The treatment of patients with inflammatory bowel diseases (IBDs) has undergone many changes recently. Novel therapeutic agents, medications, and endoscopic techniques have become available, however, the goal of long-term medical therapy remains the same—to achieve and maintain control over the inflammation and to induce remission against symptomatic or even asymptomatic disease activity.The game changers in IBD nowadays center around how can we reach these goals in everyday clinical practice and how we can succeed in creating an effective tailored therapy for patients.A combination of medical therapies can be an option for patients who suffer from the most severe and complicated phenotypes of IBD. Combinative or concomitant use of biological therapies can fill gaps in these cases, but it is not an instant solution for everyone. Many factors can influence this efficacy bidirectionally, e.g., the nutritional state, body composition, and body mass index. It is important to know the disease course, the risk factors of progression, and the development of complications to achieve an optimal and effective therapy for IBD patients.Shehab et al. investigated this question in a cross-sectional study, analyzing how biological therapies impact the body mass index of IBD patients. This study was performed in an IBD tertiary care center, and it searched for associations between BMI, type of IBD, and the type of medications taken among patients with IBD of varying weight categories. Patients received tumor necrosis factor antagonist combination and anti-integrin therapies. The primary outcome was the association between BMI and medication used in IBD. Many patients with IBD are either obese or overweight. Patients with IBD who are on anti-TNF combination therapy or vedolizumab monotherapy are more likely to be obese and overweight. In addition, patients with ileocolonic CD are more likely to be obese or overweight. These pieces of information may be important in the selection of biological therapies.The next interesting way forward in tailored therapy is how we can combine the therapies and what kind of biochemical markers or activity indexes can help to predict the disease course of IBD or even the disease activity before the appearance of clinical symptoms.Pan et al. investigated the role of seven peripheral marker ratios in blood in the diagnosis and the prediction of disease activity. Their data suggest the neutrophil-to-prealbumin ratio (NPAR) as a putative biomarker for diagnosing and predicting disease activity in patients with IBD.Song et al. analyzed the interleukin-26 (IL-26) expression in IBD and its immunoregulatory effects on macrophages. Compared with healthy controls, in IBD patients, IL-26 levels were elevated in the inflamed intestinal mucosa and reduced in the peripheral blood. The transcriptional changes in macrophages exposed to IL-26 suggest that IL-26 may amplify the aberrant immune response in IBD by activating macrophages.The disease course can be extremely different from patient to patient, and some of the patients can be at higher risk of special comorbidities, e.g., systemic inflammatory conditions.Domokos et al. investigated the specific relationship between two multifactorial diseases: inflammatory bowel disease and periodontitis. Patients with periodontitis were more susceptible to IBD, and periodontitis was significantly associated with the risk of subsequent UC but not with subsequent CD. So patients with IBD have a higher chance of developing periodontitis and are a high-risk population in dentistry. Multidisciplinary team management is very important in the complex therapy of patients with IBD. The authors emphasize the importance of prevention and that both dentists and gastroenterologists should be aware of this relationship.A systematic review and meta-analysis written by Gutiérrez et al., the ENEIDA-registry was used to compare cohorts of IBD patients who were born outside Spain with a cohort of native patients. The main ethnic groups of immigrant IBD patients in Spain are Caucasian, Latin American, and Arab. Immigrant IBD patients in Spain are younger and have more extraintestinal manifestations than native-born patients. Accordingly, the use of biologics is more frequent among immigrants. Compared with native-born patients, first-generation-immigrant IBD patients in Spain were younger at disease onset and showed an increased risk of having extraintestinal manifestations and using biologics. This study suggests a featured phenotype of immigrant IBD patients in Spain and constitutes a new landmark in the epidemiological characterization of immigrant IBD populations in southern Europe.Migration is also an important question in the wider aspects of patient management regarding the change of the disease phenotype and course. In a prospective, observational, multicenter study by Wang et al., the authors aimed to investigate the risk of liver injury in patients with IBD and those with non-IBD diseases treated with methotrexate (MTX). Patients with IBD receiving methotrexate are at higher risk of liver injury compared with patients with non-IBD diseases. The authors concluded that IBD is associated with a higher risk of MTX-related liver injury. The mechanism of MTX-induced hepatotoxicity might be different in IBD and non-IBD diseases and needs to be verified in future research.Patients with IBD can be at higher risk for liver injuries due to the side effects of medications, even the use of over-the-counter (OTC) drugs, or due to extraintestinal manifestations. In a meta-analysis and systematic review by The editors hope that the readers of the present volume of Game Changers in IBD have found some novel interesting results in the land of study of the mysterious IBD to reach the optimal tailored therapy for patients.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Insights in Cellular Endocrinology: 2022” intends to delineate major advancements and recent developments as well as future challenges and perspectives in the field of Cellular Endocrinology. Recognized experts in the field are providing their insights in seven review articles and one original article. Major advancements are often driven by technological developments, the discovery of new players, the discovery of new functions for already known players and/or the development of new pharmacological tools and drug candidates. The various contributions of the current Research Topic cover all of these aspects.The importance of Cellular Endocrinology is defined by its position at the frontier of fundamental and translational science. Understanding a cellular process and its dysregulation is expected reveal the mechanisms behind endocrine diseases leading eventually to new treatment strategies. The Research Topic on the “Dalle et al. gives an overview of the cellular processes involved in beta-cell death and the investigation of pharmacological molecules protecting beta-cells against dysfunction and apoptotic death. The review discusses also the challenges related to the translation of preclinical data into clinical trials including pharmacokinetic properties, toxicity, efficacy and specificity and selectivity in a physiological system.The first review article is related to metabolic diseases and focuses on the importance of the maintenance of the pancreatic insulin-producing beta-cell mass for the development of innovative therapies for diabetes. This comprehensive review by Nakagawa and Hosoi provides an update on the well-known anorexigenic adipokine leptin by pointing out emerging research directions of this hormone. The story of leptin is a nice example on how important it is to understand the cellular basis of hormone action to understand physiological functions and elaborate therapeutic strategies.The review article by Indeed, most obese people exhibit hyperleptinemia and are resistant to the anorexic effect of leptin, thus limiting the utility of leptin as an anti-obesity drug. As discussed by the authors, the recovery of leptin sensitivity or the bypass of leptin signaling are two main strategies of current research efforts.Farrag et al. explores another adipokine, asprosin, discovered recently, in 2016, as a glucose sensor with central and peripheral metabolic effects. Asprosin, a member of the caudamin hormone subclass, induces hepatic glucose production and influences appetite behavior via the olfactory receptor 4M1 (OR4M1), a member of the G protein-coupled receptor (GPCR) super-family. As described in this review, a number of clinical trials investigated the correlation of circulating asprosin levels with obesity- and diabetes-related diseases and gynecologic disorders. The authors point out to the potential of asprosin as a promising candidate for both novel pharmacological treatment strategies and diagnostic tools.The review article by Prasad et al. provides an extensive overview of the guanylyl cyclase C (GC-C)/cGMP system already known since the beginning of the 1970s for its critical role of intestinal fluid and electrolyte homeostasis in regulating microbiome composition and cross-talk with host immunity. In addition to these classical intestinal roles, the authors describe the recently discovered extraintestinal functions of GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes.The review article by Yepmo et al. introduces a new player in metabolic diseases, namely circular RNAs, identified in eukaryotes in 1979 in the cytoplasmic of HeLa cells. Recent studies indicate the importance of the dysregulation of circular RNAs in the onset of metabolic disorders. Prominent examples discussed by the authors are the role of circular RNAs in hepatocellular carcinoma and its role as regulators of hepatic steatosis, the main characteristic of non-alcoholic fatty liver disease.The review article by Hernandez-Bustamante et al., describes the potential interplay between type 2 diabetes mellitus and tuberculosis, which both produce pulmonary anti-inflammatory glucocorticoids. These effects are counteracted by the adrenal hormone dehydroepiandrosterone (DHEA). Patients with tuberculosis have a reduced DHEA/cortisol ratio. Diabetic patients have a tripled risk of contracting tuberculosis and having inadequate response to treatment. The authors suggest that DHEA or its synthetic analogs may be potential co-adjuvant treatment in diabetes-tuberculosis comorbidities.The last contribution, an original article by Camelidae produce single variable domains of heavy chain (VHH) antibodies, also referred to as Nanobodies (Nb). Since their discovery more than 20 years ago VHHs have attracted increasing attention with complementary applications to common antibodies. The review presented by Raynaud et al. focuses on applications of Nb in the GPCR field. Nb become very popular in this field because they recognize small and cryptic regions that are not explored by common antibodies and because of the possibility to express them as intracellular Nb. After having nicely summarized the state-of-the-art of these intracellular Nbs as new tools in the GPCR field, the authors discuss existing methodological hurdles and future therapeutic opportunities for this highly druggable class of membrane receptors.Some animals such as B) receptors. These receptors belong to the GPCR super-family, are widely distributed in the brain and responds to the neurotransmitter GABA. While GABAB receptors are well-known to be involved in synaptic plasticity, memory formation and nociception, Turecek et al. focus their attention in their review on the cellular distribution in the inner ear and auditory pathway of the mammalian brainstem and midbrain, which is much less studied. They advocate for an important function of GABAB receptors in the auditory system and speculate on the possible involvement of the GABAergic system in various pathologies of the auditory system. Finally, they discuss the challenges of specific therapeutic intervention such as auditive loss by targeting receptors with broad expression and multiple functions as the GABAB receptors.The last contribution of this Research Topic elaborates on new function of gamma-aminobutyric acid type B (GABAIn conclusion, we hope that this Research Topic will inspire, inform and provide direction and guidance to junior and senior researchers in the field of cellular endocrinology.RJ: Writing – original draft, Writing – review & editing. OG: Writing – original draft, Writing – review & editing.


