Clustering of food additive variables was used in order to determine groups of additives frequently co-occurring in food products. The clusters were confirmed by network analysis, using the eLasso method. Results. Fifty-three-point eight percent of food products contained at least 1 food additive and 11.3% at least 5. Food categories most likely to contain food additives (in more than 85% of food items) were artificially sweetened beverages, ice creams, industrial sandwiches, biscuits and cakes. The most frequently used food additives were citric acid, lecithins and modified starches . Some food additives with suspected health effects also pertained to the top 50: sodium nitrite, potassium nitrate, carrageenan, monosodium glutamate, sulfite ammonia caramel, acesulfame K, sucralose, (di/tri/poly) phosphates, mono- and diglycerides of fatty acids, potassium sorbate, cochineal, potassium metabisulphite, sodium alginate, and bixin (>800 food products each). We identified 6 clusters of food additives frequently co-occurring in food products. Conclusions. Food additives are widespread in industrial French products and some clusters of additives frequently co-occurring in food products were identified. These results pave the way to future etiological studies merging composition data to food consumption data to investigate their association with chronic disease risk, in particular potential ‘cocktail effects’.Background. More than 330 food additives  are authorized in Europe, with a great variability of use across food products. Objective. The objective of this study was to investigate the distribution and co-occurrence of food additives in a large-scale database of foods and beverages available on the French market. Design. The open access crowdsourced Open Food Facts database ( In France, the 2017 nationally representative INCA3 nutritional survey highlighted a rise in processed food consumption, mainly accounted for by industrially-processed foods7. In this context, results of observational epidemiological studies linking ‘ultra-processed’ food intake and health outcomes is accumulating worldwide17. A clinical trial also highlighted an association between ultra-processed food and increased ad libitum energy intake and weight gain over a 2-week period18. In addition to the poorer nutritional composition, the presence of neo-formed compounds and of substances migrating from packaging, food additives is one of the main hypotheses that could help explain these results. Ultra-processed foods indeed often contain mixtures of additives. They represent about 330 authorized compounds in the European Union (EU)19, where their use is legislated by Regulation (EC) No 1333/2008. The restriction may vary, for example, only 48 food additives are allowed in organic food products. The additive content of a food product is mandatorily provided on its packaging/label with a list of all substances identified by their E number (EU identifier), name (e.g. E466 carboxymethylcellulose) and function in the final product. They are commonly used as antioxidants, dyes, emulsifiers, stabilizers, gelling agents, thickeners, preservatives and sweeteners20, and some are undoubtedly useful for increasing shelf life and food safety. Most of them probably have no impact on health and some may even be beneficial . However, some concerning results, mainly derived from animal and/or cell-based experimental studies, have emerged regarding several additives. For instance, nitrates/nitrites23, carrageenans24, glutamate27, bixin29, artificial sweeteners34, phosphates36, emulsifiers39, caramel41, titanium dioxide (TiO2)42, tartrazine44 and butylated hydroxyanisole/butylated hydroxytoluene (BHA/BHT)43 were previously linked to metabolic, gut microbiota or endocrine perturbations along with carcinogenic, inflammatory and/or oxidative stress effects. Besides, some experimental results suggest that different additives may interact (among themselves and/or with the food matrix) and thus lead to synergistic or antagonist effects, but few studies have been performed on this topic to-date50.In the Western world, the last decades were marked by an increase in the consumption of ‘ultra-processed’ foods, i.e. foods undergoing multiple physical, biological, and/or chemical processes and containing various food additives20 - and the WHO-FAO JECFA at the international level51 and are theoretically intended to protect consumers against the potential adverse effects of each individual substance in a given food product. Yet, despite the substantial amount of work on the literature review and the collective expertise at these institutions, the evaluation (and subsequent recommendations and regulations) has been based only on the currently available scientific evidence which is mainly derived from in-vitro or in-vivo experimental research and simulations of exposure in humans. In that context, information regarding: (1) the health impact of regular and cumulative intake of food additives in humans, and (2) the potential ‘cocktail’ effects/interactions is still missing yet urgently needed.Maximum authorized levels of food additives are set by the European Food Safety Authority (EFSA)Furthermore, the presence of these substances in the foods available on the French market has been poorly studied. In order to pave the way for etiological studies, it is essential to document which food additives are the most widespread and in which food categories they are more likely to be found. In addition, the study of their co-occurrence in foods will identify various food additive mixtures that are relevant in real life. Thus, objectives of this work were (1) to investigate the distribution of food additives in a large-scale database of food and beverage products available on the French market and (2) to identify mixtures of food additives frequently co-occurring in food products raising the issue of possible cocktail effects.http://world.openfoodfacts.org/). Open Food Facts is an open collaborative database of food products marketed worldwide, licensed under the Open Database License (ODBL). This French initiative contains data on hundreds of thousands of products. The initiative started in France in 2012, providing extensive coverage of the French food market, and an increasing number of products are becoming available for other countries worldwide. Contributors (citizens and active Open Food Facts contributors) permanently add products to this crowdsourced database, by scanning the barcode and sending photographs of the packaging. The information is automatically treated to record a wealth of information for each food product, such as commercial name, brand, list of ingredients, presence/absence of each food additive and nutritional composition. As food products formulations may evolve, old products are regularly updated when they are re-informed by consumers.The Open Food Facts database was used to retrieve composition of food products  embedded in the barcode acts as an identifier of each product.52. Thirty-five food categories were identified  were removed for products of the same brand and same composition. The information of additives in the list of ingredients is mandatory in Europe. All products currently marketed in France with available list of ingredients were included  was described by presence/absence of each food additive . Following the ClustOfVar methodology, ascendant hierarchical clustering of variables was performed on this dataset (141 binary variables)54, thus providing clusters of food additives strongly co-occurring.In order to assess their co-occurrence in food and beverage items, clustering of food additives was performed using the R package ClustOfVar, specifically dedicated to the clustering of variablesi increases when the number of food additives of clusteri present in this food increases. In other words, the higher the number of clusteri food additives in a given product, the higher the clusteri synthetic variable for that product. For each cluster, food products with higher synthetic variable (>99th percentile of the distribution) were highlighted to show the food items which were the largest food additive carriers of this cluster. See Appendix For each cluster, a squared loading is attributed to each additive, corresponding to the strength of the correlation between the food additive and its cluster. For each cluster of food additives variables, a synthetic variable (or score) is also generated by the package. For a given food product, the value of this synthetic variable for clustereLasso method, this package is specifically dedicated to the estimation of binary data network structures and provides an overview of the co-occurrences of additives, mutually adjusted for all the relationships of the network55. It can be interpreted as follows: when two food additives are connected by a blue line, it means that they are often found together in food products, when they are connected by a red line, it means that they are rarely found together. Bolder is the line, higher is the number of products concerned. For better visualization, the network was generated for the 50 food additives most present in food products, and additives were colored according to clusters defined by the ClustOfVar method.In order to visualize the co-occurrence of food additives and to confirm the information provided by the clustering of variables by a complementary method, network analysis was performed with the R package IsingFit (see Appendix 56. This score is based on a modified version of the Food Standard Agency (FSA) nutrient profiling system, and it has been endorsed by the French, Spanish, and Belgian governments as the official front-of-pack label in these countries  unprocessed or minimally processed foods, (2) processed culinary ingredients, (3) processed foods, (4) ultra-processed foods  affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.The number and percentage of food or beverage items by food categories available in the Open Food Facts database is illustrated in Fig. In all, 329 additives were found in the database, among which 141 were present in at least 100 food products. Figure Figure The number of food products containing each food additive is presented in Fig. After graphic assessment Appendix , 6 clustth percentile of the score for cluster 1) were sweets. The distribution of their Nutri-Score was 0.6% A, 14.0% B, 6.0% C, 56.2% D, 23.2% E and their repartition across NOVA categories was 0.1% 1 and 99.9% 4.This cluster was mostly represented by carnauba wax (used to produce a glossy finish), beeswax (glazing agent), titanium dioxide (dye), curcumin (dye), brilliant blue FCF and patent blue V (dye). Foods most representative of this cluster (99th percentile) were sandwiches and sugary desserts. The distribution of their Nutri-Score was 3.6% A, 9.2% B, 24.7% C, 49.9% D, 12.6% E and their repartition across NOVA categories was 0.1% 3, and 99.9% 4.This cluster was mostly represented by xanthan gum, modified starches, mono- and diglycerides of fatty acids, guar gum and carrageenan. They have a wide range of functions, such as emulsifiers, stabilizers, colorings, antioxidants and are used in a wide variety of products. Foods most representative of this cluster (99th percentile) were biscuits and cakes. The distribution of their Nutri-Score was 0.2% A, 3.5% B, 5.4% C, 46.0% D, 44.9% E and their repartition across NOVA categories was 100% 4.This cluster is mostly represented by sodium carbonate, diphosphates, lecithins, ammonium carbonates, and glycerol. These additives are mostly used as acidity regulators, stabilizers and emulsifiers. Foods most representative of this cluster (99th percentile) were sweets (mostly chewing-gums with sweeteners) and artificially sweetened beverages. The distribution of their Nutri-Score was 13.1% A, 43.6% B, 20.3% C, 17.2% D, 5.8% E and their repartition across NOVA categories was 0.1% 2, 0.6% 3, and 99.3% 4.This cluster is mostly represented by sweeteners such as acesulfame K, aspartame, xylitol, maltitols, mannitol and the antioxidant butylated hydroxytoluene (BHT). Foods most representative of this cluster (99th percentile) were one-dish meals (mostly instant noodles) and appetizers . The