Since the pandemic situation was officially declared, part of society was immersed in searching desperately for solutions to combat it. Textile firms addressed with uneven effectiveness the challenge of creating products that helped medical and civil professionals . To do this, they had to face supply problems, lockdown, and make a significant innovative effort. This work aims to analyze the strategic response of the companies belonging to the Valencian Textile Cluster (VTC) (Spain) to the coronavirus crisis and the territorial factors that influenced it. We carried out a content analysis of the news in the main newspapers during February–July (2020). Our analysis revealed that, on average, VTC firms responded to the challenge more quickly and effectively than other Spanish textile firms. The most influential location-specific factors were the clustering developed, institutional support, and a deep-rooted tradition in producing technical-home textiles, although we also detected that social media collaborated in the process of transferring value information. The influence of all these factors was more intense in the epicenter of the cluster (Ontinyent). Consequently, our results highlight the cluster effect and offer lessons that can help manage unexpected future events more effectively. These companies also reinvented themselves by launching sanitary products that they donated to us . For us , that quick, determined, and effective action in those moments of stress, insecurity, and fear of those first days will never be forgotten".Margarita Llaudes. Directora del área de Salud de Xàtiva-OntinyentWhen the pandemic coronavirus was announced in early 2020 and, among other things, production at Chinese textile companies was halted, global supply chains were starved for textile materials and essential products   officially declared the spread of the COVID-19 pandemic  effectively innovated and continuously produced masks, personal protection equipment (PPE), and other sanitary textile products . According to Wenzel et al. , it is impossible to deny the social and strategic value. The 2019 novel coronavirus pandemic (COVID-19) has determined the value of products and their functions; the security of employees in the healthcare system, people in general, and those who depend on the industry. Without any doubt, the importance of it and its influence on the economic sphere has increased significantly. According to the Eurostat Report , it is iThe textile-clothing sector is heterogeneously dispersed geographically, diverse and different activities and industries form it. In this paper, we used the classification proposed by Puig et al. , which iAccording to Eurostat , the EurAn essential characteristic of this industry is that it tends to be geographically concentrated in a non-random manner, showing specific productive specialization patterns in certain regions Stengg, . Thus, wThe textile sector in Spain shows similar structural characteristics to the European industry, i.e., productive specialization, geographic agglomeration, small-sized companies, and uneven development. For example, while there are around 55,800 Spanish textile companies SABI, , 42% areMoreover, remarkably, this industry is located mainly in Catalonia (24%) and the Valencian Community 18.5%), followed by Andalusia (12%), Madrid (14%), and Galicia (6%), being shared the remainder 26% on rest of the Autonomous Communities of Spain. , the VTC readapted and reconfigured its production processes to manufacture masks, gowns, and gloves during a brief period, which helped citizens protect themselves from the virus. This capacity for change caused the region to transform towards sanitary and other textile products and survive the economic crisis arising from the pandemic. It manufactured from zero to 55 million masks per month in just three months, and it currently exports a proportion of its PPE to countries including India, Colombia, and Mexico  are location-specific factors as the support and collaboration of the territory's stakeholders   to the coronavirus crisis, it is necessary to note that this industry is heterogeneous (from subsectors labor-intensive to knowledge-intensive) and distinguish the cluster from the clustering. The cluster can be understood as a photograph of the geographic location of the companies within a given territory (necessary condition). At the same time, clustering can be regarded as the mechanism by which actors, who form part of the cluster, interact with each other . From this perspective, it can be argued two fundamental aspects: a) there are not two identical clusters Porter, , and b) This research aims to analyze the response of the VTC's firms to the coronavirus crisis and the territorial factors that influenced it. In line with Belso-Martínez et al. , given twww.dowjones.com). This database has been used in a large number of academic publications related to economics  produced by Dow Jones, which provides information for making decisions in companies, investments, and academic analysis  and those published by regional newspapers (22 news from 15 newspapers). Among the national newspapers, prominent news items included four news articles from the newspaper El Mundo and three news items published by La Razón and Economía Digital. We analyzed other main news articles, including four news items from the newspaper Valencia Plaza and three news items posted by Las Provincias at the regional level.Finally, the news content was interpreted using the Atlas.ti software program, the umbrella and relations defined and the recommendations proposed by Corbin and Strauss . By carrAfter this analysis, we obtain two important conclusions. First, according to the evolution of the news, in Spain, the textile industry was on social media, especially during the three first months  in which its firms were more involved in the challenge of creating products that could help medical and civil professionals, and under a situation characterized as highly complex . Second, we observed that 70% of the content referred to responses that can be classified as innovating (63), while the remaining 27 (30%) can be categorized out of this group. Specifically, 3 of them were exit, 6 persevering, and 18 retrenchment 20%. It is noteworthy that practically all of the regional news items and those from the Valencian community referred to innovating at the territorial level.As a result of the content analysis, we can conclude that existed an uneven performance in the strategic response of the Spanish textile firms. According to the newspapers, firms belonging to the VTC battled against the coronavirus crisis, mainly implementing an innovator response. It means that when these firms were the object of public diffusion, it was to echo new products developed to combat the pandemic  and a new process implemented and knowledge and research. At this point, the second question serves as a guide of this paper: the territorial or location-specific factors that influenced it. In the new part, we discuss it.Authors such as Chen  argued tThe hotel industry and travel agencies will be the most affected, along with the textile industry in general, according to Cepyme. The coronavirus crisis severely affects most Spanish business fabric, which has seen almost all its activity paralyze overnight. Large companies have already begun to present an avalanche of ERTE to face losses and try to preserve the millions of jobs that are at stake, but SMEs and the self-employed are also being seriously harmed..Experts are pessimistic about the coronavirus crisis's impact on the textile industry and anticipate a drop in their income close to 20%..The globalized supply of products and merchandise and the extended international production chains have increased the degree of vulnerability of a delocalized and decentralized economy ... Faced with this situation, sectors and citizens must move towards more local models ... greater flexibility, and adaptability to the dynamic and changing contexts that we face..Inditex, which until mid-afternoon anticipated a reduced schedule from 10:00 a.m. to 6:00 p.m. and extreme the cleaning and disinfection work for its network of stores in Spain -with temporary closure in the community transmission areas-, announced at the last minute the closure temporary of all of them "following the recommendation of the administrations." It implies the immediate closure of 1,500 establishments; the Cortefiel chain made the same decision. El Corte Inglés has decided to close down a part of its centers. Covid-19 catches the textile in what could be an excellent spring-summer campaign, with business on the rise due to high temperatures. Everything indicates that the collections will go almost entirely to the sales..If we compare the newspapers informing about "Exit" and "Retrenchment" in response to the crisis, quotes are reflected in the rest of Spain and not in the Valencian Community. Quotes including the words "lay-offs, reducing (activity), costs, closing, exit, and bankruptcy were common on all of them. As example:Many of these companies have reoriented part of their production towards the manufacture of gowns or masks..A research group at the University of Alicante (UA) works with 3D printers to adapt diving masks to which only the filters would have to be changed to fit masks, goggles, and protective screens.Although the Castellón textile sector does not currently have too many companies ... the production rebound would be welcomed like "May water" ...we have the capacity to increase our textile production in Castellón by 30% more.With a dry cleaning service, companies have machines to disinfect masks at more than 90 degrees of temperature… Any help, however symbolic it may be, is essential from the textile sector, which does not give up on the philanthropic work of everything, whatever is in your hand.In liquidation and without workers, the children's fashion company Confecciones Sulfy will reopen its facilities in the Valencian town so that volunteers can use its machinery to produce protective sanitary garments.Meanwhile, precisely the opposite situations occurred in Valencian companies, even special cases such as a bankrupt company that voluntarily reopened its facilities to produce masks for the entire population of companies that redirect their production:In line with the literature on business turnaround and crisis, the strategic response based on the exit, liquidation, or reduction of the activity is associated with interpretations of the crisis' causes as external and not controllable The shortage of basic protection material such as masks… The solution may lie in taking advantage of the textile industry of the province to manufacture these highly demanded items..Due to relocations in the sector, only the most basic ones, the surgical ones, and not the filtering