMS programmes. This project used co-creation and Delphi consensus procedures to adapt and extend the existing published international AMS checklist. The overall objective was to arrive at a contextualised checklist of core AMS elements and key behaviours for use within healthcare settings in Sub-Saharan Africa, as well as to implement the checklist in health institutions in four African countries. The AMS checklist tool was developed using a modified Delphi approach to achieve local expert consensus on the items to be included on the checklist. Fourteen healthcare/public health professionals from Tanzania, Zambia, Uganda, Ghana and the UK were invited to review, score and comment on items from a published global AMS checklist. Following their feedback, 8 items were rephrased, and 25 new items were added to the checklist. The final AMS checklist tool was deployed across 19 healthcare sites and used to assess AMS programmes before and after an AMS intervention in 14 of the 19 sites. The final tool comprised 54 items. Across the 14 sites, the completed checklists consistently showed improvements for all the AMS components following the intervention. The greatest improvements observed were the presence of formal multidisciplinary AMS structures (79%) and the execution of a point-prevalence survey (72%). The elements with the least improvement were access to laboratory/imaging services (7%) and the presence of adequate financial support for AMS (14%). In addition to capturing the quantitative and qualitative changes associated with the AMS intervention, project evaluation suggested that administering the AMS checklist made unique contributions to ongoing AMS activities. Furthermore, 29 additional AMS activities were reported as a direct result of the prompting checklist questions. Contextualised, co-created AMS tools are necessary for managing antimicrobial use across healthcare settings and increasing local AMS ownership and commitment. This study led to the development of a new AMS checklist, which proved successful in capturing AMS improvements in Tanzania, Zambia, Uganda, and Ghana. The tool also made unique contributions to furthering local AMS efforts. This study extends the existing AMS materials for low- and middle-income countries and provides empirical evidence for successful use in practice. Antimicrobial stewardship (AMS) has been recommended as a key strategy for optimising the use of antimicrobials and reducing the global threat of antimicrobial resistance (AMR) . AMS proIn 2019, Pulcini et al.  develope(1)Our focus on Sub-Saharan Africa  offers a further local adaptation of the materials.(2)Our unique methodological approach uses elements of co-creation through the strong involvement of local hospital representatives during a Delphi consensus procedure.(3)We extended the number of checklist items to capture the more nuanced differences in the AMS elements. Additionally, we incorporate open-ended questions within the AMS checklist to allow for more reporting flexibility.(4)We provide an initial evaluation of the checklist’s effectiveness by using it to measure the outcomes of an AMS intervention programme.This study takes another step toward increasing the suitability and acceptance of standardised AMS tools in LMIC settings in several different ways:The checklist was developed as part of the ‘Commonwealth Partnerships for Antimicrobial Stewardship’ (CwPAMS) programme, funded by UK aid Fleming Fund and jointly managed through the Tropical Health and Education Trust (THET) and the Commonwealth Pharmacists Association (CPA) ,14,15,16Pulcini et al.’s  global AFourteen healthcare representatives from the CwPAMS partnerships were invited from April 2019 to participate in the consensus process following the project inception training sessions with all the UK and African partnership leads involved in the CwPAMS project. The 14 representatives included eight CwPAMS health partnership leads, including pharmacists, public health specialists, and microbiologists from the UK and the four African countries, four healthcare professionals working in hospitals, national pharmacy and/or public health associations based in Ghana, and two healthcare professionals based in Uganda . The consensus process is summarised in Following a pilot with two partnership sites, the final AMS checklist was deployed as an online form in April 2019 across 19 sites in Sub-Saharan Africa, which included 14 CwPAMS project sites  and 5 regional referral centres in Uganda. Each hospital site provided information on the current state of their AMS activities based on the questions on the checklist. For the CwPAMS sites, the checklist was jointly completed through discussions between the respective UK and African lead partners. To facilitate this, a PDF or spreadsheet version of the checklist was made available. For the additional sites in Uganda, the pharmacists at each institution completed the checklist with support from independent colleagues with AMS expertise to discuss and complete the form with relevant individuals. The lead African and UK partners for each CwPAMS site completed the checklist again to provide updated information on the state of their AMS activities post-CwPAMS intervention. The respondents were also asked to include information on the members of their multidisciplinary AMS teams pre- and post-CwPAMS intervention.Across the 19 study sites, the hospitals averaged 536 inpatient beds, with