distribution of their Nutri-Score was 4.3% A, 10.8% B, 21.5% C, 42.1% D, 21.3% E and their repartition across NOVA categories was 1.3% 1, 0.2% 2, 1.9% 3 and 96.6% 4.This cluster is represented by flavor enhancers disodium inosinate, disodium guanylate and monosodium glutamate, used in synergy to provide the umami taste and potassium carbonates, disodium 5′-ribonucleotides and ammonia caramel. Foods most representative of this cluster (99th percentile) were processed meat and one-dish meals containing processed meat. The distribution of their Nutri-Score was 2.8% A, 9.1% B, 20.2% C, 42.5% D, 25.4% E and their repartition across NOVA categories was 0.8% 3, and 99.2% 4.This cluster is mostly represented by sodium nitrite, sodium erythorbate, sodium ascorbate, triphosphates and sodium acetates. Sodium nitrite is a preservative used in a wide variety of processed meat. It can be used with sodium erythorbate, which increases the rate at which nitrite reduces to nitric oxide. Foods most representative of this cluster . Other additives of the top 50 were: sodium nitrite, potassium nitrate, carrageenan, monosodium glutamate, sulfite ammonia caramel, acesulfame K, sucralose, (di/tri/poly)phosphates, mono- and diglycerides of fatty acids, potassium sorbate, cochineal, potassium metabisulphite, sodium alginate, bixin and sodium carboxymethylcellulose.Observatoire de l’Alimentation”  evaluated the frequency of use of certain food additives and the evolution between 2012 and 2018 in a selection of food products61. The most frequently used additives where consistent with our study . Their report suggests a diminution of the use of food additives since 2012 in half of the food categories studied, but an increase in some food additives such as carotenoids used as colors but also some artificial sweeteners , and sulfites in aperitive products and salsas. Our study was based on a larger sample of manufactured products present on the French market  and covered all food groups, whereas some categories such as sweets, chewing gums, and confectionary were not analyzed in the Oqali report.A recent study by the French food observatory “in-vivo/in-vitro, and - more rarely - epidemiological studies. For instance, sodium nitrite and potassium nitrate  have been associated in prospective cohorts with all-cause mortality (nitrates/nitrites from preserved/processed meat)23, and gastric and pancreatic cancers22. Phosphates have been associated with vascular effects  in experimental studies among humans36. Monosodium glutamate  might have patho-physiological and toxicological effects on human health27 and was associated with overweight in a prospective cohort26. Sulfites  have been associated with alteration of the gut and mouth microbiome in vitro at concentrations considered as safe for food62. Nonnutritive sweeteners such as acesulfame K, sucralose and aspartame  still have controversial effects on human cardiometabolic health and adiposity30 and have been linked with hematopoietic neoplasia and gut microbiota alteration in experimental studies on rodents34. Sulfite ammonia caramel , present in almost every cola, might carry 4-methylimidazole (4-MEI) defined as possibly carcinogenic to humans by the International Agency for Research on Cancer, IARC41. Carrageenan  has been linked to fasting hyperglycemia and with exacerbated glucose intolerance and hyperlipidemia without effect on weight among mice24. Carboxymethylcellulose  has been associated with changes in microbiota composition, intestinal inflammation and metabolic syndrome (in-vivo)65, pro-inflammation 69 and promotion of tumor development (in-vivo)38. Finally, an experimental study among humans suggests a link between lecithins  and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO)70. On the other hand, some food additives could be candidates for beneficial long-term health effects. For instance, bixin  has shown reduction of postprandial inflammatory and oxidative stress responses to high-calorie meals in a human randomized-controlled trial71. Furthermore, ascorbic acid  used as an antioxidant might beneficially contribute to total ascorbic acid intake, as suggested by EFSA combined exposure assessment72). Also, some food additives such as extracts of rosemary  could also be of interest as many of their components are phenolic acids. Finally, sodium alginate  has been suggested to improve liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis among obese and diabetic mice73. Contrasted health effects have been suggested in experimental data for modified starches. For instance, distarch phosphate (e1412) and hydroxypropyl-distarch phosphate (e1442) showed potential beneficial effects on postprandial glycaemia and insulin response in human trials75. In contrast, maize hydroxypropylated distarch phosphate (e1442) promoted a less varied microbiota in faeces of healthy infant donors of 2–3 months of age76.For several frequently used additives (i.e. pertaining to the “top 50” in the present study), potential adverse health effects have been suggested in eLasso was colored according to the clusters generated by the ClustOfVar method  and does not adjust for other variables as this is not the aim of a clustering method. Despite small discrepancies due to these methodological differences, the two methods provided overall consistent results, as highlighted when the network obtained by hod Fig. .Each food additive cluster occurred in several broad food sectors. Among the 6 clusters of food additives frequently co-occurring in food products identified in the present study, 2 clusters were found mostly in salty products (instant noodles and processed meat) and 4 clusters occurred mainly in sweet products . The additives that constituted each cluster had sometimes complementary functional properties. For instance in cluster 3, main food additives where sodium carbonate (e500), diphosphates (e450), ammonium carbonates (e503) and glycerol (e422) which are widely used in biscuits and cakes as acidity regulators, stabilizers and emulsifiers.More than 10% of manufactured products contained 5 or more additives. Thus, consumers are regularly exposed to mixtures of food additives, but this multiple exposure has rarely been studied in the literature. For instance, the 3 first food additives of cluster 3 (sodium carbonate (e500), diphosphates (e450) and lecithins (e322)) co-occur in 1667 products, mostly biscuits. Also, the cumulative exposure to the 3 first food additives of cluster 4 (acesulfame K (e950), aspartame (e951) and xylitol (e967)) could be of interest as these three additives co-occur in 87 products in our study sample, among which some very popular sugar-free chewing-gums.45. Neurotoxic effects were also observed between combinations of brilliant blue (e133) with L-glutamic acid (e620), and quinoline yellow (e104) with aspartame (e951) in vitro46 and a mixture of food coloring additives increased oxidative stress in rats47. Future prospective studies and experimental research should investigate the effects of chronic exposures to these cocktails of food additives, as consumed in real life.So far, detailed information on potential cocktail effects is lacking but several studies started to suggest interactions and synergies between food additives. For example, mixes of colorings with sodium benzoate (e211) were associated with increased hyperactivity in 3-year-old and 8/9-year-old childrenthe dose makes the poison” is currently being challenged in toxicology, with effects at very low doses suggested for many chemical substances. Thus, the information on presence/absence of additives is already interesting in itself. Next, the Open Food Facts database does not provide information on sales, so it was not possible to weight the analysis according to purchase volumes or frequency. To obtain a complete picture of mixtures of food additives frequently ingested, the next step will be to merge the present composition data with detailed consumption data . Finally, on food packaging, the detail on the type of modified starch is often not specified and only the broad category “modified starch” is mentioned. Thus, the number of products containing each of the specific modified starches may be underestimated in the database.Strengths of our study included the large number of food and beverage items displayed by the Open Food Facts database and the originality of the cluster and network-based statistical approach applied to depict the food additives frequently co-occurring in food products. Conversely, some limitations should be acknowledged. First, the collaborative Open Food Facts database does not exhaustively cover all industrial food items available on the French market. Such exhaustive formulation database does not exist so far. However, it provides an extensive coverage with nearly 130,000 complete references of different products, and its crowdsourced nature by consumers guarantees the fact that all frequently consumed products are registered. Second, as any contributor-based data, some errors in food composition may not be excluded and some formulation data may have evolved since their entry in the database. However, despite the fact that the information is contributor-based, errors are minimized by performant text and picture recognition algorithms allowing automated checks. Besides, systematic control campaigns including random sampling and checking of food products as well as update of information (taking into account reformulations) are regularly performed. Moreover, an increasing number of manufacturers regularly implement their validated data directly in the system. Third, this study focused on the presence/absence of additives in food products, without data on the doses of additives used. Such information is not mandatory on food labels in the current regulation. Using the relative position of additives in the ingredient list would provide very little information on the real additive amounts. Indeed, additives are generally all mentioned at the end of the ingredient list since their amounts are much lower than main ingredients . Regarding relative amounts between additives, ingredient list would bring no information for all food products with only one additive (i.e. 33% of products containing additives). Besides, even if the order of additives in the ingredients’ list is similar between two food products, it may represent very different absolute amounts of additives in the two products. However, the paradigm “77, in which commercial names and brands of industrial products consumed are reported by the participants through detailed and repeated dietary records, which is crucial for an accurate evaluation of exposure at the individual level, due to the high variability in additive composition between brands for a similar type of product. Within this framework, we have planned different strategies to collect quantitative information on food additive content, including ad hoc laboratory assays of strategic additives in specific food matrixes and pro-active collection of dose data from manufacturers. In the meanwhile and following the precautionary principle, French health authorities recommend to limit the consumption of ultra-processed foods and, in practice, to choose food products with a better nutritional quality (as scored by the Nutri-Score) and with no or as few additives as possible.This study illustrates the widespread of food additives in foods available on the French market and allowed us to identify 6 clusters of frequently co-occurring food additives. It is important that this type of industrial food composition database remains open-access and freely available to guarantee the transparency for the consumers and for public researchers and stakeholders, making it possible to monitor the trends in food additive use and to perform etiological research. To concretely expand etiological research on food additives and health, doses of additives should also be made available in complete transparency. As a key perspective of this study, our research team is currently launching a large-scale program on chronic exposure to mixtures of food additives and health that will notably rely on the NutriNet-Santé cohortSupplementary information.