ones, can be manufactured in Spain..Our industry occupies a strategic place in the Spanish economy, and we cannot allow it to be vulnerable or dependent on external agents..Once the fabric is homologated, we can start manufacturing instantly..The Valencian textile industry will finally be able to manufacture surgical masks with all the guarantees..Related to the "Persevering" code that is part of the subcodes "supply chain," "market," and "new normal," practically all the news was published referring to textiles from the rest of Spain. In March, due to supply problems from Asian suppliers, Spain had severe problems sourcing raw materials such as yarns, fabrics, and semi-finished products that were key to producing sanitary textiles other textiles demanded by society and clients. Hence the call of the institutions to resist, look for other alternatives or wait for the fair guarantees to be obtained to start manufacturing was different in Spain than in the VTC:Mueller et al.  have argFinally, upon the innovating strategic response is remarkable that it was the one that the press most echoed. On the one hand, 63 of the 90 events analyzed had to do with the reorientation and diversification of textile businesses. On the other, 24 of the 25 news items referring to the TVC reported from different perspectives. Thus, on the one hand, the press release issued in mid-March by the main Spanish national association (Consejo Intertextil Español) highlighted, indicating that "the Spanish textile industry was at the service of the government" and reporting on the actions carried out such as information on the productive capacities, availability of raw materials and other resources to dedicate them to the production of sanitary textiles. And on the other, because he explicitly cited specific examples of such responses by companies in the territory .The associations that make up the CIE, ATEVAL, and TEXFOR have asked the companies to report on their productive capacities, raw materials, and resources … One hundred companies join the emergency..When the production of the new textiles is approved, we can start manufacturing immediately..The collaboration of ATEVAL and AITEX has been crucial as it has been responsible for providing and facilitating companies that comply with certain hygiene conditions..The Municipality of Ontinyent has signed an agreement with the Association of Textile Entrepreneurs of the Valencian Community (ATEVAL) to launch an initiative to make sanitary textile a strategic industry.Authors such as Staw et al.  argue thThe Minister of Industry, Reyes Maroto, met telematically last Monday with the representatives of the leading industry associations in Spain, such as automobiles, textiles or equipment, to coordinate the manufacture of products with which to face the pandemic..The Spanish textile industry completes the production of up to 160.000 surgical masks a day to help cut the coronavirus contagion chain..The aim is not to completely transform our activity but to achieve a versatile industry that produces sufficient sanitary equipment when there are no epidemics; to be prepared to adapt to large volumes quickly, ensuring the country's supply in times of crisis..The change in the Valencian textile has no way back, and politicians and businessmen continue to make steady progress in this project..In the week from March 31 to April 13, the state of alarm was released, and the cessation of activity was extended ... the textile industry was able to continue operating, having been put at the service of the Administration for the manufacture of sanitary material..Moreover, other news related to institutional support and reduction of uncertainty about production processes would be the following:In short, after analyzing the content and scope of the written press, it is possible to obtain three key conclusions: (1) there is a coincidence between the months that have reported the most on the textile industry and the first months of the pandemic, (2) the articles published reported on the economic costs of the pandemic, but also on solidarity initiatives that textile companies were implementing  and (3) this propaganda served to guide and encourage public institutions in initiatives for change as well as to coordinate the different agents towards a single objective.The question regarding why the VTC behaved differently from other Spanish textile territories lies in two main aspects. First, the productive tradition of that place in home-technical textiles . And second, be part of a textile cluster in which all its actors interacted effectively to facilitate the challenge of fighting the challenge of the pandemic and reducing the impact of the crisis. The Annex 1: Fig. The main objective of this work was to analyze the strategic response of the VTC's firms to the coronavirus crisis and the territorial factors that influenced it. For this, we analyzed the content of press articles published during February–July of 2020 in leading Spanish newspapers. We obtained a total of 91 citations that highlighted the strategic response of textiles firms to this crisis .This analysis revealed that, as happened in the fashion industry  At a strategic level about having little control over the supply and value chain Gereffi, . (2) RegThis study has certain limitations, such as the fact that we focused on a single region  and used Atlas.ti to obtain and codify press news. Future research could replicate this study in other contexts and analyze it at the company level to identify the dynamic capabilities critical to confronting an unexpected crisis  and its effects on the structure of the territory (Schilke et al.,


Hip fracture data were retrieved from electronical medical records for the years 2017–2019 in the State of Qatar and used to create a FRAX® model to facilitate fracture risk assessment. Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi, and Kuwait but fracture probabilities varied due to differences in mortality.This paper describes the epidemiology of osteoporotic fractures in the State of Qatar that was used to develop the country-specific fracture prediction FRAX® tool.Hip fracture data were retrieved from electronic medical records for the years 2017–2019 in the State of Qatar. The age and sex specific incidence of hip fracture in Qatari residents and national mortality rates were used to create a FRAX® model. Fracture probabilities were compared with those from neighboring countries having FRAX models.Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi and Kuwait. In contrast, probabilities of a major osteoporotic fracture or hip fracture were lower in Qatar than in Kuwait but higher than those in Abu Dhabi and Saudi Arabia due to differences in mortality.The FRAX model should enhance accuracy of determining fracture probability among the Qatari population and help guide decisions about treatment. Osteoporosis is operationally defined on the basis of bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry (DXA), with recent refinements of the description focusing on measurements at the femoral neck as a reference standard . The WHOhttps://www.sheffield.ac.uk/FRAX/), recommended in more than 100 national and international guidelines . Data for 2018 and 2019 were estimated from population projections from 2017.Possible differences in incidence between the Qatari citizens and the expatriate population were explored using age-standardized annual rates based on the population distribution of Qatari nationals. Age- and sex-specific fracture incidence was compared to data available for Abu Dhabi, Kuwait and Saudi Arabia.The data on hip fracture in Qatari nationals were used to construct the FRAX model. For other major osteoporotic fractures , it was assumed that the age- and sex-specific ratios of these fractures to hip fracture risk found in Sweden were comparable to those in Qatar. This assumption has been used for many of the FRAX models with incomplete epidemiological information. Available information suggests that the age- and sex-specific pattern of fracture is very similar in the Western world, Australia, and Eastern Europe –15.The development and validation of FRAX have been extensively described , 6. The In order to compare Qatari hip fracture probabilities with those in other regions of the world, the remaining lifetime probability of hip fracture from the age of 50 years was calculated for men and women, as described by Kanis et al. . In the p = 0.0082). Thus, for the development of the FRAX model, the incidence of Qatari nationals was used for both men and women  arose in Qatari nationals. Hip fracture rates were generally higher in women than in men and increased with age. Hip fracture rates were marginally lower in the Qatari population than in the entire population. When the Qatari population was compared to the expatriate population, age-standardized annual rates were not significantly different in men . In women, however, age-standardized annual rates were significantly lower in the Qatari population . In both sexes, the incidence increased with age. In an international perspective, hip fracture incidence was low in both men and women . It is oA minority of countries that have a FRAX model also have robust information on the risk of other major osteoporotic fractures. In the absence of such information, FRAX models are based on the assumption that the age- and sex-specific pattern of these fractures is similar to that observed in Malmo, Sweden . The assWhereas the Qatari FRAX model permits the assessment of fracture probability in Qatari citizens, the question arises of how to assess fracture risk in expatriates. This community is ethnically very diverse and current evidence indicates that expatriates retain the risk characteristics of their country of origin , 25, so n = 151) despite the national catchment and 3-year study interval. Thus, age- and sex-specific hip fracture rates are bound by wide confidence intervals. The quality of studies on hip fracture incidence are usually determined on the basis of national representation and duration of observation [The limitations of the present study relate predominately to the accuracy of the FRAX model. This in turn is dependent on the accuracy of the fracture and death hazards used in the construction of the FRAX model. Whereas death rates for the general population are likely to be robust, the number of hip fractures were few (ervation . Some coIt is relevant, however, that accuracy errors have little impact on the rank order with which the FRAX tool categorizes risk in a given population , 28 but In summary, a FRAX model has been created for the State of Qatar based on a national estimate of the incidence of hip fractures. The model should enhance accuracy of determining fracture probability among the Qatari population and help to guide decisions about treatment.