This study maps out the effect of AMR originating from poultry production in Senegal and highlights the entry points for interventions from stakeholders’ perspectives. A causal loop diagram (CLD) was developed following a group model building procedure with 20 stakeholders and integrated with network analysis by translating the CLD into an unweighted directed network. Results indicate that with an eigenvector centrality of 1, 0.85, and 0.74, the production cost, on-farm profit, and on-farm productivity, respectively are the most ranked influential variables driving the complexity of AMR in the poultry production system. Two reinforcing feedback loops highlight the dual benefits of improving on-farm productivity and increasing on-farm profit. However, one balancing feedback loop that revolves around the causal link between producers’ investment in qualified human resource personnel to ensure good farm management practices underline the financial implication of producers’ investment decisions. The findings provide precursory groundings for the development of a quantitative SD model, the formulation of intervention scenarios and  Extant studies have indicated that antimicrobial resistance (AMR) of livestock origin is high in low-and middle-income countries (LMICs) like Uganda and Malawi , 2, espeSalmonella in poultry while high bird density increases Salmonella which may require antibiotics to treat infections , AMR is one of the ten global health challenges that leads to treatment failure and causes mortality of infected animals or humans. Livestock production is affected by resistant bacteria, and the impact extends beyond the farm-level to consumers in the value chain , 13. Howex-ante impact assessment of AMR.Although poultry and pigs have the highest levels of antimicrobial resistance (AMR) among livestock in the literature , 4, this2.ex-ante assessment of different livestock systems (System dynamics (SD) modelling has been used extensively for  systems . The app systems . This in systems  and comm systems .2.1.In this study, the integrated qualitative system dynamics (SD) modelling and network analysis was adopted to map out the effect of AMR in the peri-urban poultry production system in Senegal and highlight the key entry points of interventions that simultaneously maximise profit for poultry producers and minimise the economic loss for producers. For the qualitative SD modelling component of the integrated approach, a participatory group model building procedure was used to develop a causal loop diagram (CLD). The first two participatory steps (steps i and ii) in P1) that cause changes in on-farm profit (Profit [farm]), (ii) draw a connecting arrow from P1 to Profit [farm], and (iii) indicate the polarity of the linkage. Supposing an increase (or decrease) in P1 causes Profit [farm] to increase (or decrease), then a positive polarity was specified. If an increase in P1 causes a decrease in Profit [farm] then a negative polarity was specified. The procedure was repeated for the link between secondary influencing variables (S1) and P1, and the link between tertiary influencing variables (T1) and S1. Secondary influencing variables are preceded and succeeded by primary and tertiary influencing variables, respectively. Likewise, presenting antimicrobial use as the focal objective, participants mapped out the CLD for antimicrobial use following the procedure described for on-farm profit. The process allowed stakeholders to interact and debate among themselves about singular causal relationships between two variables at a time. In these iterative deliberations, the stakeholders offered their opinions on a singular causal relationship based on their experiential learning and use the opinions of other stakeholders as sounding boards to reach a consensus. For the participatory steps, participants were grouped into two poultry production systems—layers and broilers to elicit divergent views for the variable mapping. Producers were assigned to their groups based on the production system they are engaged in. The remaining stakeholders were randomly assigned to the layers and broilers group while ensuring that participants from the same institution were not in the same group. This grouping allowed for a more nuanced and comprehensive understanding of the variable interactions within each system. However, the ultimate aim was to converge these views into a consolidated explanation, as reflected in the causal loop diagram. The participatory sessions were facilitated by two researchers (an epidemiologist and a system dynamics modeller). After initial discussions among stakeholders, two output variables  were selected as the focal outputs. Using on-farm profit as the focal objective, participants were asked to (i) identify the primary influencing variables  were estimated using the igraph package in R (Cd) is the number of links (influence) that a variable has. Therefore, a variable that has more links or influences more variables in the CLD has the highest out-degree centrality score. Cd is estimated as in Cd. λ is the constant , i to nodej, and ie is the vector of centrality of e = . Eigenvector centrality (je) was estimated as shown in The developed CLD was translated into an unweighted directed network to support the assessment of the centrality of key variables in the CLD as entry points of intervention pathways. The relationship in the directed network was modelled as a graph consisting of nodes (variables in the CLD) and causal links (influence). A two-mode adjacency matrix was generated from the directed network to facilitate the estimation of centrality measures. The adjacency matrix was constructed by denoting a link from variable  developed from the group model building with stakeholders for the two focal output variables are presented in The primary influencing variables with positive causal links to on-farm profit are on-farm productivity levels, sales volume (eggs and meat), and the price of poultry products (meat and eggs). For the layer and broiler groups, on-farm productivity is determined as the number of eggs produced and kilograms of birds, respectively. On-farm productivity is positively influenced by the adoption of good farm management and husbandry practices (like biosecurity measures and vaccination), the quality of chicks purchased, and the quality of feed given to the birds. A reinforcing feedback loop (R1) was traced along the positive causal links from; on-farm profit to good farm management practice; good farm management practice to on-farm productivity; and on-farm productivity to on-farm profit. Another reinforcing feedback loop (R2) was traced around the moderating effect of the negative causal link between good farm management practice and morbidity (due to the sickness of birds) and the negative causal link between morbidity and on-farm profit. Morbidity and mortality of the birds due to diseases have a negative causal influence on on-farm productivity. Concerning on-farm profit, the morbidity of sick birds has a moderating effect on the negative causal link between on-farm profit and bird mortality via its positive causal link with mortality. Stakeholders averred that an increase in bird mortality causes the number of sick birds to reduce. Thus, a balancing feedback loop (B1) is created.cetris paribus, higher demand translates to higher sales and ultimately higher profit assuming demand is inelastic. Stakeholders posited that the employment of qualified human resource personnel presents two contrasting effects that highlight the potential need for trade-off analysis. On one hand, it leads to two desirable reinforcing feedback loops (R1 and R2). From another point of view, the employment of qualified human resource personnel increases production costs and decreases profit, creating a balancing feedback loop (B2). Thus, the trade-off is highlighted by the moderating effect of the employment of qualified human resources and the positive causal link between the adoption of good farm management practice and on-farm profit, and the negative causal link between the employment of qualified human resources and on-farm profit.Positive causal links with on-farm profit were mapped for these variables: the price of poultry products (meat and eggs), quality of chicks, sales (meat and eggs), and good farm management practices. The positive causal relationship between sales and on-farm profit serves as a mediating causal link between the demand for poultry products. Thus, 3.2.The second focal variable is antimicrobial use (AMU) on the farm. The primary factors of AMU on farms are the lack of governance of the value chain for antimicrobial uses, the incidence of disease on the farm, and bird mortality. All these factors have positive causal links with AMU on the farm-level. Increased AMU reduces the quality of poultry products in terms of residue build-up, which in turn, causes an increase in antimicrobial resistance (AMR) in consumers of poultry products leading to an increased incidence of sickness in consumers and treatment costs. However, it can be safely assumed that consumers will rationally react to the effect on AMR by decreasing demand for poultry products. The decrease in demand will affect sales and ultimately the on-farm profit for producers.The financial implication of AMU on the farm is highlighted by the moderating effect of antimicrobial use on the relationship between total production cost and on-farm profit. Thus, as AMU increases production cost increases and the potential on-farm profit decreases. This moderating effect can be attributed to the balancing feedback loop (B3) which is traced by the positive causal link from on-farm profit to the purchase of quality medicines and pharmaceutical agents for poultry production and production cost, and the negative causal link from production cost to on-farm profit. The balancing feedback loop suggests that the availability and accessibility of cheap antimicrobials will encourage continuous usage due to the low economic effect (decrease in on-farm profit). Conversely, a high cost of antimicrobials can either be a demotivation for continuous usage or instigate producers to resort to falsified and substandard antimicrobials that can stimulate AMR.3.3.The variable rankings showed concordance with the