Traditional Chinese medicine has been widely used in the treatment of allergic rhinitis. However, currently randomized controlled trials (RCTs) and meta-analysis only compare 1 or 2 types of traditional Chinese medicine therapies, and the comprehensive ranking of efficacy and safety of multiple traditional Chinese medicine therapies for the treatment of allergic rhinitis has not been completed. Therefore, the purpose of this network meta-analysis is to evaluate the efficacy and safety of different traditional Chinese medicine therapies for the treatment of allergic rhinitis.Three English databases of PubMed, Embase, Cochrane Library, and 2 Chinese databases of CNKI and Wanfang were searched from their inceptions to September 1, 2020. At the same time, in order to prevent omissions, we also compared the previous meta-analysis to determine the final included trials. The main evaluation outcome was the total Clinical Score , the secondary evaluation outcome was the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and adverse events. The Cochrane Collaboration's Tool was used to evaluate the methodological quality of articles, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument was used to evaluate the quality of evidence. Network meta-analysis was completed by using Stata Statistical Software .This study will compare and rank the different traditional Chinese medicine therapies for allergic rhinitis.This study is the first time to use network meta-analysis (NMA) to compare the efficacy and safety of traditional Chinese medicine for the treatment of allergic rhinitis, which will provide ideas and methods for the clinical treatment for allergic rhinitis.No. INPLASY202080119 The clinical symptoms were usually characterized by nasal itching, nasal congestion, sneezing, runny nose, if the symptoms were not released promptly, it will also cause other symptoms such as headache, dizziness.,8 According to the epidemiological survey of global prevalence, the incidence of allergic rhinitis is about 10% to 20% globally, due to the influence of the environments, the prevalence of various regions have differences, the prevalence in United States is 10% to 30%, in Sweden it is about 28%, in mainland China it is 4% to 38%, and studies showed that the prevalence of allergic rhinitis are trending up.,14Although allergic rhinitis does not cause death in humans, it seriously affects people's daily life and work. But, as we have seen, it is impossible to be exposed completely to allergens. On the other hand, western drugs are mainly the corticosteroids and antihistamines, taking these drugs in long-term will cause side effects such as obesity, arrhythmia, and dry mouth, which will affect human health.So far, the treatment of allergic rhinitis is mainly by avoiding exposure to allergens and drug therapy.–19 However, TCM therapy includes many types: acupuncture, moxibustion, acupoint sticking, etc., but we don’t know yet which therapeutic measure is more effective. Therefore, it is necessary to evaluate the efficacy and safety of different TCM therapies for allergic rhinitis.Considering these factors, current to search a treatment that is non-toxic and has no side effects is what we should focus on. Traditional Chinese medicine therapy for allergic rhinitis has achieved good results, and no harm to human body for the time being.22.1Systematic review and network meta-analysis.2.2This study is a secondary literature study and does not involve clinical patients or the general public.2.32.3.1Considering that the methodological quality of this paper is crucial to the conclusion, we only included the randomized controlled trials (RCTs) of traditional Chinese medicine therapy for allergic rhinitis, and the traditional Chinese medicine therapy only limited to acupuncture, moxibustion, and acupoint sticking, while traditional Chinese medicine and massage were excluded. Studies of one TCM therapy versus another TCM therapy or placebo were analyzed.2.3.2 The Rhinitis - Clinical Investigator Collaborative (AR-CIC), Chinese Journal of Otorhinolyngology Head and Neck Surgery.Among all adults (over 18 years old) were diagnosed with allergic rhinitis. The diagnostic criteria were derived from ARIA (Rhinitis and its Impact on Asthma) Guidelines,2.3.3The intervention measures are traditional Chinese medicine  for the treatment of allergic rhinitis. Among them, the acupuncture includes electroacupuncture, fire acupuncture, plum flower acupuncture, etc., the moxibustion includes ginger moxibustion, suspended moxibustion, fester moxibustion, etc. There are no restrictions on the traditional Chinese medicine used in acupoint application.2.3.42.3.4.1 was applied for scoring nasal congestion, nasal mucus, rhinitis, and sneezing with a total of 12 points. The higher score means the more severed of the symptoms.The total nasal symptom score (TNSS)2.3.4.2(1) the patients’ quality of life were evaluated from 28 questions in 7 dimensions: activity, sleep, non-nasal and eye symptoms, nasal symptoms, eye symptoms, emotion and practical problems, with a total score of 42 points. The higher score means the worse of the life quality.The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ),(2)The incidence rate of adverse events.2.3.5(1)Exclusion of reviews, animal experiments, case reports, and non-randomized controlled trials.(2)Exclusion of comparison to the treatment of different acupuncture techniques or moxibustion methods.(3)If there is any information lost or obvious error in the article, it will be screened out for further study.2.4Comprehensive searches of RCTS on traditional Chinese medicine therapy for allergic rhinitis were conducted in 3 English databases of PubMed, Cochrane Library, Embase, and 2 Chinese databases of CNKI and Wanfang, and the time of index was from their inceptions to September 1, 2020 for each database. The retrieval strategy of PubMed is shown in Table 2.52.5.1For the convenience of management, we searched from 5 databases and imported titles into EndNote Software AQ8 (V.X9). Firstly, we used the software to remove duplicate articles, then 2 team members (YT and YSF) independently read the titles and abstractions, they deleted the literature that did not meet the requirements, and read the full text of the remained articles to decide the final inclusion of the experiment. After that, cross-checking to the results of both parties was conducted. If there is any disagreement, the decision would be made via group discussion. The entire process and results are shown in Fig. 2.5.2Microsoft Excel 2016 was used to establish information data extraction table, and pre-extraction was carried out to determine the feasibility of the table. Then 2 team members (YT and YSF) independently extracted the following information after training:(1)Basic information: title, author, country, year, language, etc.(2)Baseline information: gender, age, number of persons, country, diagnostic criteria, etc.(3)Methodological information: grouping method, allocation concealment, blind method, result bias, etc.(4)Intervention measures: treatment measures, treatment time, frequency, etc.(5)Results: data of primary and secondary results.After the work is completed, the results are cross-checked, if there are differences, a group discussion is conducted to determine the final result.2.6,26The 2 authors (YT and YSF) evaluated the article methodology of inclusive trials independently, by the Cochrane collaboration “Bias risk” tool sequences generated from 6 aspects of allocation concealment, blind (or mask), incomplete data evaluation, evaluation reports, and other sources of bias selective results. Finally, for each items, we made ranking of “Low-risk bias,” “High-risk bias,” and “Unclear” based on the Cochrane collaboration “bias risk” tool.2.72.7.1If data are insufficient from the selected study, we will contact the author via email for the required data. If baseline and outcome data or other data are included, the mean and standard deviation of the change will be manually calculated according to the Cochrane.2.7.2In the network diagram, each dot represents an intervention; the larger dot area means the bigger population of the studied intervention; the line between the 2 dots represents that there is direct comparison to RCT studies among 2 interventions; the line thickness represents the numbers of direct comparison to RCT studies among 2 interventions.2.7.3Transitivity and consistency are the prerequisites for reticular meta-analysis. The transitivity was evaluated qualitatively from the perspective of methodology and was evaluated according to the PICO principle. Consistency was mainly to check local and overall consistency. Local consistency can be checked by loop consistency test (Higgins model). The global consistency test was verified by the corresponding inconsistency model according to different data.2.7.4Heterogeneity tests for all included studies were performed by using Network prediction interval graph, then to study the relationship of the weighted mean difference (WMD) at a 95% confidence interval (95% CI) and estimation zone (95%Prl) to invalid line, only when invalid line crosses perpendicularly to estimation zone but doesn’t to confidence interval, then means heterogeneity exists.2.7.5If there is a direct comparison between the experimental interventions included in the data , the Stata14.0 will be used for pairwise meta-analysis based on a random-effects model.2.7.6Two team members (YT and YSF) used statistical software - Stata  for analysis. A random effects model was used for network meta-analysis to compare the variables between different interventions. By comparing surface under the cumulative ranking curve (SUCRA), the optimum intervention measures were determined. The range of SUCRA is 0% to 100%, the higher of the cumulative ranking curve means the better of the efficacy.2.7.7Funnel plots are used to detect publication bias. If the images are asymmetric, it indicates that there is publication bias.2.7.8If the analysis shows significant heterogeneity, then the root cause will be analyzed according to the PICOS principle, and the STATA 14.0 will be used for subgroup analysis.2.7.9 2 team members evaluate the quality of the research and divide it into 4 levels of “high,” “medium,” “low,” and “very low,” then the results will be exchanged. If there is any disagreement, the final option will be selected via group discussion.According to the standards in the Grading of Recommendations Assessment Development and Evaluation (GRADE) system,2.8The secondary literature study has no relationship to the personal data of the study, so the ethical approval is not required. Evaluation of the efficacy and safety of different traditional Chinese medicine therapies for allergic rhinitis may provide evidence for clinical treatment of this disease. The results of the study will be published in a peer-reviewed journal.Data curation: Ting Yu, ShiFan Yan.Formal analysis: Ting Yu, ShiFan Yan, HaiYan Li.Funding acquisition: Lin Jiao.Investigation: SiYu Qin.Methodology: Ting Yu, ShiFan Yan, MingHui Li.Project administration: Rixin Chen.Resources: HaiYan Li, SiYu Qin, MingHui Li.Software: ZhenHai Chi, Pan Cheng.Supervision: ZhenHai Chi, Pan Cheng.Writing – original draft: Lin Jiao.Writing – review & editing: Rixin Chen.