Intermediate filaments (IFs) are a primary structural component of the cytoskeleton extending throughout the muscle cell (myofiber). Mechanotransduction, the process by which mechanical force is translated into a biochemical signal to activate downstream cellular responses, is crucial to myofiber function. Mechanical forces also act on the nuclear cytoskeleton, which is integrated with the myofiber cytoskeleton by the linker of the nucleoskeleton and cytoskeleton (LINC) complexes. Thus, the nucleus serves as the endpoint for the transmission of force through the cell. The nuclear lamina, a dense meshwork of lamin IFs between the nuclear envelope and underlying chromatin, plays a crucial role in responding to mechanical input; myofibers constantly respond to mechanical perturbation via signaling pathways by activation of specific genes. The nucleus is the largest organelle in cells and a master regulator of cell homeostasis, thus an understanding of how it responds to its mechanical environment is of great interest. The importance of the cell nucleus is magnified in skeletal muscle cells due to their syncytial nature and the extreme mechanical environment that muscle contraction creates. In this review, we summarize the bidirectional link between the organization of the nucleoskeleton and the contractile features of skeletal muscle as they relate to muscle function. Intermediate filaments (IFs) contribute to force transmission, cellular integrity, and signaling in skeletal muscle. IFs are flexible, rod-shaped fibers averaging 10 nm in diameter, a size that is “intermediate” between microfilaments (7–8 nm) and microtubules (25 nm). IFs are classified into major families, with types I–IV localized in the cytoplasm, type V comprised of the lamins inside the nucleus, and type VI comprised of neural and lens proteins. In mature skeletal muscle, the IF cytoskeleton is composed predominantly of type III IF proteins, with the muscle-specific protein desmin being the most abundant. Desmin is an intracellular protein linking individual myofibrils laterally to each other and is important for the transmission of active and passive forces within the cytoskeleton . Other IIn addition to the cytoplasmic IF network, the nuclei contain a network of lamin IF proteins. Like their cytoplasmic counterparts, the nuclear lamins are an important determinant of nuclear stiffness and are crucial in maintaining the integrity of the nuclei in the mechanically intense environment of a contracting muscle . Many stAlthough most eukaryotic cells have a single nucleus, myofibers are multinucleated. To support the large cytoplasm in the skeletal myofiber, the nuclei are evenly positioned along the cell periphery to maximize the distance between nuclei . This evThe nucleus serves as the instruction manual for cells, containing the vast majority of the genome and the site of gene regulation. Thus, how it interprets stress to alter gene expression and its position to deliver cellular materials clearly contributes to cell behavior. Like most cell organelles, the nucleus is surrounded by a membrane. However, the nuclear envelope (NE) is composed of a double bilayer lipid membrane that forms a barrier between the nuclear interior and the cytoplasm . This NEThe linker of nucleoskeleton and cytoskeleton (LINC) complex is a series of proteins that physically links the nucleoskeleton to the cytoskeleton and allows for transmission of force from the cytoplasm to the nucleus for many functions including nuclear spacing and gene regulation . In mammWithin the nucleus, the lamina is composed of ∼3.5 nm tetrameric lamin filaments and is approximately ∼14 nm thick. The lamina lines the INM, connects chromatin to the nuclear periphery, and directly interacts with transcription factors to regulate gene expression . In addiLMNA gene. Lamin B1 is encoded by LMNB1 and Lamin B2 and B3 are encoded by LMNB2 gene. Different lamin isoforms interact to form the lamina and have many binding partners, including chromatin, LINC complex proteins and NPCs. Similar to other IF family members, lamins are composed of a α-helical rod domain with a short N-terminal head and a long tail domain containing an Ig-fold. The rod and head domains are essential for lamin assembly, but other regions are also important for proper protein function. The tail domain with the globular Ig-fold contains most of the interaction sites for lamin-binding partners. Lamins govern numerous biological functions, both biophysical and biochemical  genes  genes . Conversmulation . While cn of YAP . Such stn of YAP , which aLMNA mutations  and strength. However, in muscles with mutations in the ignaling . Mutatioexercise . Patientfunction . Thus, fIncreasing stiffness of the extracellular matrix results in decreased phosphorylation of lamin A and consequently decreased degradation of lamin A . SkeletaHow mutations in genes for lamin IFs and NE proteins affect skeletal muscle function is complicated and studies are still being performed to understand the underlying mechanisms. Defects in the nuclear lamina, the LINC complex, and the NPCs can impair the ability of nuclei, and therefore the muscle cell, to respond appropriately to mechanical forces. Understanding the mechanisms of impaired mechanotransduction in aging and diseased muscle is likely to shed light on strategies designed to prevent and treat skeletal muscle dysfunction with disease and aging.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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 extensive use of antibiotics leads to antibiotic residues in frequently consumed foods. Generally, the main use of antibiotics in animals is to treat and prevent diseases and growth promotion. However, the residues and their breakdown products have several side effects on the human body and, in a broader sense, on the environment. In relation to the human body, the frequency of mutations is increased, the bone marrow is damaged (chloramphenicol), and the reproductive organs of humans are affected. Carcinogenic effects have been found with antibiotics such as sulfamethazine, oxytetracycline, and furazolidone. We summarized data from 73 scientific studies reporting antimicrobial residues in animal products that were freely available for sale. The studies were published in English starting from 1999 till 2021 and identified through the Pubmed search engine. The aims were to find out which antibiotics, legal or illegal, could be found in animal foods worldwide. Which are stable to get into the food chain and exceed the maximum residue limits (MRL) regarding the EU guidelines as a comparison. Reducing antimicrobial residues in food from animal origin and, in addition to this, fighting the tremendous growth and spread of antimicrobial resistance will undoubtedly be one of the most difficult food safety challenges in the coming years. The discovery of antibiotics and their use in animals and humans was indisputably one of the greatest achievements of the 20th century . HoweverOur review aims were as follows: (a) Which antibiotics were detected in foods of animal origin and which test methods were used? (b) How often do consumers get in contact with food contaminated with antibiotics? What country differences are there based on the published studies regarding food animal species and antimicrobial residues? (c) How often have the MRLs (EU guidelines) been exceeded in the case of positive evidence? We extracted all raw data and metrics reported in these studies, discussed the limitations of the methodologies used, and documented data gaps. We hope that this review will help regarding that. The detection of antibiotic residues in animal foods is increasingly investigated and documented, and thus, more data is made available to the scientific community.The number of first search results was huge. So, the summaries of the scientific texts had to be sorted out by hand based on the question in order to include as many papers as possible. Antibiotic residues in animal products that reached consumers had to be neatly separated from antibiotic degradation tests in tissues and methods for detecting these compounds. This resulted in the data after the first review, which was already much smaller as can be seen in As can be seen in For a clearer evaluation, all studies with salmon, other fish from aquaculture, and shrimp were combined as seafood in the evaluation, as can be seen in In Vietnam, China, and Iran, most of the studies related to antibiotic residues in animal products have been carried out, as can be seen in Compared to Asia, the picture in Europe is entirely different, as can be seen in In the data from Africa, as can be seen in The situation on the American continent is entirely different, as can be seen in The determination of antibiotic residues and the determination of their concentration in animal products were carried out in the 73 studies using different test procedures. ®test technology , Copan test kit , Delvo SP® test kit , Equinox test, SNAP tetracycline test kit, SNAPbeta-lactam test kit, the SNAPgentamicin test kit , Ridascreen chloramphenicol, and streptomycin kit ,. Microbial Inhibitor Tests and test kits were used, such as the microbial inhibition test using Bacillus subtilis ATCC-6633 .In the evaluated scientific studies, as can be seen in The use of ready-made test kits was prevalent in African countries. This may also be due to the fact that other laboratory facilities were not available. In some cases, the test kits were used to detect antibiotic residues in the samples initially and then subject them to a more detailed examination method or determine the residues more precisely using this method.Sparus aurata) and sea bass (Dicentrarchus labrax) were found in 18.3% of the samples (n = 82) [Considering all 73 scientific papers evaluated, tetracycline was detected in 39 cases, as can be seen in (n = 82) . ScientiThe maximum residue limit (MRL) is the maximum allowed concentration of residue in a food product obtained from an animal that has received a veterinary medicine or that has been exposed to an antibiotic for use in animal husbandry. The substances found include a wide range of antibiotics used in agriculture. The most critical question in this context, however, is how many substances exceeded the upper limit values. This is displayed in In this work, we reviewed 73 studies on antimicrobial residues in animal products published in English since 1999. In relation to the importance of this topic, the number of publications found was relatively small. This finding can have several causes. In the USA, the European Union, and some Asian countries, the legal guidelines regarding antibiotic residues in food are relatively strict and are also checked by state authorities. A scientific study by non-governmental research groups, therefore, does not seem worthwhile. Unfortunately, there are often rumors among the population in industrialized countries that the foods available there are full of antibiotics, pesticides, and hormones, which would cause serious health problems. It must be noted here that it is precisely in these countries that food safety is highest in terms of residues of various chemicals and pathogenic germs or parasites. Many European countries have already banned the addition of antibiotics to animal feed as a preventive measure in relation to the avoidance of diseases in livestock farms ,93. AddiPenaeus indicus) that contained chloramphenicol residues, this drug gets destroyed or degraded during heat processing treatments [Products that exceed the maximum allowed residue limits pose a serious problem. Heat treatments that occur in cooking processes can reduce the risk of ingestion of sulfonamides, tetracyclines ,96, and eatments . FurtherApart from that, concentrations of antibiotic residues vary between different edible muscle tissues . HoweverThe previous findings of this work were able to locate most of the problems with antibiotic residues in developing countries and emerging economies. It must not be forgotten that due to world trade, many of these animal products also end up on the plates of western consumers. Seafood and fish from aquaculture should be mentioned here. Due to the many positive properties in relation to a balanced diet, the consumption of these animal products is also increasing sharply ,103. ThiIn many European countries, as well as in the USA, there is a trend in animal breeding and husbandry to keep them in their natural habitat, away from factory farming in large stables. In addition, consumers want more and more meat from animals that have been treated with as few antibiotics as possible during rearing and until slaughter. However, can this desire of consumers be implemented without any problems? In a Danish study regarding consumer preferences for meat with reduced antibiotic use in pig production, two-thirds of the consumers stated a positive will to pay more for this product. However, only one in five were willing to pay more than 10% for pork produced using antibiotics, 20% less than average . While cThe presence of antibiotic residues in meat products that are above the maximum permitted limits is a serious problem. Based on the values of the maximum levels of residues