proposed interventions by stakeholders presented in 4.The drivers of AMR are complex, multi-faceted and multi-sectoral , 8. HoweTwo strategies accounting for the overuse of antimicrobials can be attributed to the economic motive of minimising production cost. These strategies are inferred from the relationship between on-farm profit and the adoption of good farm management and husbandry practices, and the relationship between production cost and on-farm profit in the causal loop diagram . The firThe second strategy is the overuse of antimicrobials as a cheaper alternative for recommended biosecurity measures for animal production. Biosecurity measures are noted examples of preventive measures to reduce antibiotics usage in poultry production. Yet, the financial implication of these measures needs to be critically examined to ascertain the return on investment for producers who will normally make economically sound production decisions without necessarily considering the ramifications post-farmgate. Thus, in place of implementing biosecurity measures, producers will overuse antimicrobials in poultry as a cheaper precautionary measure compared to ensuring good husbandry conditions like cleaning pens in intensive production systems .The complexity required to deal with the problem of AMR is apparent and the need for collaborative participation of stakeholders as a principal solution for AMR is recommended . Also, aIn this study, a participatory system dynamics modelling approach was adopted to map out the effect of antimicrobial resistance (AMR) on on-farm profit in poultry production in peri-urban areas in Senegal. One of the main findings of the paper is that the primary influencing drivers of AMR are production cost and on-farm profit. Thus, the drivers are economic in nature, and the economic motive for overuse of antimicrobials is to reduce production cost. Also, this paper shows that the moderating effect of antimicrobial use on the relationship between total production cost and on-farm profit suggests that the availability and accessibility of cheap and substandard antimicrobials will encourage continuous usage (particularly when there is a lack of regulation) due to the low economic effect on on-farm profit. However, there are unintended consequences that need to be considered.Conversely, a high cost of antimicrobials can be demotivation for continuous usage or instigate producers to resort to quack and substandard versions of antimicrobials that can stimulate antimicrobial resistance. Thus, there is a need for a regulatory framework to streamline and monitor the use of antimicrobials in animal production.The adoption of a participatory approach gave stakeholders a platform to dialogue and co-create solutions for AMR. A system thinking method facilitated a holistic understanding and appreciation of AMR by highlighting the complexity and multi-faceted nature of AMR. Also, the approach allowed stakeholders to conceptualise the unintended consequences of the decisions beyond their immediate  impact. Also, although the CLD developed from the qualitative SD modelling, a participatory approach limits the subjectivity in the CLD developed when different stakeholders engage to exchange opinions and map the causal relationships and interactions in the model.ex-ante the impact of the key interventions highlighted in this study. Thus, this study’s findings provide a precursory grounding for the cost effectiveness assessments of different scenarios of interventions to curb AMR.This study adopted a participatory approach to elicit stakeholders’ views on antimicrobial use at the farm level. Therefore, the findings are valuable within the specific context of Senegal and may not be generalisable to other developing countries. Consequently, the findings may not be relevant in other geographical contexts. Additionally, the assumption of an equal weight of influence for all the variables in the network analysis ignores the concept of leverage points whereby changes in different variables do not necessarily cause the same level of change in other variables. Thus, although the integration of network analysis with qualitative system dynamics modelling abates the criticism of the inconclusiveness of results generated from qualitative SD modelling approaches, there is a need to quantitatively assess The original contributions presented in the study are included in the article/Stakeholders’ consent was obtained through their agreement to participate in the workshop and sign the attendance sheet. This study involving human participants received ethical approval from the International Livestock Research Institute (ILRI) Institutional Research Ethics Committee under reference number ILRI-IREC2022-44.MD and JA: conceptualization and validation. JA: methodology, software, formal analysis, writing—original draft preparation, and visualisation. MD, JA, EE, BN, AGF, MS, and AF: investigation and resources. JA, EE, and MD: writing—review and editing. MD: supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.This work was funded as part of the JPIAMR consortium SEFASI with funding from SIDA grant number APH002001.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.


The science of dietary fats has evolved, and a body of evidence indicates they are complex bioactive nutrients that have different effects on health depending on their food source, chain length, degree of saturation, and other factors that can be affected by food processing, handling, and storage. As such, it is becoming increasingly clear that the effects of foods on obesity and metabolic health cannot be predicted simply with their fat content. The aim of this opinion article is to provide a brief overview of select recent research on the effects of whole-milk dairy foods on body composition and indicators of metabolic health across the lifespan to show the gap between current knowledge and dietary guidance. As the state of the science on dietary fats and human health evolves to consider the complexity of food matrices, the total nutrient package they deliver, and the health impacts associated with dietary patterns, so too must guidelines for dietary fat. In this opinion piece, a brief overview is provided of select recent research on the effects on whole-milk dairy foods on body composition and indicators of metabolic health across the life span to support the hypothesis that a gap exists between current knowledge and dietary guidance. For over a century, nutrition science has driven dietary guidance, with the earliest objectives being to ensure nutrient adequacy to prevent diseases of deficiency . Recent Nutrition science has continued to evolve, and now recognizes that the impact of diet cannot be extrapolated from any single nutrient or surrogate outcome marker . DietaryDairy foods comprise complex matrices that deliver nutrients and bioactive ingredients with different effects on long-term weight control and metabolic health ,15. CompThere is also robust clinical evidence to support observations that dairy consumption, regardless of fat content, does not increase the risk for CVD. A trial that aimed to test a higher-fat version of the Dietary Approaches to Stop Hypertension (DASH) demonstrated that the inclusion of whole-milk dairy foods improved triglycerides and had no significant effects on other risk factors for CVD compared with the standard DASH diet, despite a significant increase in saturated fat consumption among healthy middle-aged males and females . Anotherp < 0.0001) [Similar results have been reported in children and adolescents. A systematic review of observational and intervention studies assessing associations between whole- and reduced-fat dairy intake and measures of adiposity and biomarkers of cardiometabolic disease risk in children and adolescents 2–18 years of age found that cross-sectional, longitudinal, and intervention studies were consistent in finding that whole-milk dairy foods were not associated with increased measures of weight gain or adiposity . Similar 0.0001) ; however 0.0001) . A rando 0.0001) . The stu 0.0001) .A review of the mechanisms by which the dairy matrix impacts human health highlighted that the inclusion of dairy foods, including milk, cheese, and yogurt of any fat variety, may beneficially impact cardiometabolic health via beneficial effects on inflammatory pathways in the gastrointestinal tract, liver, and vasculature . Taken tDietary guidance from authoritative sources has the potential to affect the health of billions of people worldwide. Thus, it is of the utmost importance that guidelines represent the current state of nutrition science. At present, many dietary guidelines around the world recommend reduced-fat diets to help mitigate unhealthy weight gain in adults without differentiating between food sources of dietary fats or even the diversity of fatty acids within different classes of fats. The World Health Organization (WHO) suggested that nutrition transition—a shift from traditional diets composed of whole foods to diets composed of processed foods that are energy-dense and nutrient-poor—was an important factor associated with the increased incidence of an overweight status and obesity in low- and middle-income countries . This isDietary recommendations focused on limiting individual nutrients have not successfully reduced the incidence of obesity and chronic diseases globally. Reductionist dietary fat recommendations that consider fat only as a concentrated fuel source or ignore the complexity of fatty acids, the whole-food matrices, and the broader nutrient package from which they are derived do not represent the current state of the science on dietary fats and human health . There i