SPSS version 25.0 and R Core Team,2018 version 3.5.1 were used.a paired case-control study (4 controls for each case) carried out in aspecialized care service in the Southeastern of Brazil, by analyzing PLHIVmedical records. The sample consisted of 85 participants, corresponding to17 cases and 68 controls. Pearson’s chi-square test =1.84-18.42, p=0.001] and use of nephrotoxic anti-retrovirals in theprevious therapeutic regimen . Onthe other hand, age below 40 years old  was identified as a protective factor.the PLHIV under study have multi-factorial exposure associated with chronickidney disease. However, knowing these factors helps to identify theexisting risks and/or renal dysfunction, in addition to supporting theclinical decision of the health professionals who directly assist them. AIDS is the most important and devastatingcontemporary epidemic.. Among those who have already been diagnosed, four out of five areusing Anti-retroviral Therapies (ARTs) (79%). Among those who have already hadaccess to the treatment, 81% had an undetectable viral load.According to the most recent world report, until the year 2017, there were about 36.9million people living with HIV/AIDS (PLHIV), of which 75% were aware of theirserological status. After the success of combinations of anti-retroviral drugs (ARDs) tocontrol viral replication, PLHIV have achieved better quality of life and greaterlongevity(-). This scenario, therefore, attributes to the HIV infection a chroniccondition of the disease.Scientific and technological developments in the therapeutic field allowed for theadvent of ART, enabling a better prognosis and, consequently, a reduction inmorbidity and mortality. After ongevity-5. Th(-).However, PLHIV started to present high risks of developing comorbidities, as a consequence of the complexassociation between immunodeficiency, chronic inflammation, aging, and toxicity ofanti-retrovirals, expanding the focus of care for a new profile of PLHIV-7.(-). The diverse causes and pathogenic mechanisms of kidney diseases foundin these people are complex, multi-factorial and have as an aggravating factor theinflammatory processes resulting from HIV infection and the cumulative exposure ofpotentially nephrotoxic anti-retrovirals(-).Faced with the new conjuncture of the health of PLHIV, previous studies have signaleda concern with chronic diseases, among them, chronic kidney disease(CKD)-8. Thvirals-., which represents clinical, managerial and economic challenges for thehealth care of these individuals.CKD in PLHIV, therefore, presents an increasing and higher form in comparison to thegeneral population,-12, wividuals., presenting an up to 20 times greater risk of progressing to TerminalChronic Kidney Disease (TCKD).A number of studies reveal a higher prevalence of CKD in PLHIV when compared topeople not infected by the virus,-15, p, due to genetic heterogeneity, to the initiation of the ART and to the different definition methods for CKD in each region, varyingbetween 2% and 38%. A study carried out in the Southeast region of Brazil showed that 35%of PLHIV using nephrotoxic ARDs for at least 6 months showed changes in the renalfunction.The prevalence of CKD associated with HIV varies geographically, by population and byperiod of the year,-17, d the ART and to  and 38%,19. Afunction.. This increase in the number of cases leads to an increase in the useof the health resources and, consequently, to an increase in health care assistancecosts.Therefore, the high number of PLHIV with CKD portrays an issue to be addressed by thehealth systems in developing countries that have a high prevalence of HIV and whereaccess to CKD care is insufficient. This icecosts.(-) and to the scarcity of research studies on this topic at the nationallevel, it is necessary to deepen studies on it and to expand the vision ofcomprehensive care for PLHIV, with the aim of preventing diseases, promoting healthand timely treatment. In view of the above, the objective of this study is to analyze thefactors associated with CKD in PLHIV.Due to the relevance of the matter-12 anallevel, it is reatment. In vieServiços de Atendimento Especializado, SAE) for PLHIV in acity in the inland of São Paulo, from February to June 2018. This SAE serves themajority of the population of the municipality, including other surroundingmunicipalities.In this study, a case-control design was analyzed, which was initially nested in adescriptive-analytical, retrospective study, performed on clinical records of PLHIVusing ART. The study took place in one of the five Specialized Care Services with an interval of 3 months or more than one eGFR<60 mL/min/1.73 m2estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)(21)group. The criterion for selecting the controls was for convenience, that is, thefirst medical record that met the inclusion criteria was selected .The following were considered as inclusion criteria: PLHIV registered and undergoingclinical-outpatient follow-up in the SAE chosen for the study; of both genders, over18 years old; using ART for more than 6 months; having medical records and more thanone creatinine test result available; the following were the exclusion criteria:individuals diagnosed with acute or chronic kidney disease prior to the diagnosis ofHIV positive; being on hemodialysis before starting ART, and having abandoned theuse of anti-retrovirals.For this case-control study, the pairing ratio chosen was 1:4, that is, for eachcase, four controls were chosen. This proportion, according to Miettnen (1976),increases the degree of similarity between cases and controls(22). After a carefulselection of laboratory tests, according to the criteria described, from the 258medical records 17 cases and 68 controls were identified. In the present study, itwas considered convenient not to use any variable to be paired and, for that reason,all the variables were collected and analyzed as exposure variables.The data related to sociodemographic, behavioral, clinical and laboratory variablesfound in the medical records of the research participants were collected by theresearcher herself using an instrument built for this study and submitted to facevalidation and content examination by three specialized professionals (twoinfectologists and a nephrologist). The data collection instrument, the Free andInformed Consent Form, and the validation instrument of the collection instrumentwere sent by e-mail with a period of 15 days to return the assessment. Theresearchers evaluated the instrument in terms of acceptance of the questioning, easyunderstanding, relevance of the items, clarity in the wording, presence ofambiguities, and were able to make suggestions for changes. After the analysis ofthe judges and necessary adjustments, a pilot study was carried out with 15 recordsof PLHIV in this same SAE.Regarding the variables considered as specific associated factors for the developmentof CKD, the following data were collected: gender , age (>40 yearsold/<40 years old), skin color ,smoking (yes/no), personal history (PH) of Systemic Arterial Hypertension (SAH)(yes/no), Diabetes Mellitus (DM) (yes/no), cardiovascular disease (CVD) (yes/no),dyslipidemia (DLP) (yes/no), renal lithiasis (yes/no), recurrent urinary tractinfection (UTI) (yes/no), HIV diagnosis time (<5 years/≥5 years), time of use ofART (<5 years/≥5 years), use of nephrotoxic anti-retrovirals in previoustherapeutic regimens (none/one/two or more), nephrotoxic anti-retrovirals in currenttherapeutic regimens (none/one/two or more), nephrotoxic anti-retrovirals inprevious and current therapeutic regimens (none/one/two or more), hepatitis B and Cco-infection (yes/no) and the last three results and laboratory tests for serumcreatinine.(-).Age was dichotomized for statistical analysis, so greater or equal to 40 years old orbelow 40 years old were chosen. To this end, it was based on international articleson this theme, in which the age group older than 40 years old presented the highestrisk of changes in the l function-24.For the assessment of dyslipidemia, the last three recorded laboratory tests of bloodlevels of High Density Lipoproteins-Cholesterol  Low DensityLipoproteins-Cholesterol (LDL-c), Total Cholesterol (TC), and Triglycerides (TGs)were considered. The registration of lipid-lowering drugs was also considered. Thereference values of the Brazilian Guideline for Dyslipidemias and AtherosclerosisPrevention of the Brazilian Society of Cardiology were used(25), namely: DesirableTC <200 mg/dl; Optimum LDL-c <100 mg/dl; Desirable HDL-c >40 mg/dl; anddesirable TG <150 mg/dl.The SAH, DM, CVD, renal lithiasis, recurrent UTI, and hepatitis B and C co-infectionvariables were considered according to the disease report in the patients’ medicalrecords.(-), Atazanavir (ATV), Lopinavir boosted with Ritonavir (LPV/r), andIndinavir (IDV).As for the nephrotoxic anti-retrovirals, ARDs already proven in the literature wereconsidered to be nephrotoxic: Tenofovir Disoproxil Fumarate (TDF)-28, Air (IDV),29..In order to obtain the eGFR using the CKD-EPI equation, it was first necessary toconvert the conventional creatinine into Creatinine for Isotopic Dilution MassSpectrometry (IDMS), considered the gold standard, in order to minimize itsvariability.2); 3B(eGFR: 30-44 mL/min/1.73 m2); 4 (eGFR: 15-29 mL/min/1.73 m2)and 5 (eGFR < 15 mL/min/1.73 m2) were considered, since 24-hour proteinuria tests and/orAlbuminuria/Creatininuria ratio (ACR) were not analyzed in this study, it was notpossible to identify CKD stages 1 and 2.CKD staging based on eGFR and albuminuria is classified into six stages ; however, only stages 3A (eGFR: 45-59 mL/min/1.73 m1.73 m2) were coThe data were processed and analyzed using the Statistical Package for SocialSciences (SPSS) software, version 25.0. Descriptive statistics were used through:absolute (n) and relative (%), mean, standard deviation (SD), minimum and maximum,in addition to Pearson›s Chi-square association tests (Χ2) and Fisher’s exacttest.The independent variables, previously associated, were submitted to logisticregression analysis. For the logistic regression, the selection of the independentvariables was performed  through the Likelihood Ratiotest. A p value<0.05 was adopted. From the chosen model, the respective gross andadjusted Odds Ratios (ORs) of the model parameters were calculated with therespective 95% Confidence Interval (CI). In all the analyses, the level ofsignificance adopted was 5% . The program used was R version 3.5.1(31).The study was conducted in accordance with the legal and ethical standards ofResolution 