the lowest number of hospital beds reported as 100 and the highest as 2000 inpatient beds (both in Ghana). Eight out of nineteen hospitals (42%) were tertiary hospitals, five (26%) were secondary hospitals, and five (26%) were regional referral hospitals. Only one site (5%) was a primary care institution. Twelve out of nineteen sites (63%) were teaching hospitals. The names of all participating hospital sites can be found in The final AMS checklist contained 54 items across eight main sections . These iThe new items added: 24 new items were added to Pulicini et al.’s  originalThe items removed: Eight items were removed from the original checklist. Almost all of these items were part of the section on other actions aiming at responsible antimicrobial use. Item removal was determined by their relevance to Sub-Saharan healthcare settings and the limited availability of resources. An example of a deleted item includes: ‘Does your hospital support the antimicrobial stewardship activities/strategy with adequate information technology services?’The items rephrased: Eight original checklist items were rephrased to increase understanding and better reflect the local healthcare contexts. For example, the original question ‘Are clinicians, other than those part of the antimicrobial stewardship team  involved in the antimicrobial stewardship committee?’ was extended. The new question was phrased:  to specifically include a focus on nurses and pharmacists.Improvements were reported across all core indicators of the AMS checklist. The largest improvements pertained to the core AMS checklist element on the multidisciplinary organisational structures responsible for AMS. Before the AMS intervention, only three healthcare sites reported having such a formal AMS structure. After the intervention, all 14 sites gave positive answers to this question, indicating a 79% increase. Other notable improvements were observed regarding the conduct of point-prevalence surveys for antimicrobial use and the availability of multidisciplinary AMS teams to support the implementation of the AMS strategy.Smaller improvements were reported for the elements of access to laboratory or imaging services (7%) and the existence of a dedicated, sustainable, and sufficient AMS budget (14%), with the overall number of healthcare sites remaining low, even after the intervention. Lesser improvements were also observed for some items that ranked high prior to the intervention . This may be explained by a ceiling effect, whereby little further improvement could be obtained on those comparatively well-established items.The checklist also captured the new guideline development that resulted locally as a result of the CwPAMS intervention: Eight projects reported developing new documents  focused on either AMS or antibiotic prescribing as a result of CwPAMS. Four of these projects reported developing two or more new AMS documents. Three projects reported that they had revised or updated documents  focused on either AMS or antibiotic prescribing as a result of CwPAMS. Five projects reported that they had developed new documents  focused on IPC as a result of CwPAMS. Three of these projects developed two or more new IPC documents. Three projects reported that they had revised or updated documents  focused on IPC as a result of CwPAMS.The AMS checklist reports indicated that 79% (11 out of 14) of the projects had increased awareness of the WHO’s AWaRE antibiotic categories among healthcare staff during the CwPAMS project. The means used to introduce the principles of WHO AWaRe included AMS train-the-trainer workshops; specific hospital meetings on the principles; AMS workshops; and Medicines and Therapeutic Committee (MTC) meetings.The respondents were asked to report any other actions related to AMS that were ongoing within their organisation. The following individual responses were received: Accreditation and implementation of the AMS training modules as CPD for healthcare workers; implementation of training, including those developed in the hospital and national training, drug audits and surveillance; implementation of the antibiogram; plans to engage hospital management and carry out the Global Point-Prevalence Survey (GPPS). Furthermore, also included was the formation of the Medicines Therapeutic Committee (MTC); the establishment of a community of practices; plans to resume implementation of the AMS strategy and work plan that has been on hold since the pandemic; and the development of guidelines and the publication of AMS manuscripts.The AMS checklist required the participants to select a maximum of six specified barriers to effective stewardship in their organisation. This also included an option for the participants to specify their own barrier if it was not listed. In the post-CwPAMS checklist, 10 sites provided further information in response to the open-ended questions, which indicated that the checklist had prompted them to take additional actions that were not part of the original AMS intervention plan of the CwPAMS project. The participants were invited to report up to five additional activities that they had engaged in based on the checklist. Across all sites, 29 additional AMS activities were listed. The examples included: the development of empirical guidelines; GPPS completion; GPPS training; the establishment of a multidisciplinary AMS team; a collection of baseline data on antimicrobial use; and the conduct of