The rising cancer incidence and mortality in sub-Saharan Africa (SSA) warrants an increased focus on adopting or developing approaches that can significantly increase access to treatment in the region. One such approach recommended by the recent Lancet Oncology Commission for sub-Saharan Africa is hypofractionated radiotherapy (HFRT), which can substantially increase access to radiotherapy by reducing the overall duration of time (in days) each person spends being treated. Here we highlight challenges in adopting such an approach identified during the implementation of the HypoAfrica clinical trial. The HypoAfrica clinical trial is a longitudinal, multicentre study exploring the feasibility of applying HFRT for prostate cancer in SSA. This study has presented an opportunity for a pragmatic assessment of potential barriers and facilitators to adopting HFRT. Our results highlight three key challenges: quality assurance, study harmonisation and machine maintenance. We describe solutions employed to resolve these challenges and opportunities for longer term solutions that can facilitate scaling-up use of HFRT in SSA in clinical care and multicentre clinical trials. This report provides a valuable reference for the utilisation of radiotherapy approaches that increase access to treatment and the conduct of high-quality large-scale/multi-centre clinical trials involving radiotherapy.Not available yet. Cancer is an increasing health concern in sub-Saharan Africa (SSA). In 2020, there were 801,392 new cancer cases and 520,158 cancer-related deaths in the region [In addition to the limited availability of treatment resources, cancer treatment in SSA is complicated by the high costs of medical, surgical and radiation therapies, limited patient access to healthcare, shortages of skilled personnel and late patient presentation of disease . ConsequExisting studies have found HFRT to result in non-inferior outcomes compared to conventional radiotherapy for treating many cancers, including prostate and breast cancer, two of the most common cancers in SSA –11. WhilConsidering prostate cancer has the highest cancer-related incidence  and mortAs described above, the aim of the HypoAfrica study, initiated in 2022, is to assess the feasibility of applying moderate HFRT for localised prostate cancer in SSA. This clinical trial was designed to mirror the European CHHiP study . A totalThe patients will be treated using 3-Dimensional Conformal Radiotherapy and Intensity Modulated Radiotherapy (IMRT) techniques on linear accelerators . Patient-specific quality assurance (QA) will be performed for IMRT treatments using either film or portal dosimetry techniques. Image-guidance is provided by portal films or images compared to digitally-reconstructed-radiographs from the preceding CT simulation for position verification. More information on the protocol can be found here (doi: 10.6084/m9.figshare.21913200).The study will include 1 year of patient recruitment (ongoing) and treatment, and 5 years of patient follow-up. The primary endpoints for this study are toxicity at the end of treatment and toxicity 3–24 months post-treatment. Secondary endpoints are PSA failure-free survival at 5 years, relapse-free survival at 5 years, overall survival at 5 years and cost-effectiveness of HFRT. Weekly team meetings, as described above, were organised to discuss and address opportunities and barriers to implementing HFRT in SSA settings.et. al [Prior to the start of the HypoAfrica trial, we conducted an online survey to assess the readiness of African radiotherapy clinics to adopt curative HFRT. Criteria for readiness were based on the stereotactic body radiotherapy recommendations in the American Association of Physicists in Medicine Task Group Report 101 and other professional organisations , 14. Theet. al . The surRadiotherapy QA and treatment protocol adherence have been found to correlate positively with patient survival –17, highIn assessing QA needs for implementing the HypoAfrica clinical trial, the availability of needed infrastructure to ensure high-QA was identified as a challenge: not all sites had the equipment and established routines that facilitate the required QA for implementing HFRT. This infrastructure challenge appears consistent with findings in the survey  and corrAnother challenge identified during the HypoAfrica trial was machine maintenance, an issue highlighted in previous studies on radiotherapy in SSA –24. MachWhile multicentre clinical trials have many advantages, including increased sample size, greater generalisability and the ability to conduct more robust analyses, the challenge of harmonising study components across all sites comes with them. Indeed, homogenising patient recruitment, data collection and nomenclature to ensure the data collected are comparable and protocol-adherent are all critical to the success of a multicentre clinical trial. Harmonisation of QA techniques in the HypoAfrica study has been described in the previous section. For patient recruitment, the inclusion criteria outlined in the study protocol facilitated the selection of patients at each study site that matched the target population. To homogenise data collection, we introduced a centralised platform with data collected in a relational database within the existing Networks of Imaging eXcellence (NIX) infrastructure, used in other multi-centre studies . NIX allIn conducting the HypoAfrica trial, the need for continuous medical education  became apparent. CME would facilitate greater adoption of approaches like high-quality HFRT in SSA, and is currently utilised for this function in the United States. Our survey anticipated that minimal additional training for practicing HFRT was necessary for many clinics, since 59% of survey respondents reported that their site already practises HFRT for palliative care . HoweverBesides creating a platform for continuous education regarding HFRT, the HypoAfrica study has highlighted other opportunities that can facilitate greater adoption or scale-up of HFRT in clinical practice and trials in SSA. One opportunity that has emerged as a longer-term solution for some of the challenges seen in the HypoAfrica trial is the development of a consortium with funding proposal towards establishing an Imaging and Radiation Oncology Core (IROC) in Africa. In the United States, IROC supports multi-centre clinical trials by providing radiotherapy quality control programmes and equipment to ensure that the radiation doses administered to patients in trials are ‘accurate and comparable between participating institutions’ . IROC AfA third opportunity we identified through HypoAfrica to facilitate wider adoption of HFRT in SSA is telehealth. This study has highlighted an opportunity and model for global health in radiation oncology leveraging advanced information and communication technologies to provide remote QA, peer review and support through teleoncology. HypoAfrica has also provided significant opportunities for Western oncology health professionals and trainees to participate in global health experiences, working across cultures and learning about the remarkable work done by healthcare professionals in resource-limited settings and different cultures. Collaboration through the HypoAfrica project has indubitably tested a model for telehealth that can be scaled in North-South collaborations.The HypoAfrica study emerged out of the desire to improve access to cancer treatment in SSA by introducing therapies that are resource-efficient and equivalent to conventional therapies. HFRT is a modern technique that guarantees such efficiency and results in non-inferior outcomes compared to conventional radiotherapy in studies with predominantly Western populations. The unique tumour genetics and living experiences of the SSA population warrant trial assessment of the effectiveness and feasibility of HFRT in SSA. Our multicentre feasibility study examines the feasibility of applying HFRT for localised prostate cancer in the SSA setting. This article details the challenges we encountered while implementing the HypoAfrica study, as well as the opportunities that emerged. Notably, we encountered challenges to QA, study harmonisation, and machine maintenance and noted opportunities for continuous education, IROC Africa and telehealth. Combatting the challenges was essential to maintain the integrity of the trial and to ensure patient safety. The software introduced as solutions  were well received by each site, but required that the on-site researchers receive additional training to appropriately utilise them. Based on a review of the literature, this is one of the first multi-centre clinical trials involving radiotherapy in SSA. We hope that the lessons from our trial will serve as valuable recommendations for future oncology clinical trials in SSA, including planned trials combining HFRT with immunotherapy.At present, the strengths of our study include: 1) the creation of a framework for radiotherapy QA at three sites; 2) multicentre study harmonisation that can be used in future clinical trials in SSA; 3) the establishment of a multi-continent collaboration between oncology health professionals; 4) increased awareness about barriers to cancer treatment and the implementation of clinical trials in SSA; 5) potential for improved outcomes for patients enrolled in our study; 6) implementation of existing software  at clinical sites in SSA and 7) opportunities to improve these tools based on this experience.Limitations of our study include its confinement to three hospitals in three SSA countries. However, the additional perspective provided by the survey suggests that some of the challenges apply across many SSA countries. The HypoAfrica trial is only focused on prostate cancer, and the challenges observed may somewhat differ when HFRT is implemented for other cancer sites, like breast cancer where evidence-based HFRT has also been established. More studies involving more sites are needed to pellucidly investigate the barriers and facilitators for implementing HFRT in clinical practice in SSA. Such investigations would further advance our understanding of the utility and practicality of implementing HFRT in the SSA setting.Through the HypoAfrica clinical trial, we identified potential barriers to the broader adoption of HFRT in SSA. Opportunities identified could be leveraged to strengthen the capacity of SSA countries to scale up HFRT and significantly increase access to treatment. We hope that the lessons from our experience will serve as valuable resources for subsequent studies. This project provides a significant impetus for broader implementation of scientific research assessing the barriers and facilitators of adopting evidence-based approaches like HFRT and telehealth to increase access to care in SSA.The authors declare that they have no conflicts of interest.