466/2012. The study was approved by the Research Ethics Committee of theRibeirão Preto Nursing School at the University of São Paulo under protocol No.2439.373. Under CAAE No.: 79881717.8.0000.5393, approved on December 14th, 2017.Of the 258 records analyzed initially, 6.5% (n=17) met the CKD criteriapre-established in the study. They were classified as case. After analyzing thedata, it was identified that, of the 85 study participants, 17 were cases and 68controls.Among the participants included in the cases, the majority, 16 (94.11%), were over 40years old; of these, 82.35% were over 50 years old, 9 (52.94%) were male, 10(58.82%) were white-skinned and 4 (23.52%) were brown-skinned. Regarding theparticipants included in the controls, the majority, 45 (66.17%), were in the agegroup above 40 years old, and the predominant gender was male with 47 (69.11%).White and brown skin colors had the same frequency: 24 (35.29%).The distribution of the last three eGFR of the cases and controls according to theCKD stages is shown in Among the 17 cases and 68 controls analyzed in this study, we found that the age,SAH, and nephrotoxic anti-retrovirals in a previous treatment regimen variableshowed a statistically significant association with CKD. Being less than 40 yearsold is a protective factor and, as associated factors, having SAH and makingprevious use of nephrotoxic ARDs are noted..The main findings of this study indicate the importance of detecting the associatedfactors for traditional CKD, those intrinsically related to the fact of living withHIV and being treated with potentially nephrotoxic anti-retrovirals. Internationalstudies have addressed this issue in recent times due to its relevance in thepopulation living with HIV,,,32.(-). This fact justifies the need to investigate the main predictors forCKD in PLHIV using the case-control methodology. This study, therefore, is the firstthat addresses this type of design in this theme at the national level.Chronic Kidney Disease has a low incidence of PLHIV, although it is considered animportant worldwide public health problem and is more prevalent among PLHIV than inthe general population-34. T was observed.From the pre-established criteria for the definition of CKD, we found a prevalence of6.5%, which is equivalent to the cases described in this study. Among the 17 cases,stages 3A, 3B and 4 are found, with PLHIV not being identified in stage 5- TerminalChronic Kidney Disease. This result characterizes the cases of this study. Theprevalence found confirms the result obtained in a prospective multi-center Europeancohort study in which it followed PLHIV between the years 2006 and 2014, in which anincrease from 4.1% to 6.9% of CKD was obs. Based on the first systematic review that provided prevalenceestimates for CKD in PLHIV in various regions of the World Health Organization,using the CKD-EPI equation, an overall prevalence of 4.8% was identified (CI:2.9-7.1), with the highest prevalence found in Africa and the lowest inEurope.A wide variation in the prevalence of CKD is found in different locations, which isjustified by the heterogeneous population, regional, cultural, structures of accessto health services and differences in diagnostic criteria,,28. BnEurope..In studies that used the CKD-EPI equation and did not evaluate the presence ofproteinuria, the variation comprised between 3% (Texas), 3.3% (Brazil), 5%, 5.4% (London) and 13.4% (Africa), among people living withHIV,,-37.2 and presence ofproteinuria in more than one measure, in a recent study showed a global presence of11.7% of CKD, with 7.6% being diagnosed only by the proteinuriacriterion. As well as what is represented in the Dutch (18.3%) and Vietnamese cohorts (8.3%). Data which show a high prevalence of the disease when using the twodiagnostic criteria.While those who analyzed GFR<60 ml/min/1.73 mriterion. As wel (18.3%) and Vies (8.3%). Data w(-).Being under the age of 40 has been shown to be a protective factor for CKD, that is,PLHIV under the age of 40 are less likely to develop CKD than those over 40 yearsold. This corroborates with other researchers who point out that, with increasingage there is a greater predisposition to lower eGFR, to greater regression of renalfunction and, consequently, to develop CKD-24.. The same is also identified in this study, in which the cases have amean age of 61.4 years old and, in the controls, 49.9 years old.Among the non-modifiable associated factors for developing CKD, advanced age isconsidered an independent marker of decline in renal function in PLHIV by severalscholars,-,-39. T.The relationship between increasing age and CKD was also studied in a multi-centercohort carried out over nine years with 23,000 PLHIV, in which an increasingprevalence of CKD was identified with the advancing age groups in which theseindividuals are inserted. Among people aged between 50 and 60 years old, there wasan increase from 5.2% to 7.2% while, among those over 60, there was an increase from18.5% to 23.2% of CKD.. This assertion is in line with the results found in a retrospectiveobservational study over a six-year period, which revealed a reduction in the meanage among those who had CKD from 49.4 to 46.4 years old (p<0.0001).However, the characteristic of premature aging among PLHIV causes middle-aged adultsusing ART to have a high inflammatory exposure and, therefore, premature onset canoccur of chronic comorbidities, such as CKD,40. T.Regarding the comorbidities identified, SAH was the only chronic disease that had astrong association with CKD. PLHIV diagnosed with SAH are 5.8 times more likely todevelop CKD compared to those who do not have SAH. This finding confirms thathypertension is a significant factor and is independently associated with the rapiddecline in PLHIV’s eGFR, as found in recent international cohorts-,,-42.. In addition, other researchers have shown a higher burden ofhypertension among PLHIV when compared to the general population(-).A study carried out in Spain with 1,596 PLHIV corroborates this information whenconsidering that the absence of hypertension is an independent marker of improvementin renal function over time . In addpulation-45..Another variable that showed a significant association was the use of nephrotoxicanti-retrovirals in a previous therapeutic regimen. Individuals who used them were3.3 times more likely to develop CKD compared to those who did not. This fact can beexplained by the longer time of exposure to these specific ARDs in previous ARTcompared to the current one.. Therefore, PLHIV who had GFR>90 ml/min/1.73 m2 andstarted the ART with Tenofovir, Atazanavir, Lopinavir enhanced by Ritonavir, andDarunavir showed a significant and growing association of CKD.A multi-center cohort study corroborates with this study by showing that thecumulative exposure of nephrotoxic ARDs during the first five years of follow-upshows a progression in renal impairment rates. Theref2.Due to the nephrotoxicity of TDF recognized by the literature, the Ministry of Healthrecommends the discontinuation of this drug in a timely manner (six months ofexposure) and its replacement by another ARD if, when using this drug, there is a25% decline in baseline eGFR or GFR<60 ml/min/1.73 m. Both the high prevalence of the use of nephrotoxic ARDs in a previousand current scheme, and the cumulative exposure of these ARDs may justify the numberof cases found in this study.By postponing the discontinuation of nephrotoxic ARDs, transient damage to renalstructures can become permanent,,46. B.In this context, the nurse, as a member of a health team, is a professional whoarticulates, coordinates and conducts care interventions through goals,interventions and, consequently, obtaining satisfactory results. Its role isfundamental for the identification of the factors associated with CKD and problemsolving.. Thus, providing the protagonism of care for PLHIV from the knowledgeof the risks to the chronic diseases that they are exposed to, CKD being animportant comorbidity that can affect these individuals.In addition, the nursing team must perform health education actions in theprevention, early detection, and management of CKD in order to change behaviors andlifestyle habits. Thus, As for the limitations of the study, although there is methodological rigor from thepreparation of the study model to the analysis of the data, some should be noted dueto the retrospective nature of the study. Data collection was performed exclusivelyfrom secondary data in medical records of patients and, therefore, there were somegaps in obtaining the information.2. Therefore,the identification of CKD stages 1 and 2 were impaired, whereas only the presence ofalbuminuria≥30 mg/24 hours or albuminuria/proteininuria ratio (APR)>30 mg/g inmore than one measure for more than three months characterizes suchclassifications.Another limitation of the study concerns the unavailability of more than one resultof 24-hour proteinuria or ACR tests. In view of this, the definition for CKDdepended only on the criterion of eGFR<60 ml/min/1.73 m.Such limitations did not prevent the research from being carried out, asinternational studies also pointed out similar difficulties with access toproteinuria tests and, therefore, used the same definition adopted in thisstudy,,36.The factors associated with CKD in PLHIV were the presence of SAH and nephrotoxicanti-retrovirals in a previous therapeutic regimen. Another factor also associated,however, as protection for CKD in PLHIV was age below 40 years old.The people living with HIV under study have multi-factorial exposure associated withchronic kidney disease. The presence of SAH and nephrotoxic anti-retrovirals in aprevious therapeutic regimen were considered factors associated with CKD in PLHIV.On the other hand, age under 40 was considered a protective factor against CKD inPLHIV.Thus, knowing the factors associated with CKD helps in its identification and/or inthe identification of the renal dysfunction existing among PLHIV, in addition tosupporting the clinical decision of the health professionals, including nurses, whodirectly assist them. This with a view to implementing interventions for theprevention, detection, and adequate management of CKD through frequent monitoring ofrenal function and existing comorbidities.For this reason, frequent updates to the SAEs are advised on changes in the profileof PLHIV, training courses aimed at the prevention and management of CKD,construction of care protocols, as well as raising the awareness of the healthprofessionals to interdisciplinary work and comprehensive care.