an AWaRe analysis of the antibiotic prescribing patterns at their hospital. The complete list is provided in Box 1Cascading training to other health care providers in the hospital.Institution of a Hospital Antimicrobial Stewardship Team.Development of an adult empiric guideline based on common indications seen at the hospital. Annual guideline review.Engaging with Community Durbars.Global Point Prevalence Survey (GPPS).Antibiotic Guidelines.Radio Programmes November.AMS Training Manual.SurveillanceAuditing.Dissemination of report.GPPS Trainingmade a film focused on IPC and attendant behaviour.Increase awareness of AMS.Increase awareness of IPCIt enabled us to set out the goals of our partnership clearly.To establish a multidisciplinary AMS teamTo gather base line data on antimicrobial useTo conduct PPS training and studiesConduct an AWARe analysis of antibiotic prescribing pattern at the hospital.Conduct regular AMS training of the staff using the Scottish Triad approachEstablishing the MTC/Plans to reconstitute alcohol hand rub.Global Point Prevalence StudyUse of MicroGuide app to promote guidelinesLarger cohort of HPs trained.Strengthening Hospital AMS Committee. Ensuring clarity on roles and responsibilities of AMS committee members.Revising AMS committee membership, Developing a clear and timely action plan.Contextualised co-created AMS tools are necessary for managing the use of antimicrobials across different healthcare settings. Our work set out to develop and implement a new checklist of core AMS elements with a regional focus on Sub-Saharan Africa.A modified Delphi process that included participants involved in partnerships of UK institutions with hospitals in Tanzania, Zambia, Uganda, and Ghana was used to ensure that the final AMS checklist was relevant and understandable for local healthcare staff in Sub-Saharan Africa. The final tool was cognizant of the unique settings in which they operate and the differences in practice from high-income settings. Compared to the original global checklist by Pulcini et al. , the AMSThe consensus process targeted the lower resource settings of LMICs in Sub-Saharan Africa by considering context-specific information and the involvement of experts from a broad range of specialities. Our work extends ongoing attempts to develop baseline assessment tools in Africa. This includes a Kenyan study in 2020, investigating the AMS policies and structures in 16 Kenyan hospitals while adapting the UK NICE AMS system to the Kenyan healthcare system . AnotherBy involving local healthcare staff in the development of our checklist, we also fostered a sense of ownership and commitment, thus serving as an example of successful co-creation. Compared to the LMIC AMS checklist contained within the WHO Practical Toolkit for healthcare facilities , which cThe initial results obtained from the use of our AMS checklist across 19 sites revealed large variations in the AMS’s capacities and local needs regarding support. Several healthcare sites had available expertise on infection management and stewardship, education and practical training, up-to-date recommendations for infection management, national antimicrobial prescribing guidelines, and continual monitoring and surveillance. Comparatively few sites, however, reported the presence of senior management leadership towards AMS, published AMS protocols, accountability structures, regular reporting and feedback, and routine ward rounds focused on infection and antimicrobial prescribing.The results on the use of the checklist post-CwPAMS programme, including a range of interventions ,28,29,30The findings obtained through our contextualised AMS checklist mirror the published AMS reports in LMICs, which highlight the presence of national antimicrobial prescribing guidelines in the countries where the sites are located ,31,32,33The initial findings from using the checklist across partnership sites reveal that the barriers that mostly existed pre-intervention were still major issues post-intervention. Some of these barriers  could require major institutional changes to be overcome. However, other barriers  highlight opportunities for further AMS intervention and workforce engagement.In addition to identifying local AMS capacities and needs, our new checklist was successful in capturing the post-intervention changes in local programmes.While some of the improvements noted above are the results of a funded AMS intervention that was part of the CwPAMS project, our end-of-project survey noted results that were not attributable to the initial CwPAMS project plans. Indeed, healthcare staff reported that the mere completion of our AMS checklist prompted them to engage in a revision of their AMS activities and led to important changes in their daily practice. Twenty-nine additional AMS activities were listed by the participating healthcare sites as having resulted from completing the checklist. While some of these activities (notably improved recommendations around infection control) may be explained by the global pressures of healthcare-associated infections and, latterly, the COVID-19 pandemic, other activities  were directly related to AMS. Our results thus suggest that the newly developed contextualised AMS checklist has the potential to make a positive impact on the effectiveness of AMS interventions in Sub-Saharan Africa.A key strength of this work was that the study employed a modified Delphi consensus process, which is a standard method of developing checklists or similar tools and has been widely used for designing AMS programmes in hospitals. We engaged local stakeholders, including senior management, frontline healthcare professionals, and public health specialists, in the consensus process, thus increasing elements of co-creation and a subsequent sense of ownership for the materials. This also meant that the checklist modifications were context-specific and relevant to health institutions. The representatives were recruited based on their level of expertise, level of interest, heterogeneity, accessibility, and the intended size of the panel, as recommended by the existing literature ,39. Furt(1)Our narrow focus on Sub-Saharan Africa  allows for further local adaptation of the materials.