Table CorrectionIn the original publication , there wText CorrectionThere was an error in the original publication. The manuscript stated “four” analytical concepts when there are in fact five.A correction has also been made to the Section 7, Paragraph 1 and should read:Functionality, Accessibility, Safety and Security, Social Activity, and Autonomy and Identity are warranted. These implementations could improve the well-being and housing stability of OPEH.The AIRP-ENV and AIRP-ENV SO audit tools can be used to effectively evaluate different types of temporary and permanent supportive housing across the housing continuum for OPEH. By linking the AIRP-ENV and AIRP-ENV SO tools to existing AIRP indicators, this research fills a gap in the literature on the environmental role of the AIRP on OPEH. The findings from the AIRP-ENV tool can support further identification of areas for environmental interventions at housing sites targeted for OPEH. Additionally, the tool can inform planning and design guidelines for housing that support marginalized OPEH who experience a range of individual health and functional statuses. Continued efforts in the THP to improve and adapt environmental features related to the five analytical concepts of The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated.


This study investigates the thermal efficiency and exergy efficiency of a thermoelectric power generation device for recovering power cable surface waste heat. Numerical simulations are conducted to analyze the impact of different types of cooling fins on the system’s performance. The results demonstrate that the installation of cooling fins improves heat transfer efficiency and enhances the thermoelectric power generation device’s output power. Among the various fin designs, the system equipped with cooling fins with 17 teeth exhibits the highest performance. These findings highlight the importance of fin design in optimizing the system’s thermal efficiency and exergy efficiency. This study provides valuable insights for the development and improvement of thermoelectric power generation systems for power cable surface waste heat recovery applications. With the continuously growing energy demand and increase in environmental issues, the scientific community has intensified their research and development efforts with respect to renewable energy technologies. Thermoelectric power generation, a renewable energy technology that converts natural temperature differences into electrical energy, has gained considerable attention. On one hand, power cables are essential components of the power system for long-distance electricity transmission. On the other hand, conventional transmission cables release thermal energy into the environment during energy transmission, leading to reduced energy utilization efficiency. To address this issue, researchers have explored integrating thermoelectric power generation technology with power cables to recover the heat generated during cable operation and convert it into usable electrical energy. This combined solution has the potential to significantly enhance secondary energy utilization efficiency, improve energy recovery efficiency, reduce energy waste in power systems, and contribute to the sustainable development of the power transmission industry. Thermoelectric power generation technology operates based on the Seebeck effect of semiconductor thermoelectric materials, generating electrical energy when there is a temperature difference across the material. Although the technology has been successfully applied for small-scale energy recovery, its application in large-scale power cables is still limited. By integrating thermoelectric modules into the cable surface and utilizing the temperature difference between the cable surface and the environment, the waste heat generated during cable operation can be efficiently converted into electrical energy, improving the overall energy utilization efficiency and reducing our reliance on traditional energy sources.Thermoelectric power generation technology offers significant advantages, such as the efficient utilization of low-quality thermal energy sources, environmentally friendly operation, and applicability in various sectors. Continued research and innovation in this field can lead to cleaner and more sustainable energy solutions, reducing our reliance on traditional energy sources and addressing environmental challenges. Zhao et al. demonstrated the potential of thermoelectric generators in capturing energy from waste heat in wet flue gas recovery research. This technology improves energy utilization efficiency and reduces energy wastage . Their fAmong the various methods of enhancing the performance of a thermoelectric power generator, the addition of fins is a convenient and effective approach. Fins represent a common heat conduction enhancement element that can increase the efficiency of the heat transfer between the thermoelectric generator and the heat source, thereby improving the energy conversion efficiency. By adding fins, the surface area of the TEG is increased, allowing it to better absorb the heat released by the heat source and convert it into electrical energy. This increases the power generation capacity of the TEG while reducing energy waste and improving energy utilization efficiency. Therefore, adding fins is a simple and effective method that can be used in various applications to enhance the performance of a thermoelectric power generator. Wang et al.  focused By combining power cables with thermoelectric power generation technology, it is possible to achieve the green, environmentally friendly, and efficient secondary utilization of renewable energy. This innovative approach involves recovering the waste heat generated on the surfaces of transmission power cables during operation and converting it into electrical energy, thereby improving energy utilization efficiency. In further enhancing the efficiency of recovering waste heat from cables, incorporating heat sink fins plays a crucial role. Heat sink fins are common thermal conduction enhancement elements that can increase the heat transfer efficiency between the thermoelectric power generation device and the heat source. By optimizing the design and layout of the heat sink fins, the surface area of the device can be increased, allowing it to better absorb the heat released by the cable surface waste heat. Therefore, this study investigated the integration of heat sink fins into the surfaces of the cables in a waste heat recovery thermoelectric power generation system. The research results show that this method improves the energy conversion efficiency, increases the device’s output power, and reduces energy wastage. Additionally, the study comprehensively evaluated the performance of the power-cable-surface-waste-heat-recovery thermoelectric power generation device from different perspectives, using thermal efficiency and exergy efficiency as two assessment criteria.Nu) values with those reported in the reference, we found a discrepancy of 6%. Considering the existing literature, this level of error in our simulated Nu values falls within an acceptable range. This comparison provides substantial evidence for the reliability of our computational model and underscores the accuracy of our simulation results.In this study, we employed a comprehensive fluid–solid–electric coupled model which operates under the assumption of a steady-state condition. The model encompasses a three-dimensional representation of the fluid, which is characterized by an incompressible turbulent flow. The material properties within the model are assumed to be isotropic, allowing for a simplified yet representative depiction of the system. It is important to note that certain aspects are not accounted for in the computational process. Specifically, we did not consider contact thermal resistance and radiation effects within the scope of this study. While these factors can influence the thermal behavior of the system, their omission enabled us to focus on the core interactions of fluid dynamics, solid conduction, and electrical phenomena. This approach facilitates a focused exploration of the interplay between these primary variables and their implications for the device’s performance.The mass, momentum, and energy conservation equations are as follows:p,n,copperλ—p-leg, n-leg, and copper thermal conductivity, ceλ—ceramic plate thermal conductivity, p,n,copperT—p-leg, n-leg, and copper temperature, TS—source of energy, J—current density, and σ—electrical conductivity.The solid heat transfer equations are as follows:The numerical simulation software used in this study was ANSYS Fluent 2021 R2. The heat transfer process was computed using the fluid–thermal coupling approach. In this study, the SIMPLEC algorithm was employed, and a second-order upwind scheme was used to solve for the momentum and dissipation rate.Typically, the performance evaluation of a heat-recovery thermoelectric power generation device uses thermal efficiency as a reference criterion. However, in this study, an additional evaluation metric called exergy efficiency was introduced to assess the performance of the cable-surface-waste-heat-recovery thermoelectric power generation device model. These two kinds of evaluation metrics provide a comprehensive assessment of the performance of the thermoelectric power generation device from different perspectives. Thermal efficiency primarily focuses on the overall energy conversion efficiency and measures the proportion of heat energy converted into electrical energy by the thermoelectric power generation device. It reflects the efficiency and conversion effectiveness of energy utilization and provides a direct evaluation of the device’s performance in energy conversion. On the other hand, exergy efficiency emphasizes the utilization efficiency of the available temperature-difference resources by the thermoelectric power