Oxidative stress due to the high levels of reactive oxygen species (ROS) that damage biomolecules  results in acute inflammation. However, without proper intervention, acute inflammation progresses to chronic inflammation and then to several chronic diseases, including cancer, myocardial infarction, cardiovascular diseases, chronic inflammation, atherosclerosis, and more. There has been extensive research on the antioxidants of natural origin. However, there are myriad possibilities for the development of synthetic antioxidants for pharmacological applications. There is an increasing interest in the identification of novel synthetic antioxidants for the modulation of biochemical processes related to ROS. In this regard, derivatives of supramolecules, such as calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, porphyrin etc. are gaining attention for their abilities to scavenge the free radicals. Supramolecular chemistry offers excellent scaffolds for the development of novel antioxidants that can be used to modulate free radical reactions and to improve the disorders related to oxidative stress. This review focuses on the interdisciplinary approach for the design and development of novel synthetic antioxidants based on supramolecular scaffolds, with potentially protective effects against oxidative stress. The development of synthetic antioxidants is attractive, as it allows one to manipulate the physicochemical properties to improve the antioxidant properties for various applications. It is crucial to notice that there are several reports on the inclusion complexes of these macrocycles, including cyclodextrins with antioxidant activities ,28,29,30This review aims to explore the advances in the development of antioxidants, based on calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin .p-alkylphenols in the presence of a strong base arene moiety, was comparable with the ascorbic acid (92.0%), which is used as a standard in the assays.In 2012, Patel et al. reported the synthesis and evaluation of calix[4]arene based 1,3,4-oxadiazole and thiadiazole derivatives 11–19  45]. Th. Th11–1920, 21 and 22,  showed strong antiradical activity compared to the corresponding monomers.There have been several reports on the methods to substitute the upper-rim and lower-rim of calix[4]arene ,48. Pur 26–35 for their antioxidant and antibacterial activities by linking them to Ag nanoparticles  with anticandidal activity  with an aldehyde in an acidic environment  57,58].,58.57,5848, 49) derivatives (50–53) by the aminomethylation of resorcinarene octols with 4-amino-TEMPO TEMPO , and studied their antioxidant activities. They found that the Tetra- TEMPO resorcinarenes (50–53) are efficient scavengers of DPPH radicals and showed superoxide dismutase-like activity. These compounds were also found to have a high efficiency for inhibition of ABAP-induced peroxidation of linoleic acid. The macrocyclic structure of resorcinarene and intramolecular hydrogen bonding had a considerable contribution to the antiradical activity of these compounds. Recently, Ngurah reported the antioxidant activity of C-methoxyphenyl calix[4]resorcinarene 54 (56 showed reasonable antioxidant activity (IC50 = 79 ppm), but less than that of vitamin C (IC50 = 20.96 ppm), which was used as a standard in this study. Oliveira et al. reported the synthesis and comparative study on the antioxidant and anti-toxoplasma activities of vanillin 56 and its resorcinarene derivative 57  56 and 57 demonstrated a substantial safety margin indicated by lack toxicity up to 300 mg/kg during 14 days after administration. The obtained compound 57 exhibited more significant antioxidant activity (84.9%) as compared to vanillin 56 (19.4%). These results indicate that the resorcinarene has excellent potential for the development of antioxidant and antiradical compounds. Recently, Abosadiya et al. reported the synthesis, characterization, x-ray structure, and biological activities of c-5-bromo-2-hydroxyphenylcalix[4]-2-methyl resorcinarene 60  in scavenging the DPPH free radicals. Since compound 60 is a polyphenolic compound, it inhibited the oxidation of DPPH, preferably using the hydrogen atoms to form the stable non-radical form of DPPH indicated by the formation of a pale-yellow color.The in vivo acute toxicity assays of arene 60 b 70]. T. T56 andTyrosol is an essential antioxidant molecule with various biological activities. There has been an increasing interest in the development of strategies for the clustering of single drug units in order to design novel drugs. It is understood that the cluster effect can increase the pharmacological effect of a drug to a single drug unit .64, which is a novel cluster of tyrosol (64 has superior antioxidant activity (>5 fold) as compared to the single tyrosol unit. The enhanced antioxidant activity is attributed to the cluster of four impacted tyrosol units that show a synergistic effect in interactions with radicals.Keeping this in mind, Pur et al. developed a novel calixtyrosol  tyrosol  72]. Th. Th64, wCalix[4]pyrroles have attracted substantial attention as supramolecular containers during the past two decades ,74. The 70 wrapped Au nanoprobes for the detection of Pb(II), antioxidant, and radical scavenging activities [Even though the calix[4]pyrrole offers an excellent scaffold that can be tailored for the development of potent antioxidants, it has been understudied in this regard. However, the complex of Au and calix[4]pyrrole has been studied for the antioxidant and radical scavenging efficiencies. Kongor et al. reported the synthesis and modeling of calix[4]pyrrole derivative tivities . The cal73 with formaldehyde in the presence of strong acid [cucurbitaceae family). The cucurbituril is often abbreviated as CB[n], highlighting the n glycoluril building blocks in the macrocycle uril, is a supramolecule obtained by the condensation of glycoluril ong acid . The maccrocycle ,80  functionalized with the biomolecules (81) was evaluated for its ability to catalyze the reduction of H2O2 to H2O. This derivative was found to possess a dual function as SOD and catalase. The carbohydrate conjugated MnP (82) facilitated the anchoring of the conjugate on the cell surface by binding to a receptor. The results of this study suggest that the porphyrins can be modified to generate analogues with potent antioxidant activities.Asayama et al. reported the manganese porphyrins  and evaluation of its antioxidant activity by electrochemistry arene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin were used for the development of radical scavengers . Calixarene, resorcinarene, calixtyrosol, calixpyrrole, cucurbit[n]uril, and porphyrin. There are several reports on the modification reactions of these molecules to product functional compounds of desired properties. However, the application of these macromolecular scaffolds for the development of potent radical scavengers with pharmacological activities are not studied to its full potential. Therefore, this review elaborated on the derivatives of various supramolecules and their antioxidant activities. Porphyrin derivatives have a significant amount of research on their radical-scavenging abilities and reaction mechanisms supporting them. Similar to porphyrins, the calix[n]arene, resorcinarene, calixtyrosol, calixpyrrole, and cucurbit[n]uril derivatives offer great potential for the development of ROS modulators with significant pharmacological activities to prevent and treat the disorders resulting from oxidative stress.


He showed a great improvement under ibrutinib therapy and took to artificial nourishment and adequate muscle rehabilitation until he recovered his autonomy. In August 2018, a 5-days-a-week training program was started: Physical activity for at least 20 min consisting of a fast walk in the open air three times a week and a moderate physical activity in the remaining two days of at least 20 consecutive minutes . The exercise program included also aerobic, upper and lower limb resistance training, chore stability and stretches. The physical condition further improved and remained excellent throughout the follow-up period. In December 2018, his clinical condition was quite normal; a CT showed a great decrease of all lymphoadenomegaly, and FISH test did not show del(11q). He continued to cultivate his land, while still being treated with ibrutinib. The combination of the right therapy, adequate nutrition, and muscle rehabilitation is the best solution to improve the clinical condition of old cachectic CLL del(11q) patient.Chronic lymphatic leukemia (CLL) is the most frequent type of leukemia in western countries and when association with del(11q) is correlated with a worse prognosis. We reported the clinical case of an 80-year-old patient with CLL related to del(11q) and a BMI of 16.4 kg/m Chronic lymphatic leukemia (CLL) is the most frequent type of leukemia in western countries, and in patients >65 years-of-age (70% of cases) with a median age of 72 years. CLL incidence rate is around 4/100,000 inhabitants per year . ClinicaIn our case, after a cardiological evaluation, when he had regained his autonomy, the patient was encouraged to intensify the physical activity he carried out progressively, avoiding excesses that caused palpitations or dyspnea to occur. After this step, it was easier to make use of the previously-mentioned physical activity programs modified for our patient’s ability, attitudes, clinical, and social conditions. The ultimate goal was to bring the patient back to the type of activity he did before the disease.This paper describes the first clinical case of a patient with little chance of survival treated with ibrutinib and underwent a program of physical activity. The aim of our report is to underline the importance of rehabilitation which, associated with the pharmacological treatment was of great help for 80-year old CLL del(11q) patient.2. On 2 May 2018, he performed all blood chemistry tests that showed the following anomalies: Erythrocyte sedimentation rate (ESR) 71 mm; C-reactive protein (CRP) 54 mg/L; fibrinogen 637 ng/dL, lactate dehydrogenase (LDH) 498 U/L; albumin 2.6 g/dL; triglyceride, cholesterol and glicemy levels were at the lower limits of normal; a moderate anemia with hemoglobin 9.5 g/dL, a lymphocytosis . At cardiology consultation and echocardiogram he showed good functionality. Chemotherapy was changed and ibrutinib 420 mg/day was introduced in June 2017. In addition, a rehabilitation physio kinesitherapy program and parenteral nutrition were started associated with intravenous (i.v.) albumin every day and, erythropoiesis-stimulating agents (ESAs) subcutaneous (s.c.) every week. Peripheral parenteral nutrition included the intake of glucose, lipids, branched chain amino acids, B vitamins, and folate. The muscle exercise program was based on an attempt to bring the patient back to physical capacity 4 months before bedtime. After one month, the general conditions began to improve. He started walking with support and gradually he was able to walk and eat independently. His performance status improved progressively, and he was recommended to walk for 30-minutes a day at mild intensity in July 2018 [An 80-year-old Caucasian man was observed at our clinical center in January 2018, for unintentional weight loss of 5 kg, itching without any skin lesion ,24, and uly 2018 . His CT uly 2018 ,34,35. Tuly 2018 ,36,37. AThe diagnosis and management of CLL impact quality of life (QoL) , and alsThe associated physical activity program allowed our patient to reach a good shape and to remain so for all the observation period ,46,47,48The CLL with del(11q), usually show a poor prognosis and a very old patient is not the ideal candidate to respond to treatment. According to the international Prognostic Score (CLL-IPI), our patient was to be considered in very high-risk with a 5-year overall survival (OS) of about 23%. However, the new tyrosine kinase inhibitors (TKI) allow the older patients who usually present comorbidities and poor physical condition because they are more tolerable than conventional chemotherapy . HoweverAssociated to treatment, adequate nutrition, muscle rehabilitation and psychological support allow a better chance of recovery, our patient in on reliable example of this ,24.