in animal tissue and in relation to the daily consumption calculated on the bodyweight of the person, these residues should not pose a health risk. Exceptions are allergic reactions to antibiotics. In this context, however, a possible connection must be mentioned.There appears to be a relationship between antibiotic use and the increase in obesity in people. The number of publications on this topic is increasing steadily. Some authors point out that there is a direct link between the increased use of antibiotics in animal breeding and the increase in the number of obese people in our society over the past 70 years . It woulhttps://pubmed.ncbi.nlm.nih.gov/, the website was accessed on 15 March 2021) was used to search for original scientific papers published in English from January 1999 to March 2021. The following terms were used to search scientific papers using the following keywords:  AND . All retrieved records were saved for further review. Publications not reporting original research data or written in languages other than English were further excluded. Publications containing antimicrobial residues data in the abstract were selected for a first investigation. All scientific papers that dealt with residues of antibiotics were excluded, but in the sense of detection methods or residues in the environment, as well as pollution of animal manure, the rest that contained only research data regarding antimicrobial residues in animal food were reviewed with full content. In addition to the techniques used to detect antibiotic residues, the size of the sample was also an important quality criterion for us. We divided the sample sizes into 6 categories. Up to 50 samples were documented in 16 publications. Up to 100 samples were documented in 19 papers. Up to 200 samples were documented in 20 papers. Up to 300 samples were documented in 12 papers. Up to 400 papers were documented in 6 papers. Twelve papers were summarized for a sample size of over 400 up to 25,000. All work with a sample number below 50 was subjected to a thorough analysis regarding sampling and analytical methods. If this was correct or meaningful, this data was included in our evaluation. Publications were broadly classified by the country where the research took place, year of publishing, and further categorization regarding the animal food product.The PubMed engine : (1) country of study, (2) year, (3) type of animal product, (4) sample size, (5) animal production type, (6) antibiotics found, (7) detection method, and (8) over maximum residue limits.All data were entered as single records (‘datapoints’) in Excel (Microsoft Office). Antimicrobials and antimicrobial classes listed were those included in the World Organisation for Animal Health (OIE) classification: veterinary critically important antimicrobial (VCIA) agents (10 classes); veterinary highly important antimicrobial (VHIA) agents (8 classes); and important veterinary antimicrobial (VIA) agents (8 classes) .The problem of antimicrobial residues in animal products is not new. However, due to the globalization of the food trade, we are constantly facing new challenges. Reduction of the antimicrobial volumes currently used by humans and livestock and limiting the use of broad-spectrum and critically important antimicrobials would be essential. Educational work regarding antimicrobial residues in animal products and the associated development of multi-resistant germs must be stepped up in developing countries. This can only be reduced through increased monitoring of the use of antibiotics in animal breeding. In any case, users must be informed about the health consequences for their customers regarding antibiotic residues in animal products and the development of multi-resistant germs. The ban on the disposal of rubbish, sewage, and manure containing antibiotics must also be mentioned in this context. Alternatives to antibiotics, such as various vaccinations, the use of phages, and phage therapy, must be promoted. The use of prebiotics and probiotics in animal feed and the use of traditional medicinal herbs must also be further researched to ultimately reduce the use of antibiotics in animal breeding to a realistic amount.


In clinical research, ethical review is required prior to conducting the research. A surgical procedure is a complex intervention with properties that make it more difficult to evaluate rigorously and monitor than drug treatments. This study aimed to clarify the current status and issues in the ethical review and monitoring of surgical research. We developed a self-administered questionnaire on surgical ethical review. The questionnaire was distributed to university hospitals in Japan and collected from November 2018 to February 2019. The distributed questionnaire consisted of the reviewed items, items with difficulties, and important items on ethical review. Fisher’s exact test or the chi-square test was used for analysis. The questionnaires from 39 medical university hospitals were completed with appropriate answers to all items. “Technical review” was conducted at a significantly lower proportion . “Evaluation of the progress and results” was also . University hospitals in which “technical aspects and ethical review” was regarded the most important and difficult were higher . Respondents considered not only items written in the study protocol but also those on monitoring or oversight of surgical research as difficult. Our findings suggest that it is necessary to improve the ethical review system and provide supports to conduct an appropriate review for surgical research, e.g., technical aspect review or study progress/result evaluation.  After several painful lessons in the past decades, various principles or guidelines have been established for human research (6). Ethical reviews based on these principles are conducted worldwide, and medical researchers conduct clinical studies under these guidelines.In clinical research that entails work with human participants, ethical review is required prior to starting the research A novel treatment or intervention is expected to improve clinical practice and provide better medical therapeutics, and its ethical aspects are highlighted. Ethical review should be conducted rigorously in implementation research and in managing risks associated with the research. In the case of the developments of new investigational pharmaceutical drugs or medical devices, clinical trials should be reviewed, performed, and overseen by Good Clinical Practice (GCP) guidelines to maintain their scientific, safety, and quality control. In contrast to the ethical review or oversight of a new drug or medical device, norms for surgery have not been established strictly thus far.(8). Moreover, surgical research is highly flexible and difficult to monitor and oversee. Previous studies have reported that there is no standardized approach to assist surgeons in assessing ethical challenges in surgical innovation (10). Gupta et al. proposed few possible oversight frameworks to regulate it, and one was institutional review board (IRB) approval (9).A surgical procedure is a complex intervention that is more difficult to evaluate rigorously for safety and efficacy than drug treatments owing to its components (11). The regulation also provided the definition of the novelty and difficulty of medical technology, the skill of the surgeon, the implementation system, and informed consent for hospitals subject to the regulation based on the concept of medical safety. Currently, it is required for hospitals to manage and maintain the surgical care and procedures based on the regulations. A previous study reported the current practice and supervision issues in new clinical surgery (12). On the other hand, clinical research on surgical research in Japan is covered by the Ethical Guidelines for Medical and Health Research Involving Human Subjects (4). In this guideline, the ethical review committee should include an expert in natural science, such as a medicine and medical care professional. Medical professionals, however, might not be always specialists in surgery or the research field. The issues of ethical review for surgical research were reported in previous studies, e.g., patients, operators, intervention, comparators, and ethical aspects (13). Specific problems in surgical research, e.g., randomization, blinding, sham arm, study design, evaluation of scientific validity, and conflict of interest, have remained issues that require attention (15). However, the actual situation of ethical review and what are considered more difficult are unclear.Regarding the rules for surgical care and procedures in Japan, the Ministry of Health, Labour and Welfare reissued the Regulation for Enforcement of the Medical Care Act in 2016, and some hospitals were obliged to implement and manage the process of introducing the new medical technology and procedure with high difficulties (3). Although this act is primarily targeted at clinical research within pharmaceutical bodies, Article 2 of this act’s Supplementary Provisions states: “The government considers measures to verify the effectiveness and safety of advanced medical practices that do not necessarily have sufficient scientific knowledge. Based on the results, we will take legal and other necessary measures.” These advanced medical practices include surgery research. Therefore, we hypothesized that there were differences in the implementation and status of ethical review and monitoring of surgical research among university hospitals. The purpose of this study was to clarify the current status and issues in the ethical review and monitoring of surgical research using a questionnaire survey for the condition of university hospitals in Japan.Moreover, the Clinical Research Act was implemented on April 2018 in Japan as a result of data falsification in clinical trials by pharmaceutical companies (15) on ethical reviews of research and medical care for surgery by mail via postal services. The questionnaire was distributed to each hospital head of 134 university hospitals in Japan. Respondents received an informative letter regarding our study and a pre-stamped envelope with the address of our department for the respondents’ replies. In addition, an electronic file of the questionnaire was sent to those who wished. The questionnaires were again sent to all non-responding hospitals one month later. All targeted hospitals were confirmed to receive the questionnaire once or twice by phone and asked to answer and send it back.This study was conducted from November 2018 to February 2019. In this prospective study, data were collected via a self-administered questionnaire (15). We conducted a literature review and summarized previous reports from Japan and other countries (19). Further, we had a discussion with many domestic and overseas surgeon researchers. Following the discussions with these surgeons, a set of questions was developed for the self-administered questionnaires (12). The distributed questionnaire consisted of the following chapters: reviewed items to be examined, items with difficulties on ethical review for surgical research, and important items on ethical review. The first chapter consisted of a series of three parts: the necessity of review (one item), the review (six items), and the results (two items) (20). Chapters 2 and 3 consisted of two similar parts: content related to research implementation and review of study protocol and items on research monitoring or operational management such as management burden (center/research group) or the relationship between research and medical care. Each chapter of this questionnaire consisted of two parts: surgical research and medical care.For the purpose of this study, we developed the questionnaire on surgical ethical review. We searched several documents using various databases, including Medline, Web of Science, Social Science Citation Index, and Ichushi for Japanese articles. The search terms included keywords such as ethical examination, surgical technical examination, and new technical examination from the viewpoint of safety and efficacy (21)).In this study, we analyzed the data on ethical reviews of research for surgery collected using the questionnaire. The answers to the questions were first coded for statistical analysis and double-checked. In the coding of the answer, an answer of “yes” was coded as Yes, and “no” and “no answer” were coded as No. Assuming that the groups for the two items of the questionnaire were independent because each content of the questionnaire was different, Fisher’s exact test or the chi-square test was used. The null hypothesis in those analyses was that no relationship exists on the distribution of two elements that were the responses to the test item and those to the reference; they are independent. The odds ratios obtained from the analysis were interpreted as the degree to the response of “Yes” of the test items compared to those of the references. Statistical analysis was performed using statistical software R version 3.5.2  was 43%.The characteristics of the questionnaire respondents on surgical research were as follows: Of the university hospitals that responded, 69.2% were national university hospitals, 20.5% were private university hospitals, and 10.3% were public university hospitals. The median number  of hospital beds of the respondents was 736 (613-856), and the annual median number (IQR) of operations was 7,663 . The median number (IQR) of annual approvals for ethical review of clinical studies on surgical research was 3 (0.5-8). Information was also collected on the characteristics of the institutions in which the respondents were based.The present study evaluated the ethical review for surgical research in Japanese university hospitals. Reviewed items on surgical research in the ethical review committee of Japanese university hospitals were unknown. In the present study, we found that aspects on ethics, safety, research team systems, and informed consent for surgical research had been reviewed in most of the ethical review committees. Therefore, we noted that ethics committees of most university hospitals were screened properly. Conversely, some items such as technical aspects or the study progress and results can have a low percentage of review by ethical committees.