generation device. It considers the relationship between energy losses and the available temperature difference, providing an evaluation of energy conversion under the given temperature-difference conditions available. Exergy efficiency pays more attention to the sustainability and effectiveness of energy utilization, reflecting the degree of the device’s utilization of low-grade energy. The combined use of thermal efficiency and exergy efficiency provides a comprehensive understanding of the performance of the thermoelectric power generation device.P—output power; R—external resistance; I—current; The thermal efficiency The exergy efficiency The cable-surface-waste-heat-recovery thermoelectric power generation device is a system that utilizes the Seebeck effect to convert waste heat on the surface of a cable into electrical energy. To enhance the performance of this system, fins can be used to improve the heat transfer between the hot and cold sides of the thermoelectric power generation device, as shown in Based on the research results, it can be observed that the cable-surface-waste-heat-recovery thermoelectric power generation device equipped with cooling fins (Case 1–6) exhibits a higher level of output power compared to the device without cooling fins (Case 0). Among the configurations with cooling fins, the device with 17-tooth cooling fins (Case 6) demonstrates the highest output power, while the device with single-tooth cooling fins (Case 1) exhibits the lowest output power. This can be attributed to the improved heat dissipation efficiency on the cold side of the thermoelectric power generation device when cooling fins are installed. The design of the cooling fins allows for the faster conduction of heat from the cold-side surface to the fins, facilitating heat dissipation and reducing the temperature. Therefore, the installation of cooling fins effectively lowers the temperature on the cold side of the thermoelectric modules on the cable surface, providing a larger temperature difference and increasing the thermal efficiency of the thermoelectric power generation device. Additionally, the presence of cooling fins expands the heat exchange surface area on the cold side of the thermoelectric power generation device. The installation of fins increases the area of contact with the ambient low-temperature air, making more surface area available for absorbing coldness from the environment. As a result, the thermoelectric power generation device can more fully utilize the temperature difference between the hot and cold sides, facilitating more efficient heat transfer and consequently improving the output power. Furthermore, different designs of cooling fins also have an impact on the output power. As shown in the figure, the device with 17-tooth cooling fins exhibits the highest output power, while the device with single-tooth cooling fins shows the lowest output power. This is because the design of the 17-tooth cooling fins induces a gas flow disturbance when the low-temperature air passes through the fins. With more fins present, the air flow experiences more redirection and flow changes between the fins. This intensified gas flow disturbance increases the contact area between the gas and the fin surface, enhancing heat conduction and heat transfer. By increasing the contact area between the gas and the fins, the 17-tooth cooling fins can more effectively absorb coldness from their surroundings and transfer it to the thermoelectric power generation device. In contrast, the single-tooth cooling fins have fewer fins, resulting in less gas flow disturbance and a relatively smaller contact area, thereby leading to a weaker heat conduction capacity. In summary, the intensified gas flow disturbance caused by the 17-tooth cooling fins has a positive effect on the output power of the thermoelectric power generation device. It provides more contact area and enhances heat conduction, thereby increasing the heat transfer from the cold side and subsequently raising the temperature difference and open circuit voltage of the device. On the other hand, as the number of teeth on the cooling fins increases, the temperature difference and open circuit voltage of the device also increase, as shown in It can also be observed from the figures that the thermal efficiency and exergy efficiency of the cable-surface-waste-heat-recovery thermoelectric power generation device are higher when cooling fins are installed compared to when they are not installed. Furthermore, the thermal efficiency and exergy efficiency of the thermoelectric power generation device with 9-long-tooth fins (Case 5) and 17-tooth fins (Case 6) are higher than those with other types of fins, and the initial increasing trend of the exergy efficiency is more significant than that of the thermal efficiency. The reason for this result is that the installation of cooling fins increases the heat dissipation surface area on the cold side of the thermoelectric power generation device, providing more surface area for heat exchange and enhancing heat conduction and absorption. This facilitates a more efficient utilization of the temperature difference resource and improves both the thermal efficiency and exergy efficiency. Cooling fins also improve the conduction of heat within the thermoelectric power generation device. By increasing the number and length of fins, the conduction path of the heat within the device becomes more extensive, enhancing the device’s heat conduction capability. This helps to increase the conduction of heat from the cold side to the fins, thereby improving the thermal efficiency and exergy efficiency of the system. Similarly, cooling fins enhance heat dissipation by increasing the surface area and surface structure. More fins provide a larger surface area for heat dissipation, facilitating the rapid dissipation of heat into the surrounding environment. This reduces the increase in temperature on the cold side of the device, maintains a higher temperature difference, and improves the thermal efficiency and exergy efficiency of the system. The thermoelectric power generation devices with 9-long-tooth fins (Case 5) and 17-tooth fins (Case 6) can more effectively utilize the available temperature difference resource. The designs of these fins are better-suited for the current temperature difference conditions, enabling them to capture and utilize the temperature difference resource more effectively, thereby improving the thermal efficiency and exergy efficiency. The more pronounced initial increasing trend of the exergy efficiency compared to the thermal efficiency when the external resistance increases is due to the fact that at lower external resistances, the thermoelectric power generation device can more fully utilize the available temperature difference resource to enhance the intensity of thermal energy conversion and improve the system’s exergy efficiency. As the external resistance increases beyond the total internal resistance of the system, the gain in convertible thermal energy output diminishes, resulting in a relatively flattened growth trend for the exergy efficiency.The installation of cooling fins on the thermoelectric power generation device improves the performance by enhancing heat transfer and heat dissipation. With an increased number of fin teeth, the temperature on the cold-side surface becomes more uniform and reaches its lowest value. The device with 17-tooth fins exhibited the highest maximum output power and heat transfer coefficient due to its larger heat transfer surface area, improved heat transfer efficiency, and reduced temperature on the cold side.The thermoelectric power generation device demonstrates an increase in its output power with an increase in the external load resistance, reaching its peak value at a certain threshold. However, beyond this critical point, the output power starts to decline. Therefore, achieving the optimal matching state between the external load resistance and the output power becomes crucial for maximizing the device’s overall efficiency.The thermal efficiency and exergy efficiency of the thermoelectric power generation device are higher when cooling fins are installed compared to when they are not installed. The devices with 9-long-tooth fins and 17-tooth fins demonstrated higher efficiencies compared to other types of fins. The initial increasing trend of the exergy efficiency is more significant than that of the thermal efficiency, indicating the sensitivity of exergy efficiency to variations in the external resistance of the device.Both the thermal efficiency and exergy efficiency of the thermoelectric power generation device increase with an increase in the temperature difference between the hot and cold sides. However, the increase in the thermal efficiency is more significant than the increase in the exergy efficiency. The improvement in thermal efficiency is influenced by factors such as enhanced heat conduction and the properties of the thermoelectric module, while the increase in exergy efficiency is limited by energy losses during the heat conduction process.This study investigated the thermal efficiency and exergy efficiency of a cable-surface-waste-heat-recovery thermoelectric power generation device and examined the impact of using different types of cooling fins on the system’s performance through numerical simulations. The following conclusions can be drawn from the analysis and research results:Overall, the installation of cooling fins and the optimization of external load resistance and temperature difference can significantly enhance the performance of a cable-surface-waste-heat-recovery thermoelectric power generation device. The combined use of thermal efficiency and exergy efficiency provides a comprehensive evaluation of the device’s performance from different perspectives, considering its energy conversion efficiency and the utilization of available temperature-difference resources.