To describe the clinical profile of children and adolescents hospitalizedwith community-acquired pneumonia (CAP). They were divided into two groups:those with and those without comorbidities. An observational, cross-sectional, descriptive study with prospective datacollection, was carried out in a cohort of patients aged zero to 11, whowere hospitalized with a clinical and radiological diagnosis ofcommunity-acquired pneumonia, from January 2010 to January 2012. As anexploratory study, the two groups were compared through logistic regressionfor possible risk factors associated with community-acquired pneumonia.Relative risk (RR) was used with a 95% confidence interval (95%CI). Theprocess of selection for independent variables was stepwise forward, with asignificance level of 5%. There were 121 cases of community-acquired pneumonia evaluated, and 47.9%had comorbidities. In the bivariate analysis, patients with comorbiditiesdemonstrated higher chances for: age >60 months (p=0.005), malnutrition(p=0.002), previous use of antibiotics (p=0.008) and previoushospitalization for community-acquired pneumonia in the last 24 months(p=0.004). In the multivariate analysis, these variables were independentpredictors of community-acquired pneumonia in patients with thecomorbidities: age >60 months ;malnutrition ; previous use ofantibiotics ; and previoushospitalization for community-acquired pneumonia . Most patients with community-acquired pneumonia and comorbidities were aged>60 months, were malnourished, had used antibiotics and had beenhospitalized for community-acquired pneumonia. Comorbidities were associatedwith a higher chance of malnutrition and hospitalizations forcommunity-acquired pneumonia in an older age group, compared to childrenwithout comorbidities. Knowledge of this clinical profile may contribute tobetter assist pediatric patients with community-acquired pneumoniahospitalized in referral centers. In children under one year old or from one tofour years old, the average annual reduction in mortality rates from pneumonia was0.12 and 0.07, respectively.Pneumonia is the leading infectious cause of death in children worldwide, accountingfor the death of 920,136 children under five years old in 2015, which is 16% of alldeaths in this age group.CAP may be defined by the presence of signs and symptoms, such as coughing, fever,tachypnea, dyspnea, chest pain or referred abdominal pain, wheezing from respiratoryauscultation in a previously healthy child due to infection acquired outside thehospital. Wheezing-free tachypnea, with or without dyspnea, is the most common andimportant symptom for the diagnosis. In developing countries, the term “lowerrespiratory tract infection” may be adopted, as it does not require a radiologicalexamination.,The risk factors for host-related CAP, according to the literature, are:malnutrition, young age, comorbidities ,low birth weight, previous episodes of wheezing and pneumonia, lack ofbreastfeeding, incomplete series of vaccinations and viral respiratoryinfections.Most articles that involve risk factors for childhood CAP exclude patients withcomorbidities from their analysis, thus making it difficult to compare groups withCAP that also may or may not have an underlying disease. This study aimed todescribe the risk variables for CAP in hospitalized children with CAP, separatingthem into two groups: those with comorbidities and those without.Instituto de Puericultura e Pediatria MartagãoGesteira - IPPMG), a unit of the Universidade Federal do Rio deJaneiro (UFRJ), which provides outpatient and hospital care forchildren ages 0 to 11 years old. IPPMG has outpatient clinics from all pediatricspecialties, thus generating a greater number of customer care opportunities andhospitalizations of patients with chronic diseases in their beds. There are sixwards, one for patients with onco-hematological diseases and the other for pre- orpostoperative patients with general pediatric surgical diseases. The others werehospitalized for various diseases. It is worth noting that, because they are at auniversity level, they have a lot of comorbidities, with the most prevalentunderlying diseases being: encephalopathies, hemoglobinopathies andonco-hematological pathologies. There are eight beds in each ward, except for thehematology ward, where there are six beds, making a total of 46 beds. More detailsabout the study site were described by Ferreira et al.A cross-sectional study with prospective data collection was conducted with childrenaged zero to 11 years old, who were hospitalized with clinical and radiologicaldiagnoses of CAP, from January 2010 to January 2012. The study was carried out inthe wards of the Pediatrics Department of the Martagão Gesteira Institute ofChildcare and Pediatrics .invitro and in vivo resistances of Streptococcuspneumoniae in PAC.An adapted form of the Risk Factors Investigation Fact Sheet of the Caribbeanprospective multi-center study was developed simultaneously in 12 health centers inthree countries , from July 1998 to December 2002. It aimed to evaluate the The patients were divided into groups with and without comorbidities . The following host-related variables were evaluated:Clinical - nutritional status, classifying the patient as eutrophic,malnourished  curve) or in the risk zone (between the thirdand tenth percentile on the NCHS curve); previous antibiotic use beforehospitalization  and reason foruse; previous hospitalization for CAP in the last 24 months; previouswheezing in the last 12 months; and exclusive breastfeeding time .Demographic - sex, patient’s age and number of patients older than 60months.A database was developed in the Microsoft Office Excel program and was then analyzedwith the Statistical Analysis System (SAS) software, version 6.11. Then, adescriptive analysis was performed for numerical data expressed as an average ±standard deviation (SD) and median; frequency (n) and percentage (%) for categoricaldata. For the exploratory bivariate analysis, the prevalence ratio (PR) between theexposure or lack of exposure to the variables in both groups was calculated, with a95% confidence interval (95%CI). Logistic regression analysis was performed toevaluate the simultaneous influence of host-related variables in children andadolescents regarding the occurrence of CAP in cases with comorbidities. Theindependent variables selection process used was stepwise forward, at a significancelevel of 5%. The project was approved by the Research Ethics Committee of theIPPMG/UFRJ, under number 42/09.=0.19) between both groups.One hundred and twenty-four patients were studied and three were excluded due toincomplete data from the medical records. Therefore, a total of 121 patients wereanalyzed. In the descriptive analysis of the studied population, 63 (52.1%) had nocomorbidities (Group 2) and 58 (47.9%) had comorbidities (Group 1), the mostfrequent being hemoglobinopathies (11.6% -- 14 cases) and encephalopathies (10.7% --13 cases). The remaining 31 cases (25.6%) were: wheezing infants and asthma (7/58),AIDS (5/58), congenital airway malformation (3/58), prematurity (3/58), congenitalimmunodeficiencies (2/58) and others (11/58). There were 69 (57%) male patients. Theaverage age of the population was 40.6±35.8 months (median = 32 months), and themajority of the population was under five years old. The mean age was 53±40 and29±27 months in Groups 1 and 2, respectively (p<0.05). With regard tohospitalization length, the average stay was 12.1±19.6 and 8.2 ± 3.7 days, in Groups1 and 2, respectively, but there was no statistically significant difference and exclusivebreastfeeding time (p = 0.83). There were statistically significant differencesbetween the groups regarding age older than 60 months (p = 0.005), malnutrition (p =0.002), prior antibiotic use (p = 0.008), prior hospitalization for pneumonia (p =0.004) and completed basic vaccination (p = 0.021).Logistic regression analysis was performed with the variables shown in The present study describes clinical aspects of patients with and without comorbidCAP, who were hospitalized in the wards of a university pediatric hospital. Arelevant frequency of the following risk factors was demonstrated in the generalpopulation: previous antimicrobial use, mainly by the CAP; lack of exclusivebreastfeeding for at least four months; under 60 months and male.Approximately half of the sample had comorbidities. In a study conducted in Tanzaniainvolving 100 hospitalized children with CAP, 32% of the patients had comorbidities,with malaria, typhoid fever and anemia being the most prevalent. This was related tothe greater severity and complications of CAP. This study also did not find longerhospital stays in patients with CAP and comorbidities.In the assessment of the possible association of risk variables analyzed with Group1, the most prevalent were: malnutrition, previous antimicrobial use and previoushospitalization for CAP. The group was 3.6 times more likely than Group 2 to be >60 months old (this age range was an independent variable for CAP in this group),with PR = 5.39. This is probably due to the fact that, with the evolution ofunderlying diseases, new infections and hospitalizations are favored over time.Although most children were eutrophic, there was a greater chance of malnutrition inGroup 1. This was an independent variable in this group, probably due to cases ofchronic diseases that are concomitant with undernutrition. Malnutrition has beenreported as a risk variable for CAP acquisition, hospitalization and mortality.Teepe et al. demonstrated that low weight for age and low weight for height wererelated to the increased risk of CAP.After a comprehensive literature review, few studies describing risk variablesrelated to CAP in children with underlying diseases were found. The meta-analysisperformed by Jackson et al. in children hospitalized for risk factors related tolower respiratory tract infections (CAP or bronchiolitis), showed a significantassociation of respiratory disease with: low birth weight, air pollution,malnutrition, incomplete immunization in the first year, HIV, lack of breastfeedingand crowding at home.In the present study, just over half of the cases had previously used antimicrobials,mainly due to previous CAP. The bivariate analysis showed that the risk of previousantibiotic use was 2.67 times higher in Group 1 patients than in Group 2 (95%CI1.20-5.97), probably because they experienced a higher occurrence of respiratoryinfections requiring antimicrobial therapy. From the multivariate analysis, priorantibiotic use was an independent variable for PAC in Group 1 patients, as well asprevious hospitalization for PAC, with a PR of 3.03 and 2.91, respectively. Asimilar finding was found in a case-control study in New Zealand, where previousrespiratory infections in children or families led to a higher risk of acquiringCAP.S. pneumoniae andH. influenzae up to five years of age. Sickle cell diseaseprogresses with auto-splenectomy, due to the presence of thrombi and infarctions,which culminate in atrophy and fibrosis of the spleen, predisposing individuals toinfection from encapsulated germs.Hospitalization for PAC in the last 24 months was more associated with comorbiditiesin Group 1 and was an independent variable for CAP in this group, with a PR of 2.91.Recently, the importance of comorbidities influencing the severity of CAP wasrelated to congenital heart disease in a pediatric ICU study in China.,Wheezing in the past 12 months was present in almost half of the group withcomorbidities, but there was no statistical association. The presence of a previousepisode of wheezing may correspond to an underlying disease, such as asthma, orepisodes of viral respiratory infections. Some authors have shown that infants withone or more wheezing episodes in the first three months of life and children andadolescents with asthma had a higher risk of developing CAP, although this was notan objective of the present study.Although breastfeeding has a protective effect against childhood respiratorydiseases, especially in the early years, as it is related to the amount of breastmilk received and the time of breastfeeding, most children in our study, under 24months of age, were exclusively breast-fed for less than four months. However, thisdata was not relevant in either group. A limitation to this variable was the factthat the person interviewed was not always the mother, which may have hindered thereliability of the information provided. In the US, exclusive breastfeeding for aperiod of six months or more promoted greater protection against respiratory tractinfection.The present study had some limitations. Due to its cross-sectional design, it was notpossible to further accompany the patients in order to identify CAP sequelae andeventual readmissions. In addition, to assess the associations of variables in thegroups with and without comorbidities, all underlying diseases of different severitylevels were included, due to the small number of cases in each comorbidity subgroup.Other limitations were possible respondent memory bias at the time of the patients’hospitalization, as well as the reduced number of patients during the months ofcollection. This was because the wards were temporary closed for two months due toadministrative problems. On the other hand, the present study was developed in atertiary hospital and included all CAP patients hospitalized in the study period,with a single investigator, and standardized care at the institution. It is alsoworth considering that our data were collected about seven years ago and that themanner of giving assistance during this period did not undergo major changes in theinstitution. Thus, it is worth acknowledging that the clinical knowledge of childrenand adolescents with CAP and comorbidities contained in this study may contribute tobetter assistance of pediatric patients hospitalized in referral services.