(22). Moreover, Steiger reported that surgical procedures are usually highly technical and therefore difficult to judge by the IRB (23). IRBs may have difficulties evaluating surgical innovations either because they lack the necessary expertise or the ability to do so (24) or because surgical procedures are usually highly complex (23). In this study, many medical universities might recognize technical review for surgery as important but might find it difficult to implement at the same time because of the absence of an IRB member to understand the details and technique of surgery. Therefore, regarding the technical examination of surgical procedures, support is desired. As described by Steiger (23), it might be possible to consider relying on external experts for IRB reviews and developing a system for introducing surgical reviews.In contrast to reviews of ethical aspects or safety and informed consent, approximately 20% of medical institutions were not conducting technical reviews on surgical research. In addition, approximately 61% of medical institutions said that ethical review  was considered important, and 66% of medical universities face difficulties. The previous study reported the lack of expertise to adequately judge surgical innovation in some IRBs (4). This ethics guidelines state that the results, progress, and adverse events of research should be reported to the ethics review committee. Although evaluation of results by the ethical review committee was not specified in the ethical guidelines, evaluation of adverse events was conducted. In Japanese university hospitals, some principal investigators report results to the ethics review committee based on ethical guidelines. However, it was thought that the reporting system based on the ethical guidelines was not operating properly. Reporting of results and adverse events is an important item as required by GCP as well. For early-phase studies, reporting of selective outcomes is likely to lead to overoptimistic assessment of new interventions and under-reporting of adverse effects in many surgical areas (25). This raises the risk of outcome reporting bias. Therefore, it was considered necessary to take counter responses for medical institutions that had not implemented the reporting of results, including adverse events.In this study, most university hospitals examined items related to clinical trials such as ethics, efficiency, safety, and informed consent. Numerous university hospitals may be focused on reviewing the study plan intensively before a trial begins. Furthermore, in this study, not many medical university hospitals answered that they were conducting examinations on items related to progress and report on results, including adverse events, compared to the other IRB review items. Approximately 90% of medical universities’ hospitals reported receiving the study progress and results, and approximately 60% of them evaluated them. In Japan, the Ethical Guidelines for Medical and Health Research Involving Human Subjects was established in 2014 Regarding important items, emphasis is placed on the examination of the research protocol because contents related to research implementation, such as the implementation conditions, informed consent, and definition of novelty, were considered important items. On the other hand, the importance of items, especially the evaluation of the results other than the examination of the study protocol, was not understood, and the implementation ratio was low.For difficult items, informed consent, trial registration, and evaluation of the results were significantly lower in the scope of the items related to the ethical review. The detail scope of the informed consent and trial registration were stipulated in the ethical guidelines, and current understanding of researchers on trial registration was increasing. It is thought that the understanding of the researchers was improved by the provision of guidelines. On the other hand, the research results have not been evaluated in ethics review committees, and above all, the necessity might not be understood for respondents. They also answered that it was difficult even for items other than those related to conducting research, such as the monitoring and the efforts and burdens involved in operation. It was considered difficult to conduct other monitoring and oversight operations.(11). In a case, it might be useful to provide the guideline written with the detailed procedures. Second, because clinical trial registration also requires reporting of the study results (26), we would have researchers understand the necessity and awareness of the reporting and evaluation of progress and results. In addition, it is important to design a process for continuous assessment of adverse events, study results, and other events in ethics review. As a result, it might be expected that this will also lead to strengthening of the function of monitoring and/or oversight.Our findings lead to few recommendations for the management of ethical review on surgical research. First, the findings suggest the involvement of technical experts to ensure a technical perspective in ethical reviews. If it is difficult to find an appropriate expert because of a restricted area, we may consider the option of adopting a procedure such as a request of cooperation from the academic society or, if possible, combining it with a review of medical surgery The present study had some limitations. First, this report included a small number of hospitals. Because the questionnaire was distributed to each hospital head, it was also possible that the questionnaire was not passed to the person in charge of clinical research review. Therefore, the findings might not be universally accepted or comprehensive. However, it might be possible that the ethics review committee of the university hospitals that responded in this survey functioned more properly compared to that of university hospitals that did not respond. In that case, it is conceivable that non-responding university hospitals are in a worse condition. Therefore, the results of this study might be underestimated or overestimated. Second, in this study, “no response” of an answer was coded as No in data processing. A missing value was treated as No and included for this analysis. It might be possible to include in “No” a situation in which the problem was not understood, apparent, or recognized as important. The results may be more conservative. However, we paid close attention to this bias and consulted with surgical experts. Third, owing to the space of the questionnaire, the explanation of the question was restricted. It was possible that it may be difficult for the respondents to understand the intent of the question. It might be that some of the non-responders could not answer because they did not understand the questions. When we made phone calls and requested to return the questionnaires, we could sometimes have opportunities to receive the questions and answer them. Lastly, the respondents to this survey were the secretariat or the head of the ethics review committee. A member of an ethics review committee is most likely a physician, but this might differ from the views of researchers, such as physicians conducting clinical research on surgery. It is necessary to understand that this study depended on a situation for committee members.Further studies are needed to clarify the problems and the useful tips in designing the processes for the involvement of technical experts and the evaluation of research progress and results. It may be useful to conduct an in-depth interview survey for hospitals that were conducting a technical review in this study, those that were evaluating the research results, and those that did not. Useful and detailed information could be obtained for advancing a more appropriate ethical review.Appropriate evaluation and ethical review in surgical research are difficult to evaluate appropriately because of a complex intervention. In addition, surgical research is highly flexible, and monitoring and oversight are difficult. Our findings show that the ethics, safety, research team system, and informed consent aspects of surgical research were reviewed by most ethics review boards and the technical aspects and the evaluation of research progress and results had a low review proportion. For the improvement of the ethical review for the technical aspects, it is necessary to strengthen the examination system of the ethics review committee. We expected the involvement of experts in the concerned field in ethics review for surgical research. With the involvement of those experts, it is possible to ensure the scientific and ethical aspects in the function of the ethics review committee. Moreover, with the improvement of the evaluation of the study results, that is by consistent reviewing from the beginning of the research to the conclusion, the role of the ethics review committee is expected to further strengthen, including monitoring and oversight. As a result, the quality of clinical research for surgical research is expected to be consistently improved.NoneThis work was supported by a Health Labour Sciences Research Grant  2018-2019 from the Ministry of Health, Labour and Welfare, Japan [grant numbers H30-Tokubetsu-Shitei-014].We would like to thank the university hospitals that cooperated with us in this survey.MD: methodology, formal analysis, investigation, data curation, writing - original draft. KY: methodology, validation, writing - review & editing. HS: conceptualization, methodology, writing - review & editing, supervision, project administration, funding acquisition. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.Not required


To systematically review studies on HRQOL, measured by the WHOQOL-Bref instrument, of refugees in general and clinical populations who are settled in the community of the hosting country, and outline the differences in scores among the two population groups and across the four domains of WHOQOL-Bref  as well as factors impacting those outcomes.Several databases were systematically searched by using a broad search strategy. Additionally, a hand search for grey literature was performed. Studies had to comply with the following inclusion criteria: (a) population of refugees; (b) living in the community of the country of destination; (c) assessing HRQOL through the WHOQOL-Bref instrument.15 studies were identified and divided into two subgroups: (a) general population of refugees (b) clinical population of refugees, who were specifically selected for their mental status or because they had experienced relevant past traumas. Although we can outline common patterns among the two groups, in terms of domains scoring the highest and the lowest, heterogeneous values of HRQOL are observed across the studies included.Individuals who were included in the clinical refugee group have a lower quality of life in respect to the general population of refugees. However, among the two groups different patterns can be outlined considering each domain of HRQOL: higher scores for the Physical and lower for the Environment domain when considering the general population of refugees and higher scores for the Environment and lower for the Psychological domain when referring to the clinical one. These lower scores are probably due to having a higher rate of mental distress and being more exposed to somatization, stigmatization and barriers to access the healthcare system of the hosting country.The online version contains supplementary material available at 10.1186/s13031-021-00378-1. There are currently over 79.5 million people who are forcibly displaced in the world, among them 26 million are refugees, a number that more than doubled in the last decade . Open-enThe large majority of refugees are exposed to traumas. In their country of origin, they experience pre-migration traumas like human right violations, murder of relatives, imprisonment, torture and war. In transit to their destination are often exposed to physical and sexual violence, as well as maltreatment by traffickers and authorities. Finally, after arrival at their