Malignant transformation of oral lichen planus (OLP) into oral squamous cell carcinoma is considered as one of the most serious complications of OLP. For the early detection of oral cancer in OLP follow-up, accurate localization of the OLP center is still difficult but often required for confirmatory biopsy with histopathological examination. Optical coherence tomography (OCT) offers the potential for more reliable biopsy sampling in the oral cavity as it is capable of non-invasively imaging the degenerated oral layer structure. In this case-series study with 15 patients, features of clinically classified forms of OLP in OCT cross-sections were registered and correlated with available histologic sections. Besides patients with reticular, atrophic, erosive and plaque-like OLP, two patients with leukoplakia were included for differentiation. The results show that OCT yields information about the epithelial surface, thickness and reflectivity, as well as the identifiability of the basement membrane and the vessel network, which could be used to complement the visual clinical appearance of OLP variants and allow a more accurate localization of the OLP center. This forms the basis for further studies on OCT-assisted non-invasive clinical classification of OLP, with the aim of enabling decision support for biopsy sampling in the future. Any permanent oral lesion can lead to oral cavity cancer . TherefoWith regard to the current clinical management of OLP, the initial diagnosis is predominantly based on visual findings of the characteristic clinical features of OLP, which can be confirmed by oral biopsy examination with histopathology in conspicuous cases to exclude malignancy ,18. For In this case-series study, we present the results of the depth-resolved OCT imaging of visually diagnosed OLP of the human oral mucosa in vivo during follow-up examination by means of the clinical use of a customized fiber-based probe . For difIn order to perform accurate follow-up diagnosis of patients with OLP or other pathological changes leading to oral cancer, a miniaturized OCT probe was tested in a clinical study. The study was authorized by the ethics commission of the Faculty of Medicine of the TU Dresden (EK 96032018 2018-11-16 and EK 39112018 2019-01-22).For the imaging of OLP and leukoplakia of the human oral mucosa, we used the fiber probe OCT system described in  clinicalm (FWHM) .To evaluate the use of the OCT miniprobe in routine examinations, 15 patients  with visually diagnosed non- and symptomatic oral lichen planus (OLP) and, for differential diagnosis, leukoplakia were included in the observational study. Patient selection took place during the weekly oral mucosal consultation of the Clinic and Polyclinic for Oral and Maxillofacial Surgery of the University Hospital Dresden. In combination with the patient’s symptoms and medical history, the diagnosis of OLP was made by clinical visual observation of the oral mucosal surface of the pathologically altered region and, in two individual cases, supported by biopsy followed by histopathological examination. All patients (≥18 years) with OLP and leukoplakia  who agreed to undergo non-invasive in vivo OCT imaging of the existing lesion after informed consent were included in the study. Patients with local infectious diseases , with multidrug-resistant germs and/or diseases requiring isolation  were excluded. Data collection was performed weekly over a two-month period for a total of seven days. Each patient was clinically examined only once during the medical appointment.Based on the clinical visual diagnosis, 13 patients were diagnosed with oral lichen planus (OLP) (patient I–XIII) and two patients with leukoplakia (patient XIV) and dysplastic leukoplakia (patient XV), respectively. The medical history and medication for each patient are summarized in OCT imaging was performed during the clinical consultation directly after anamnesis and visual–tactile examination and diagnosis by an experienced oral and maxillofacial physician. The decision to take a biopsy was made subsequent to the clinical examination without consideration of OCT imaging. Before OCT cross-sectional imaging, the miniprobe was disinfected  and covered with a dental disposable plastic sleeve   form of OLP is often asymptomatic and includes reticular, papular and plaque-like OLP. These asymptomatic OLP forms do not require treatment with glucocorticoids or immunosuppressants, only medical monitoring at regular intervals depending on the variability of the pathology. In addition, supportive measures such as regular professional tooth cleaning, abstaining from nicotine and alcohol, switching to surfactant-free toothpaste and the removal of amalgam fillings are recommended to prevent the worsening of OLP ,45. The With respect to OCT imaging, classification parameters are defined based on previous feasibility studies ,40. For The image data compiled below underlie the classification of the clinical appearance. The aim is to correlate the in vivo depth-resolved cross-sectional OCT image information with the clinical diagnosis.Patient I and II were diagnosed with a reticular form of OLP . The visThe OCT scan detected in the center of the OLP  were assigned to the reticular atrophic form of OLP , which cFor all three patients studied, the OCT imaging depth in the center of OLP is comparable to that of the peripheral region. Due to the structural changes in the distinct OLP, the stratification character of the oral mucosa is only recognizable to a very limited extent in the OCT scans of the lichen center , and is reduced for patient V (289 µm). For all three patients, the BM does not form sharply. The vascular network of patient V is slightly increased in the LP with a greater number of smaller vessels.The findings shown in For OCT imaging, the center of atrophic OLP is characterized by a general hyporeflectivity of OM. There, the differentiation between EP and LP is difficult. The BM as a demarcation line is not visible due to acute inflammation combined with the loss of the EP layer characteristic for this OLP form . In addiThe clinically inconspicuous OM surrounding the atrophic OLP shows an expected hyporeflective EP and a hyperreflective LP with embedded larger vessels. The EP has a smaller layer thickness  than typical for the buccal mucosa area [By clinical palpation with a blunt instrument, the altered oral mucosa of patients IX, X, and XI  was founPeripheral areas at a larger distance from the OLP center show an expected characteristic layering of OM structures with hyporeflective EP and hyperreflective LP with clearly visible larger vessels. The EP thickness amounts to 539 µm (patient IX), 479 µm (patient X) and 363 µm (patient XI) ,40.According to the follow-up of patient XIII , the cliThe results of OCT imaging of two patients with visually diagnosed leukoplakia are shown in The visually assessed inhomogeneous leukoplakia of the posterior buccal side of patient XV was histologically diagnosed as oral squamous cell carcinoma (OSCC) and appears in the OCT cross-sectional image as particularly striking and different from the previous OCT cross-sectional scans of OLP. In detail, a strongly uneven EP surface and advanced structural remodeling of the EP layer is present. In addition to the highly reduced OCT imaging depth, increased shadowing of the cluster-like circular structures of the EP is also visible. Compared to the OCT depth scans of the different forms of OLP in sections 3.1 to 3.6, the center of this pathology shows neither a decreased stratification of the OM cp.  nor a hoThe OCT scan of the adjacent visually inconspicuous region (surrounding OM) of patient XV also appears altered: the backscattering of the EP layer is increased and the boundary with the LP appears as a highly backreflective demarcation line above an untypical hyporeflective LP.For patients IV and XV, biopsies were taken during consultation, allowing a qualitative comparison to in vivo OCT measurements performed with the miniprobe system. Patient IV was clinically diagnosed with the reticular atrophic form of OLP . The thrFor patient XV , differeThe cloud-like structures of the altered OM in the in vivo OCT cross-section are confirmed in the histological result by prominent circular structures (left column in In the presented study, patients with visually diagnosed clinical non- and symptomatic OLP and, for differential diagnosis, leukoplakia were imaged with OCT in vivo during the routine annual follow-up. The clinically classified forms and mixed forms of OLP were correlated with the depth-resolved in vivo insight into the altered OM. The morphological information provided by OCT augments the clinical appearance and may provide the opportunity for more accurate localization of a representative biopsy, if needed. Using the small sample of patients in our study, we extended the clinical diagnosis by the corresponding characteristic features of OCT imaging see . These iThese results were confirmed by previous studies ,39,40,47From the clinical perspective, the results of this study, as well as the findings of previous publications, suggest that OCT might complement the visual examination of the oral mucosa at the initial clinical consultation and at the annual follow-up. The example of patient XV, initially clinically diagnosed as inhomogeneous dysplastic leukoplakia but later found to be an OSCC on biopsy, illustrates the possible added value of OCT for valid biopsy sampling. In this context, OCT imaging could potentially serve as an additional decision aid to determine whether a control biopsy should be performed or whether the patient should be readmitted. Concerning, for example, oral leukoplakia, OCT imaging might also support the differentiation of OLP from other oral lesions . FurtherWith regard to future research, it will be necessary to extend the OCT imaging of OLP to a larger number of patients to validate the results of the present study. Thereby, the variants of the erosive OLP and especially the more treatment-intensive red forms of OLP should be focused on. In addition to in vivo OCT imaging, the ex vivo imaging of biopsy specimens in combination with consecutive histopathological evaluation may also be useful to further correlate OCT and histological findings more accurately ,40,47. MAny form of OLP can degenerate malignantly over time. In various well-conducted studies, data on the malignant transformation rate of OLP range from 0.3% to 14.3% with an average of 1.1% and a median follow-up of about 5.5 years ,11,15. M


This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the  Fu. Fu84]. A non-apoptotic cancer cell death via disruption of the structure and function of the cell nucleus, downregulation of c-myc expression, and damage of cyclin-dependent kinases using a commercially available CG, UNBS1450, was an earlier plausible anti-tumor mechanism . CellulaThere has been a considerable increase in the investigation of the anti-cancer properties of cardiac glycosides, and several reports have provided insight into the anti-cancer mechanism of these compounds. As we have demonstrated above and summarized in Table Some of the most effective existing cancer therapeutics target DNA damage and the DDR pathway. Hence, it is not surprising that many studies of CG’s mechanistic role implicate DNA damage or repair. DNA damage and DDR signaling are promising targets for drug discovery because of their role in the progression and response in cancer therapy. Several studies have recognized the utility of CGs as potential agents that can increase the sensitivity of different cancer cells to other cancer therapies such as IR, doxorubicin, and cisplatin to mention a few , 77, 88.Each of the four structural features  of CGs have been identified to play a significant role in driving the efficacy of the compound from increasing the lipid solubility to serving a particular function, e.g., initiating apoptosis , 89. HowA key challenge in the successful development of glycosides as DDR inhibitors might arguably be their lack of specificity. The inherent complexity of the network of DNA damage signaling kinases and proteins is not the only obstacle. As discussed above, the glycoside-induced DNA damage and repair can trigger other signaling pathways such as growth factors, stress, and transcription , 25, 84.While we have provided a comprehensive analysis of the relevant data from which we can draw conclusions, we have to emphasize that there remain many unanswered questions. Definitive proof of the complete signaling pathways to explain the different mechanisms in the different cancers is lacking. We have explored and discussed the multiple DNA damage and DNA repair regulation proteins influenced by different CGs. However, we need more studies with various CGs to fully comprehend the mechanistic impact of CGs in activating these DDR-related proteins in order to allow the application and our understanding of these basic studies to direct and guide their clinical utility in cancer treatment.