(2)Our unique methodological approach uses elements of co-creation through the strong involvement of local hospital representatives during a Delphi consensus procedure.(3)We extended the number of checklist items to capture the more nuanced differences in the AMS elements. Additionally, we incorporate open-ended questions within the AMS checklist to allow for more reporting flexibility.(4)We provide an initial evaluation of the checklist’s effectiveness by using it to measure the outcomes of an AMS intervention programme.This study, which commenced prior to the publication of the WHO AMS toolkit for LMICs, provides an additional step toward increasing the suitability and acceptance of standardised AMS tools in LMIC settings in several different ways:The Delphi process was limited by not having an opportunity for face-to-face discussions about specific items. The small number of study sites could be considered a limitation; however, the similarity of the results across multiple countries suggests the results are transferable and that the approach can be implemented within other countries.Our study has tested a successful methodology for making regional adaptations to global AMS tools and demonstrated the effectiveness of a contextualised AMS checklist in the challenging healthcare setting of Sub-Saharan Africa. This effectiveness was shown to go beyond the mere capture of the AMS changes following an intervention. Indeed, our results suggested that completing the checklist prompted local healthcare providers to review their initiatives and increase their AMS efforts. Our AMS checklist is widely available for use in health partnerships and institutions and extends the existing tools, such as Pulcini et al.’s  global A


The Mediterranean diet has significant beneficial health effects and wheat is a major component of the Mediterranean diet, mainly in the form of bread and pasta. Modern wheat generally refers to varieties that were developed after the introduction of dwarfing genes in the 1950s, while old varieties are considered those developed before that time. Research findings on Italian wheat varieties showed that the total polyphenol content in both old and modern durum and soft wheat varieties are similar; but the old varieties have a higher number of polyphenols and of isomer forms. In particular, the durum wheat Senatore Cappelli genotype shows a very high variety of polyphenolic components. Recent studies have demonstrated healthy cardiovascular effects  as well as a marked reduction in gastrointestinal and extra-intestinal symptoms in non-celiac gluten sensitivity subjects with the consumption of pasta obtained by old durum wheat Senatore Cappelli variety, even though this type of wheat contains high amounts of gluten. In conclusion, old wheat Italian varieties, and in particular the Senatore Cappelli genotype, are characterized by multiple nutraceutical specificities that could suggest their use for health-promoting purposes. Additional research is needed to confirm these findings, focusing attention also on the effect of different environments and years. The Mediterranean diet has significant beneficial health effects. Many studies showed inverse associations with overall mortality  and reduIt is well known that wheat is a major component of the Mediterranean diet, mainly in the form of bread, pasta and couscous ,7. AccorThe history of wheat in the human diet goes back to the beginning of agriculture. Carbonized grains dating to at least as early as 6750 B.C. have been found in Iraq and in other places of the Middle East: this is probably its area of origin. Subsequently, wheat spread throughout eastern and western Mediterranean areas and all over Europe no later than the Stone Age. Nowadays, thousands of wheat varieties are grown around the world. Modern wheat generally refers to varieties that were developed after the introduction of dwarfing genes in the 1950s, while old varieties are considered those developed before that time. Recent decades have seen a relevant increase in the prevalence of two diseases linked to wheat: the celiac gluten-induced enteropathy and non-celiac gluten sensitivity ,9. TheseOne of the most important dietary components of the traditional Mediterranean diet is certainly pasta, derived from durum wheat (Triticum turgidum L. subsp. durum). In recent decades, the commercial use of durum wheat has been chosen mostly on the basis of the type and amount of proteins of the grain, which influences the technological features of the semolina and subsequently of the pasta-making process. Since the 1950s, the food industry has increased its use of wheat proteins . Gluten