destination, refugees are exposed to post-migration stressors, such as feelings of being alone and uprooted, social exclusion sometimes culminating into open hostilities, and hardships in securing their subsistence. Factors that put them under immense pressure and worsen an already precarious mental health state in refugees who have been already subjected to trauma. All these aspects are strongly associated with mental health problems, namely PTSD, depression and anxiety –16. The As the experiences made by refugees might affect different aspects of health, it is necessary to employ a more general definition of health to describe the health status of this population. The health-related quality of life (HRQOL) is an outcome which aims to respond to the necessity of assessing health through a non-disease specific instrument «capturing changes of health that matter to the patients and the societies they live in» . In thisThe holistic definition of health provided by the WHO  was at to systematically review studies examining HRQOL of refugees using the WHOQOL-Bref, considering both non-clinical and clinical groups, when living in a community setting;to identify factors that impact HRQOL;to provide a starting point for future investigations of individuals having refugee status, belonging to a general or clinical population;to inform possible policies aimed to enhance the HRQOL of refugees.In particular, the purpose of this paper was as follows:We conducted a systematic literature search in Medline, PubPsych, BioMed Central, CINAHL, APA PsychInfo, APA Psycarticles, Index Islamicus, Cochrane Library and the Open System for information on Grey Literature in Europe (OpenSIGLE). Furthermore, we scanned the references of the studies selected and conducted an additional hand search focusing on potentially relevant journals . We chose a broad search strategy using the following terms: “refugee*”, “asylum seeker*”, “undocumented”, “Migrant*” and “Immigration” (due to possible inconsistencies in the definition of refugees) combined with “HRQOL”, “Health-related quality of life, “QOL” and “Quality of life”.Studies meeting the following criteria were included: (a) population of refugees; (b) living in the community of the country of destination and being resettled in High-Income Countries (HICs) or in Upper-Middle Income Countries (UMICs) as classified by the World Bank criteria ; (c) assThe eligibility check consisted of two steps. First titles and abstracts were checked for potentially relevant content. Second, publications deemed potentially relevant were screened in full text.We considered refugees as defined by the Protocol of the Refugee Convention in 1951 as any person “who is unable or unwilling to return to their country of origin owing to a well-founded fear of being persecuted for reasons of race, religion, nationality, membership of a particular social group, or political opinion” . In the It appeared to be appropriate to observe a more homogeneous population living in comparable environments, facing the same opportunity and difficulties of being integrated into a new country. Therefore, we decided to exclude those studies taking into consideration individuals living in a more precarious situation, as refugee camps, specific housing facilities or detention centres, which often represents a phase of transition towards a new dwelling and where it is observed a higher rate of depression  and abusWe made a distinction between refugees belonging to the general population group of refugees and a clinical one. Among the first group, the selection was based solely on the participants refugee status. The second group of refugees was selected among people having experienced highly traumatizing events or having a formal diagnosis of PTSD, anxiety and/or depression or scoring above the cutoff values using self-report instruments such as Hopkins Symptom Check List-25 (HSCL-25), for anxiety and depression, and Harvard Trauma Questionnaire-PTSD (HTQ-PTSD) for diagnosis of post-traumatic stress disorder. It has been observed that refugees having been exposed to comparable types of stress produce different symptomatic patterns  and thatThe WHOQOL-Bref consists of a 24-item self-reported questionnaire divided into four domains  plus 2 items to measure individual perceptions of global QOL and health status , 45. OutThe data extraction was designed to show the main characteristics of the studies and the samples taken into consideration, as well as their primary outcomes. As baseline characteristics we extracted: sample size, gender, age mean and marital status of the participant, their country of origin and the country where the study was performed. Information regarding the characteristics of the study outlined in the table are: study location, recruitment method and year of data collection. When considering the general population of refugees only the values of WHOQOL-Bref was evaluated as an outcome.From studies considering the population of refugees with clinically relevant mental health problems we extracted also their employment status and duration of stay in years, and outcomes evaluating the psychological status of the participant in terms of anxiety, depression and PTSD. Regarding those outcomes, we extracted information on the average scores of the questionnaires used to evaluate their mental health condition and, in some cases, the percentage of the sample suffering from those mental disorders. Information that was not displayed consistently among studies or in a non-comparative form, such as education level, were excluded.The well-known and widely used NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies  was usedThe initial search generated 7391 results. 5243 were duplicates. After abstract screening, 79 publications were deemed potentially relevant. 66 studies were excluded as they were not meeting the inclusion criteria. 21 were excluded because considering a mixed population of refugees and asylum seekers, or not clearly defining their status; 10 were considering refugees living in camps, housing facilities or detention centers; 28 were not using the WHOQOL-Bref but other instruments to assess the HRQOL ; 6 were excluded because they were not displaying the outcomes of WHOQOL-Bref at the baseline making those incomparable to the other studies included; 1 study considered underage participants which are characterized by other vulnerabilities and needs in respect to an adult population. Additional screening of reference lists and additional hand search considering relevant journals, resulted in identifying two further publications. Among the studies selected, 11/15 were performed in High-Income Countries and none of them were RCTs. Detailed information is provided in the PRISMA flow diagram in Fig.All studies in this group were observational studies. The aim of these studies was diverse: to compare differences between refugees and local population  or betweTable Most studies showed no clear gender differences and no evident distinction between studies performed in HICs and UMICs can be observed.Table The majority of the studies were performed in specialized psychiatric and rehabilitation facilities located in HICs. The samples included individuals who were recruited through a direct recruitment method. The Harvard Trauma Questionnaire was the instrument most frequently used to diagnose PTSD. The cutoff score considered was ≥2.5 for all the included studies, which is the standard cutoff for this instrument . The HopIn epidemiological studies, the researchers aimed to observe an association between different elements characterizing this population and their HRQOL. We want to highlight the following findings: in the study of Teodorescu et al. , depressWe do not observe peculiar differences in HRQOL’ outcomes at the baseline, comparing intervention and epidemiological studies. The only scores, which are noteworthy by being above the outcomes reported by the epidemiological studies, are the ones of Carlsson, Olsen et al. . Here, wOn average, the scores of WHOQOL-Bref for the group of clinical refugees are lower in comparison to the ones of the general population of refugees but we can still notice some exceptions, especially when looking at the environmental domain. The lowest outcomes were observed for the physical and the psychological domain, for which scores below 30.0 were assessed, while the highest were observed for the environmental domain reaching a value of 50.0 in the sample considered by Huijts et al. . These lTable The aim of this literature review was to highlight the evidence on the HRQOL of refugees, gain awareness for their needs, as well as present the elements having a greater impact on it.In the studies selected, we can notice a wide heterogeneity among the scores obtained, in particular when referring to the general population of refugees: from a minimum score of 38.0 for the environmental domain, to a score of 73.1 for the physical domain. When observing the clinical group of refugees, lower outcomes were assessed for the physical and the psychological domain, scoring also below 30.0, while higher scores were assessed for the environmental domain reaching a value of 50.0. Nevertheless, it is possible to outline some elements having a considerable repercussion on specific domains and the differences among the two groups of refugees, general and clinic population, that we defined.Regarding the Physical health domain, lower scores could be related to difficulties to access and understanding of a new healthcare system which might be demanding in terms of documents needed to access and cost of services. In particular, the lack and/or misuse of interpreters and culturally sensitive approach, which undermine the delivering of a correct and efficient treatment, represents one of the most decisive barriers to access healthcare service especially for refugees and asylum seekers –78. HoweLow scores in the Psychological health domain, that characterize particularly the population of clinical refugees, are bound to the traumatic and stressful events experienced which can have direct impact on psychological health . MoreoveThe Social relationship domain is strongly bound to community loss and cultural gap experienced in the new country. Family separation is an element that negatively affects the HRQOL in the Social relationship as well as in the Psychological domain due to a lack of supportive network, causing emotional distress and affecting their integration process . This inRegarding the Environment domain, we observe a misalignment between the two groups. For the group of general population refugees, it represents the domain with the lowest scores as for the group of clinical population of refugees it is, almost for all the studies included, the highest. The reason for having lower scores in the environmental domain for the group of the general population of refugees could be bound to the low level of employment among refugees , which cIn the literature, clear cutoff values for the WHOQOL-Bref have not been set yet. Skevington et al.  refer toTo have a clearer perspective on the values shown by the selected studies in this review, we can consider the results obtained by Skevington et al. , who recOne of the main limitations of this review concerns the selection of participants in respect to their language skills: in some studies not knowing the language of the hosting country was an element of exclusion , 59, so This is the first systematic literature review that includes exclusively studies with populations of refugees living in the community of the hosting country and which considers studies assessing the health-related quality of life using the same evaluation tool. Several factors can explain the outcomes observed in the population of interest, which, for both groups, are lower than the scores reported by Skevington et al.’ general population. Lower employment rate and income, loss of family and social network, lack of full access to healthcare services, higher rate of mental disorders are an example of those factors, which incidence is higher in refugees populations. Among the two groups different patterns could be outlined considering each domain of HRQOL: higher scores for the Physical and lower for the Environment domain when considering the general population of refugees and higher scores for the Environment and lower for the Psychological domain when referring to the clinical one. Additionally, it is observed that individuals who were included in the clinical refugee group have a lower quality of life in respect to the general population of refugees. These lower scores are probably due to having a higher rate of mental distress and being more exposed to somatization, stigmatization and barriers to access the healthcare system of the hosting country in respect to the general population of refugees.The overview presented should help to take awareness on the complexity of the experience of this population and acknowledge the multitude of elements determining their HRQOL. The WHOQOL-Bref appears to be a good tool for this purpose and could be used for future investigations as a tool to assess the effectiveness of integration policies in hosting countries.Additional file 1.