Global health researchers face multiple challenges in proceeding with research programmes during crises, including ethical and safety questions, equitable participation of community members and the collection of robust data.In Sri Lanka, the multicountry global health programme ECLIPSE adopted innovative research methods in a context dictated by pandemic conditions, and strengthened by community engagement and involvement (CEI), to achieve its goals, provides a model for global health researchers working in crisis settings.Following the government regulations in combination with scientific guidelines, closely monitoring the pandemic and timely prediction, adopting a robust CEI approachat the early stages of research and using innovative methods that moves beyond virtual mode can help navigation of research without disruption.Incorporated crisis preparedness and alternative plans focusing on encouraging the use of CEI in grant proposal development by researchers and a the demand of global health research funders on these key aspects would enhance the ability of research programmes to sustain during crises.Global health researchers encounter challenges in conducting research during crises, including pandemics, natural disasters and humanitarian conflicts.5 6The COVID-19 pandemic had a significant impact on global health research, particularly in low-income and middle-income countries (LMICs). Both funding acquisition and scholarly output in LMICs were affected.8 9Here, we share the experience of the Sri Lankan team of the multicountry global health research programme ECLIPSE. We highlight three aspects that will inform the global scientific community in safeguarding research during crises: (1) positioning the research within the crisis context; (2) using CEI for ongoing research and (3) innovating methods and moving beyond the virtual mode.ECLIPSE is a multicountry global health research programme with the full title: ‘Empowering people with Cutaneous Leishmaniasis: Intervention Programme to improve the patient journey and reduce Stigma via community Education’. ECLIPSE is strongly underpinned by CEI in underserved communities in Brazil, Ethiopia and Sri Lanka.The ECLIPSE Sri Lanka 6-month ethnographic study was planned from September 2020 onwards. However, as part of the government response to the pandemic, there was a complete country lockdown, police curfews and movement restrictions, and it was impossible to commence CEI-oriented research at that time. Hence, the team needed to wait (despite the timeline of the main project) until December 2020, when a degree of normalisation returned, to establish community stakeholder groups that engaged in designing the study with the researchers. With due partnership built on trust, we initiated ethnographic fieldwork in January 2021. The researchers conducting participant observation were living in ECLIPSE communities. However, the prediction by leading Sri Lankan epidemiologists of the emergence of a large COVID-19 outbreak in April 2021 necessitated modifications to our ethnographic approach. Recognising the scientific validity of these predictions, we planned alternative ethnographic methods as a risk-reducing measure to sustain the ECLIPSE programme see .Within a span of 2 weeks, the research team responded to changing the methodological approach from conventional participant observation to a community-led autoethnographic diary study. Community members were actively involved and were trained as community researchers to ensure the continuity of the ethnographic study during the period when ECLIPSE researchers could no longer live in the communities. We established a remote monitoring system underpinned by CEI principles, wherein community members were included as team members. These trained community researchers had, by the nature of living in the field site, continuous access to the study participants.When Sri Lanka experienced its first large COVID-19 outbreak, between April and June 2021, the research team had already implemented an alternative methodology to ensure the uninterrupted progress of their research efforts. Notably, the alpha variant of SARS-CoV-2 was responsible for the surge in COVID-19 cases during the study period. Foreseeing the window of opportunity between the two waves  the team formulated its subsequent actions by adopting a strategy of collecting diaries with minimal in-person contact and engaged in ongoing iterative analysis to inform the upcoming stage. The next phase of the study involved conducting in-person semistructured interviews with individuals with CL. The research team developed a Participant Experience Reflection Journal (PERJ), in which participants could document their experiences and reflections on the CL patient journey.The second and most significant wave of the COVID-19 pandemic in Sri Lanka occurred between August and October 2021. The research team worked on comprehensive analysis of participant diaries and developing interview guides for postdiary interviews. Concurrently, individuals with CL completed the PERJ mediated by the remote monitoring system. In October 2021, the Sri Lankan government lifted restrictions following the reduction in the number of cases and the communities were willing to have researchers back in the field. We conducted ‘postdiary’ and postjournal’ interviews12To conduct effective global health research, especially during times of crisis, research teams must have a comprehensive understanding of the political, economic and societal contexts and community perceptions, behaviours, policies, and regulations that may affect their work. Appropriate positioning of research activities within this context requires a scientific approach that responds to challenges while maintaining the rigour of the research methods. Our experience with ECLIPSE demonstrates the importance of understanding and evaluating the complex variables involved in field research to ensure that research activities are appropriately positioned within a given context.CEI refers to various approaches in which people are included in health research decision-making, de-centred participatory planning, knowledge coproduction and resource sharing.In light of these challenges of virtual data collection methods,Global health research programmes are integral in addressing the healthcare needs of disadvantaged societies, knowledge generation and capacity building. However, the limited evidence surrounding adapting methodological approach in order to meet the same objectives and discussion of such alternative research methods and crisis readiness highlights the need for increased attention of funding bodies in study proposal and protocol development.To address this gap, funding organisations must prioritise the demand for emergency preparedness in research programmes particularly given ongoing environmental, humanitarian and biomedical challenges. Risk management and alternative crisis preparedness plans need to be incorporated into research proposals, encouraging the use of CEI in the early stages of research. Additionally, a platform for sharing novel methods governing equity and inclusion should be developed and shared to enhance the knowledge, creativity and skills of researchers. It is time to recognise the importance of crisis preparedness in research programmes, ensuring the equitable and inclusive engagement of communities in the research process.


The discovery and development of new drugs are extremely long and costly processes. Recent progress in artificial intelligence has made a positive impact on the drug development pipeline. Numerous challenges have been addressed with the growing exploitation of drug-related data and the advancement of deep learning technology. Several model frameworks have been proposed to enhance the performance of deep learning algorithms in molecular design. However, only a few have had an immediate impact on drug development since computational results may not be confirmed experimentally. This systematic review aims to summarize the different deep learning architectures used in the drug discovery process and are validated with further in vivo experiments. For each presented study, the proposed molecule or peptide that has been generated or identified by the deep learning model has been biologically evaluated in animal models. These state-of-the-art studies highlight that even if artificial intelligence in drug discovery is still in its infancy, it has great potential to accelerate the drug discovery cycle, reduce the required costs, and contribute to the integration of the 3R  principles. Out of all the reviewed scientific articles, seven algorithms were identified: recurrent neural networks, specifically, long short-term memory (LSTM-RNNs), Autoencoders (AEs) and their Wasserstein Autoencoders (WAEs) and Variational Autoencoders (VAEs) variants; Convolutional Neural Networks (CNNs); Direct Message Passing Neural Networks (D-MPNNs); and Multitask Deep Neural Networks (MTDNNs). LSTM-RNNs were the most used architectures with molecules or peptide sequences as inputs. Therefore, the success of deep neural network model-guided drug discovery rests heavily on coupling these approaches with appropriate experiments. Before in vitro studies, the results of the deep learning models were filtered based on other methods. Generated molecules were evaluated using SOMs and pharmacophore modeling on the basis of crystal structures in complex with DDR1 , kinase Changes in the frequencies of the selected model architectures per year are shown in Drug discovery based on artificial intelligence has received much attention, since it has had a significant influence on developing novel drugs. Owing to the rapid advancements in computer hardware, coupled with the growth in size and availability of publicly accessible datasets, deep learning has met unprecedented success in the field of CADD ,100. AdvIn the present study, a systematic review of peer-reviewed research articles from 2018 up until April of 2022 is presented. The scientific articles considered were used to extract information regarding trends in deep learning models for drug design that were complemented with in vivo animal studies. The outcomes of this review include the deep learning architectures developed, the molecular representations, the workflow of each study, the animal model for the validation of the selected compounds, and the resulting compounds. The deep learning algorithms that were selected were LSTM-RNNs, AEs, CNNs, MTDNNs, and D-MPNNs. LSTM-RNNs were the more frequently used algorithms.It is important to note that although several studies have examined the potential role that deep learning models could play in the discovery of new drugs, applications of these models in “real cases” are still uncommon due to the need for additional computational and experimental validation. This review selected breakthrough studies that started from a deep learning model and continued to in vivo studies to provide a validated process. We believe that deep learning will become an essential part in drug discovery in the near future, and as highlighted by the presented studies, and will assist medicinal chemists in generating new ideas and accelerate the cycle of drug discovery.