Multiple genetic research projects on wheat were made to improve both yield and pasta-making technology, with a narrowing of the genetic variability ,12. At tTriticum aestivum L.) varieties and evaluated their antioxidant activity. The most effective scavenging effect was observed for the old variety Verna, while the modern variety Palesio and the old variety Inallettabile showed the lowest ones; the other old wheat varieties demonstrated intermediate antioxidant capacity [Interesting data were obtained when the evaluation of the grain functional components of old and modern Italian durum wheat cultivars was conducted. Leoncini et al. evaluated the pattern of grain phenolic extracts of one modern and five old common Italian wheat . Two pinosylvins were found in the free and bound phenolic fractions of Senatore Cappelli wheat. Pinosylvins are stilbenes and these phenolic compounds are observed in a wide number of plant extracts. They protect the plant against viruses, bacteria, ultraviolet exposure and various diseases. Resveratrol is the most well-studied stilbene with marked anticancer, anti-inflammatory and anti-oxidant activities [The study of the free fractions evidenced four unique compounds detected only in the old genotype Senatore Cappelli (vanillin and pinosylvin) and Kamuttivities .Lignans are a group of phytoestrogen substances characterized by antitumor ,20, antiThe varied phytochemical pattern of old wheat genotypes is characterized by a significantly higher number of phenolic and flavonoid total compounds and total isomers, in free as well as in bound fractions. The relevant genetic diversity of old wheat varieties suggests the potential advantages of these types of wheat with regard to functional properties due to the various and well-known favorable pharmacological effects of polyphenols. . In thisMultiple epidemiological observations show that celiac disease has increased 2- to 4-fold over the last 50 years ,26. Non-Aggressive processing of wheat is mostly made up of severe fractionation of grains with the possible development of a gluten-resistant fraction reaching the colon with interaction with microbiota. These aspects may trigger low-grade gut inflammation. Moreover, the marked flour refinement may favor the increase in reactive glutens due to the loss of endopeptidase activity, which is mostly found in the bran rather the endosperm ,31.Recently, various studies have demonstrated healthy cardiovascular and gastrointestinal effects with the consumption of pasta obtained by old durum wheat Senatore Cappelli cultivar. The Senatore Cappelli variety was obtained in 1930 by the breeder Strampelli, through the selection of Jennah Khetifa. This wheat variety was widespread in central and southern Italy in the first half of the last century and widely used by Strampelli in genetic research programs for the development of new varieties with improved lodging tolerance and suitability for pasta making. The durum wheat old variety Senatore Cappelli is biologically characterized by a significantly higher number of both free and bound polyphenol compounds and isomers, including unique compounds in comparison to modern varieties .Ghiselli et al. studied the effect of pasta consumption obtained by the Senatore Cappelli durum wheat variety on cardiovascular parameters related to the atherogenetic process . In thisAnother recent clinical study evaluated the effects of the consumption of Senatore Cappelli wheat pasta in 42 non-celiac gluten sensitivity (NCGS) patients diagnosed according to the Salerno criteria and adherence to a gluten-free diet for at least 12 weeks from screening.NGCS patients do not have celiac disease, but their gastroenterological and extra-gastroenterological symptoms improve following a gluten-free diet (GFD). The interesting issue is that it is not yet clear if gluten or other wheat components are responsible for these symptoms. Ianiro et al.  studied The Senatore Cappelli durum wheat variety has specific biological properties that differ from standard modern wheat pasta, even though the total amount of polyphenols observed in old and modern wheat varieties is similar. The higher variety of polyphenols of Sanatore Cappelli wheat could be associated with the positive clinical effects observed in the study of Ianiro et al. . This isMoreover, the properties of Senatore Cappelli variety have been shown to be less influenced by environmental conditions than other varieties and this may affect gliadin content and its consequent immunogenic potential . A cruciIn conclusion, old wheat Italian varieties, specifically the Senatore Cappelli variety, are characterized by multiple nutraceutical differences as compared to modern varieties. These differences are mostly based on a higher number and variety of polyphenol compounds and isomer forms: this finding could suggest their use for health-promoting purposes .Favorable cardiovascular and gastroenterological effects have been demonstrated with the consumption of pasta made with the Senatore Cappelli old durum wheat variety. These results are possibly associated with the presence of multiple phytochemical specificities of this genetic type of wheat. Additional research is needed to confirm the potential health advantage of the consumption of old Italian wheat varieties, and in particular of the Senatore Cappelli old durum wheat variety, focusing attention also on the effect of different environments and years.