To improve the coverage of intermittent preventive treatment of malaria in pregnancy (IPTp) in Africa, Medicines for Malaria Venture (MMV) developed, tested and validated a new packaging of sulfadoxine–pyrimethamine (SP), as well as specific communications tools designed to improve knowledge of IPTp and the motivation of women to adhere to it, particularly if it is distributed by community health workers (CHW).This article describes and analyses the results of an empirical research carried out in the Democratic Republic of the Congo (DRC), Nigeria and Mozambique, to evaluate the perception and social acceptability of SP for healthcare providers, CHW and pregnant women, and to assess the ability of the new SP packaging and the communications tools to change their perception of SP and improve their attitudes towards IPTp.The results indicate that SP’s new individual packaging was perceived by pregnant women and healthcare providers as a “hygienic” and “safe”, with a specific identity. The graphics used in IPTp communications tools were modified according to the respondents’ feedback to make them more culturally and socially sensitive, and then validated. However, although the new blister packaging and IPTp communications tools generated greater confidence and motivation, SP side effects as well as preconceived ideas, particularly regarding its efficacy, remain a challenge that must be addressed to improve IPTp acceptance and compliance by healthcare providers and pregnant women.This participatory approach to social research based on ongoing feedback to the graphic designer provided more empirical evidence to improve and adapt the textual and visual content of communication tools  to local contexts and user preferences. Tested and validated in different socio-cultural and socio-political contexts, these tools provide a good basis for the promotion of IPTp in Africa. Although the scaling up of malaria interventions has helped reduce malaria deaths worldwide, this disease remains a concern in Africa. In 2019, with an estimated 229 million malaria cases and 409,000 malaria deaths, the World Health Organization (WHO) African Region accounted for about 94% of cases and deaths globally [Since 1998, the WHO recommends the administration of sulfadoxine-pyrimethamine (SP) for IPTp in all eligible pregnant women during antenatal care (ANC) visits, starting as early as possible in the second trimester of the pregnancy . In 2012A recent systematic review and meta-analysis  suggest While waiting for future clinical trials to test the efficacy and safety of other antimalarial drugs to prevent malaria during pregnancy, the WHO still recommends continuing using of SP for IPTp, especially in moderate to high transmission areas. However, IPTp coverage, which means that the woman consumes at least three doses of SP during pregnancy, from the second quarter in particular is still low in sub-Saharan Africa. In 2019, in 33 countries which have adopted IPTp in their policy, 80% of all pregnant women visited ANC clinics at least once during their pregnancy, of which 62% received at least one dose of IPTp, 49% received at least two doses of IPTp, and only 34% received the minimum recommended three doses of IPTp  or the sMedicines for Malaria Venture (MMV) received a grant from Unitaid to support the development of new, high-quality SP formulations, prequalified by the WHO. It developed graphic information for the primary (blister) and secondary (dispensing box) packaging for pregnant women to be distributed by community health workers (CHW). In addition, a user guide for community relays and a leaflet for pregnant women were designed with simplified graphics and pictograms communicating on IPTp, SP, and ANC. This project focusing on the supply side of IPTp was in complement with the "Transforming IPT for an optimal pregnancy" (TIPTOP), a Unitaid funded project, managed by Johns Hopkins Program for International Education in Gynecology and Obstetrics (JHPIEGO), assessing the impact of the integration of CHWs on IPTp coverage in the DRC, Madagascar, Mozambique and Nigeria.The assumption made here is that an individual SP packaging with a specific IPTp indication, no longer recommended for the treatment of uncomplicated malaria, would help correct misinformation, generate a more positive image, and could improve IPTp acceptance and compliance by the drug providers with limited training and by women with little access to information on IPTp. Assuming the community level context where the IPTp intervention will be made available, a participatory research approach  involvinParticipatory research is a collaborative, iterative design that focuses on a “process of sequential reflection, planning carried out with and by local people rather than on them and emphasizes direct engagement of local priorities and perspectives , 23. ThiThe key difference between participatory and non-participatory techniques lies in community dialogue, partnership, and handing power from the researcher to research participants , 25. It Nevertheless, some researchers raise the various challenges that make a fully participatory project unrealistic , 26–28. How did the healthcare providers, CHWs, and pregnant women view the SP packaging ?Were the key messages and pictures contained in the communication tools clearly understood and answered their preoccupations?Did it influence their perceptions and attitudes towards SP and IPTp?Were they acceptable to the population and likely to enhance their IPTp compliance?And if not, how can its acceptability be improved?The field research using participatory approach was conducted in the DRC, Nigeria, and Mozambique, countries where community IPTp pilots were on-going, to address the following questions:The attitudes, points of view, and knowledge of the participants regarding the SP packaging and the IEC tools were documented, and the potential influence of these tools to improve the users’ perceptions of SP and their IPTp compliance was analysed. The added value of the collaborative approach between the graphic designer (tools designer) and the social research teams (as the relay) to test tools with end-users and adapt them to local contexts and preferences is also discussed.The qualitative study combined in-depth individual interviews (IDI), focus groups discussion (FGD), and direct observations, which offers the advantage of cross-referencing what participants say about SP with their actual practices. Furthermore, the points of view put across in the individual interviews were compared with the data provided by the FGD to interpret the information. IEC tools thus were developed using an iterative and collaborative process. They were first produced by a graphic designer, with the help of the TIPTOP consortium, before being tested empirically. The discussions tested the understanding of the tools by pregnant women and community relays, without giving them any explanation beforehand, to identify the gaps and make the appropriate changes. Results of these tests were analysed with local teams and participants daily, shared with the graphic designer (remotely based in Geneva) on an ongoing basis, who took the insights collected into account to produce updated versions to be retested, and validated by participants. The researchers interacted directly with community participants on the field, by listening to them, and by collecting their opinions on how tools could be improved.The research was conducted in the DRC, Nigeria, Mozambique, three countries hosting the IPTp TIPTOP project and characterized by low IPTp coverage and high rates of malaria infection among pregnant women. For example, in the DRC, 69% of pregnant women received IPT2 and 34.5% IPT3 . The resIn each country, a district was selected in an area with low IPTp3 coverage and with an IPTp3 coverage rate lower than IPTp1 . The sampling used either routine or national data available in each country, or the results of baseline surveys carried out by JHPIEGO in each of these countries as a prelude to the implementation of the TIPTOP project. Kenge , Nhamatanda , and Ohaukwu  were selected. In each district, three health zones were chosen for their higher number of pregnant women, identified by the local health authorities in ANC clinic registers. In each health zone, a locality was selected based on the same criteria, and households were identified with the help of the CHWs. Healthcare providers were selected to be interviewed based on their involvement in maternal and child health programmes.At the household level, the research targeted primarily pregnant women living in the selected localities, their husbands, as well as women who had recently given birth less than 6 months before. CHWs and health authorities were part of the sample. A total of 294 people were interviewed in all three countries, with 103 individual interviews and 191 through focus groups.Data were collected in each country by a local team of investigators recruited remotely, proficient in the local languages , trained by senior researchers . The individual interviews and focus groups were transcribed from local languages into French (DRC) and English . The data was exported to the ATLAS Ti software to be encoded and categorized. Thematic content analysis was used and themes generated from the data based on a mixed approach. First, a deductive coding was carried out based on the major variables of the survey for each country. Then, it was completed by an inductive coding, based on new themes that emerged from the fieldwork and the transcripts. Results were triangulated according to the tools and targets investigated: the coding process was applied for data individual interviews and focus group. Also, the data interpretation took into account the variability of interviewed categories. By cross-referencing their views concerning a theme, the interpretation of the data should be enriched.A report was generated per country after completion of field work in respective countries. This was complemented by a synthetic analysis of the three data sets recognizing the various disparities between them including, health systems in place, infrastructural, social and cultural contexts limiting the conclusion. The attempt of this piece of research was to generate evidence from various end-users’ perspectives on IPTp intervention and to identify ‘universal’ pictograms and visual aids contextualized, which could be understood by the majority of the respondents.To conduct the surveys, the approval of the ethics national committees for research was obtained, at the national (Kinshasa), state  or university (Maputo) levels. During data collection, an information sheet and the consent form were read and shared with each respondent for approval.The analysis highlighted major themes across the data collected: (a) the perceptions of IPT for malaria prevention by pregnant women and CHWs, especially attitudes towards SP drugs; (b) the opinions on the SP blister for IPT in pregnant women; (c) the comprehension, opinions, and acceptability of the of communication materials and (d) the willingness and ability to change SP use behaviour.I only had the first dose and I threw away the next one. I did not take it anymore during my pregnancy because it made me dizzy. Also, some people said that the tablets were not hygienic, and others said that it could affect the health of my child. FGD_DRC_Kenge_Barrière_Sas_Woman_E3In all three countries, very few women had taken the required 3 doses of SP during pregnancy. The identified contributing factors included the negative perceptions of SP and side effects which did not motivate women to take all three doses.A woman can turn up to the appointments given to her. But when she gets to the health centre, she notices that there is a shortage of drugs. IDI2_DRC_Kenge_Health Authorities_Nurse SupervisorAlso, some women expressed doubts about the hygiene and safety of SP. White tablets without any distinctive sign make them undistinguishable from counterfeit drugs, which are suspected of harming the pregnancy’s outcome. Moreover, the unreliability of the ANC clinics due to SP stock-outs  creates missed opportunities for IPTp.Besides, some women did not take all three SP doses due to a lack of information given by the healthcare providers. The latter expected to promote IPTp often have doubted themselves about SP, and its effectiveness for preventing malaria in pregnancy, and as a result do not talk about it during the consultation with the patient. Also, the importance of socio-cultural practices and traditional medicine making pregnancy a social event hurts ANC attendance and access to SP. Taking drugs to prevent a disease that has not happened is not taken seriously, and should the women become ill, plants and herbs would be preferred, in line with local emic representations of malaria.In the Kenge district (DRC), the first version of the SP blister see Fig.  was test“What interested me the most here was to know the expiry date of the product, because with tablets in bulk, the woman who takes the product does not know it. We give her only the 3 tablets” IDI_DRC_ Kenge area chief medical officer.The SP blister was seen as safe and practical, offering better protection against rain or dirt, but it also provides information (expiry date) that can reassure women.Compared to SP distributed in bulk, the blister packaging makes the tablets more hygienic and ensures a correct dosage. However, the women noted that the blister did not have easily recognizable distinctive signs identifying the tablets as a malaria prevention product for pregnant women. Furthermore, as white SP tablets are undistinguishable from other drugs and paracetamol in particular, they asked for coloured tablets (e.g. pink), and for diagrams representing mosquitoes and a pregnant woman on the packaging.The graphic designer produced a new version of the blister, taking into account some of these suggestions, which were tested in the DRC (Mukila), then in Nigeria and Mozambique , and that the X sign should be used to reinforce the prohibited use.In Mozambique see Fig. , the womThe leaflet for pregnant women included diagrams for key messages. Below, two examples describe the women’s reactions and the changes made to its content as empirical tests were carried out. The first diagram shows the necessity for pregnant women to seek a diagnosis if they develop a fever or signs of malaria see Fig. .Fig. 5ReIn the version tested in the DRC, the women found it difficult to understand the message. The diagram was generally perceived as a woman with a red forehead and a man with intestinal problems. Respondents did not recognize him clearly as a healthcare provider. The thermometer was thought to be a pregnancy test and the stethoscope was seen as intestines.Tests carried out in Nigeria showed that the new version was easier to understand. With this second version, women recognized the signs of vomiting and high temperature (thermometer), the diagnostic test being carried out, and the presence of a healthcare provider. In the Mozambique version, the need to show the diagnostic procedure was taken into account. The user guide included another diagram showing the need to go the health centre in the event of side effects from the medication see Fig. .Fig. 6ReIn the first version, the picture was thought to represent a CHW, or a road policeman (they wear green vests) talking to a pregnant woman with a fever. Suggestions were made to make the caregiver more realistic wearing a white coat, and to make the visit to a health centre more explicit. In the revised version 2 (Nigeria), the picture of a hand scratching the arm as a side effect was confusing and did not relate to the most common side effects experienced by pregnant women, i.e. headache and vomiting. The picture was also thought to represent a caregiver saying goodbye to the woman after the consultation. In the modified version tested in Mozambique, women recognized several side effects as well as the message to seek medical help at a health centre. The CHWs asked for a backdrop to be added to the picture, to emphasize the health centre.R: The SP in bulk may be damaged and sometimes the women may not believe you. But a blister packaging is well protected and women can be convinced more easily. IDI2_DRC_Kenge_Saint-Esprit_Kapanga_CHWIn all three countries, pregnant women said they were more motivated to take SP, as they trusted its individual packaging to provide a safer and more hygienic product. The difficulties to open the blister pack and problems relating to the tablet’s size, documented in previous studies , were noR: I'm glad the tablets are packaged in a blister because it makes things easier. But if you want me to take SP, it's not enough. When I look at the medicine, it's the same, it hasn't changed. If I take it, it will make me vomit like before... IDI2_Mozambique_Nhamatandha_ Siluvo_pregnant woman.However, although the blister packaging increases women’s trust, it is not enough to bring about a change in behaviour regarding the use of this drug and the way forward. Underlying negative perceptions of SP did not change much, due to women’s experiences of side effects.Several studies  have shoThe pre-tests carried out on the communication tools, in particular on the user guide for CHWs, highlighted the need to use socially and culturally sensitive graphics, with recognizable people and clothes, as well as messages rooted in local health policy guidelines to improve social acceptability and appropriation . While iThe participatory research utilized to develop and to contextualize health-related information/products in three various countries has been pertinent. Analysing beliefs, social norms; listening to communities understandings, specifics of contexts, were essential to change the design and production of communication tools for IPTp social marketing. It is important to make special efforts in obtaining community inputs in ways that extend beyond responding to researcher plans or agendas.In the wider global health literature, efforts have been made to assess how participatory approaches have affected the coverage/participation in health interventions. For example, in Laos, using this approach in the Targeted Malaria Elimination programme has contributed to high levels of community participation in mass anti-malarial administration (above 85%) by adapting the approach according to their needs and responses to the various study components . This reListening to communities’ opinions, involving them helped in improving the communication tools to promote IPTp. This approach allowed to make the contents context-specific, and update them based on the feedback, the understanding of the messages improved by participants. It helped to ensure that the contents, images, illustrations reflect the perspectives, cultures, priorities, or concerns of those who are targeted. Validated in different socio-cultural and socio-political contexts, the additional tools such are the user-friendly patient information or CHW job aid, should they be adopted, are a basis and could be adapted based on the context . Their implementation is expected to be combined with community relays training and information provided to pregnant women during ANC visits, to reinforce their knowledge.The iterative collaborative approach with a reworking of the tools by the graphic designer, based on the respondents’ feedback from the field, has proved to be effective. Interactions throughout the study provided much more empirical evidence to guide the production of the tools . This stThe qualitative research included testing the communication tools and updating them by anticipating user needs and making them user-friendly and adapted to social contexts. However, while the SP blister packaging and communication tools adapted to local contexts are useful to motivate healthcare providers to distribute the product at community level and pregnant women to adopt IPTp, they alone are unlikely to lead to a change in behaviour. For that, further measures will be needed, including improving the offer and the availability of quality-assured SP in health facilities, addressing the problem of SP side effects, and enhancing the low motivation of healthcare workers to deliver IPTp by providing, for instance, appropriate training, a problem that is not always solved by using CHWs for community-based distribution.