Since the end of December 2019, the outbreak of coronavirus disease 2019 (COVID-19) epidemic has occurred and spread rapidly throughout China. At present, China's epidemic situation has been basically controlled, but the number of cases worldwide is increasing day by day. On March 11, the WHO officially announced that the COVID-19 had become a global pandemic. However, there are currently limited data on pregnant women with COVID-19 pneumonia and their infants. In this paper, a case of a pregnant woman infected with COVID-19 pneumonia is reported.We report a clinically confirmed COVID-19 pregnant woman. The patient was tested negative 4 times in nucleic acid test, but immunoglobulin G was positive and immunoglobulin M was negative before delivery, suggesting a previous infection.The pregnant woman underwent a computed tomography scan of both lungs at 29 + 2 weeks of pregnancy, and scattered stiffness and frosted glass shadows of both lungs were observed. According to the diagnostic criteria for COVID-19 pneumonia in the “New Coronavirus Prevention and Control Plan Fifth Edition” of the National Health Commission of China, she was diagnosed as a clinically confirmed case.The pregnant women received nebulized inhalation and oral cephalosporin treatment in a community hospital and was discharged after the symptoms disappeared. After that, she was isolated at home.The pregnant woman gave birth to a healthy baby after being cured from COVID-19 infection. The nucleic acid test of the neonatal pharyngeal swab was negative, and the neonatal serum test showed positive for immunoglobulin G and negative for immunoglobulin M.The findings of this case report are useful for understanding the possible clinical features of COVID-19 infection in pregnant women, the duration of the antibody, and passive immunity of the fetus. According to the World Health Organization’ s report on April 10, 2020, there have been more than 100 countries in the world suffering the outbreaks of COVID-19, and the number of confirmed cases worldwide has exceeded 1.5 million, including more than 90,000 deaths.As of April 11, 2020, there have been more than 80,000 confirmed coronavirus disease 2019 (COVID-19) cases in China, including 3339 deaths. The mortality rate of the severe acute respiratory syndrome (SARS) and middle east respiratory syndrome epidemic was 15% and 27%, respectively. Pregnant women seem more likely to have a mild symptom of COVID-19 infection or to be an asymptomatic case, and the risk of COVID-19 infection for pregnant women may be much lower than SARS or middle east respiratory syndrome. The previous studies also show that pregnant women may be particularly vulnerable to COVID-19 infection. Thus, prevention and control of COVID-19 infection among pregnant women have become a major concern. In this paper, we will introduce a case report of a pregnant woman infected with COVID-19 pneumonia.During the epidemic, there is another special group that needs to be taken more care of, that is, pregnant women. The WHO-China Joint Mission Report introduced an investigation of 147 pregnant women cases  in China from February 16 to February 24, among which 8% were severe cases and 1% were critical cases.2°C and 37.8°C. She was diagnosed with common pneumonia and treated by oral cephalosporin at a community hospital for 3 days. Her pulmonary computed tomography (CT) scan on January 30, 2020 (29 + 2 weeks gestation)  released by the National Health Commission of China on February 3, 2020, she was diagnosed as a clinically confirmed case, so quarantine treatment combined with nebulized inhalation and oral cephalosporin was applied for her. Five days later (30 weeks gestation), her body temperature returned to normal and the symptoms such as cough and expectoration disappeared. Subsequently, the pharyngeal swab test of SARS-CoV-2 revealed twice negative at a community hospital on March 5 and March 7, 2020 (34 + 4 weeks gestation). The pulmonary CT scan on March 24, 2020 (37 weeks gestation)  by quantitative real time polymerase chain reaction from throat swab. The pregnant woman with 28 + 5 weeks gestation developed cough and expectoration on January 26, 2020, and then had a fever on January 27 with her body temperature fluctuating between 37.5°C, heart rate was 78 bpm, respiratory rate was 20 bpm, blood pressure was 111/61 mm Hg. No abnormalities were heard on cardiopulmonary auscultation. On the day of admission, she underwent cesarean delivery (CD) due to her previous CD in 2015. The operation went smoothly. The birth weight of the newborn was 3200 g, and the 1-minute and 5-minute Apgar scores were all 10. The newborn was tested with the COVID-19 Colloidal Gold method on the birth day by serum, and the test result was positive for IgG and negative for IgM. On April 7, 2020, the pharyngeal swab test for the newborn revealed negative. During hospitalization, she developed no fever, cough or other symptoms. Five days after CD, she was discharged.On April 5, 2020, at the gestational age of 38 weeks and 5 days, the pregnant woman was admitted to the hospital with small amount of vaginal bleeding. The admission check showed that her body temperature was 36.4The study was reviewed and approved by the Ethics Committee of Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology (Record number [2020] IEC[XM002]). All included women signed informed consent for therapeutic procedures and also for the publication of this case report.3 Although CT and clinical manifestations and treatment monitoring of COVID-19 pneumonia patients have been extensively studied, there are few researches on pregnant women with COVID-19 pneumonia. It is highly important to systematically investigate the clinical characteristics and outcomes of pregnant women with COVID-19 to provide strong guidelines for prevention, treatment, and management.On March 11, 2020, WHO officially announced that the COVID-19 infection had become a global pandemic. Between March 5 and April 7, her pharyngeal swab test revealed negative for nucleic acid 4 times, and 3 chest CT scan images showed that the lung lesions were absorbed well. Moreover, she and her baby were tested positive for IgG and negative for IgM during hospitalization.This case report investigates a pregnant woman who developed symptoms as early as January 26 and had typical signs of lungs on CT examination on January 30, 2020. She had a close contact with a confirmed COVID-19 pneumonia case within 14 days of onset, but did not accept throat swab nucleic acid test for SARS-CoV-2 at first. She was classified as a clinically diagnosed case at that time in Wuhan, China. Pulmonary CT scan plays an important role in diagnosis of COVID-19 infection and observation of therapeutic effect, and the typical imaging features is typically helpful in early screening of highly suspected cases. At first, the patient was misdiagnosed as common pneumonia without treatment in an isolation suite. If she continuously stays with other common patients, severe cross infection would happen among normal patients and medical staffs. During the outbreak of COVID-19, the diagnostic criteria have been adjusted to a certain extent, that is, no positive result of nucleic acid is required for clinical diagnosis of COVID-19 cases according to the fifth edition. The management of clinical confirmed cases was as same as laboratory confirmed cases, including quarantine at isolation suite of hospital for 2 weeks plus isolated at home for 2 weeks after cured from COVID-19 infection. For this case, it took 70 days from the onset of typical symptoms (fever and cough) to laboratory confirmation (IgG positive).Considering the difference of sample site, the difference in experience of the operator, and the actual quantity of virus, there could be false negatives on occasion for oropharyngeal or nasopharyngeal swabs tests. Since the outbreak and spread of COVID-19 is rapid, there is no data on long-term immune response. Data on SARS-CoV-1 indicates that the titers of IgG and neutralizing antibodies peak 4 months after infection, and then decline at least 3 years after infection. The pregnant women and her baby were tested positive for IgG and negative for IgM, with a duration of 70 days from the onset to delivery.In a study involving 82 confirmed COVID-19cases and 58 suspected COVID-19 cases from China, the median duration of IgM testing was 5 days after the onset of symptoms (quartile range 3–6 days), and the median of IgG test was 14 days after the onset of symptoms (quartiles 10–18 days). Studies have shown that the maternal immune system is fully prepared to resist the invasion of foreign pathogens. For example, innate immune cells (such as NK cells and monocytes) respond more strongly to viral attacks, although some adaptive immune responses decrease during pregnancy, such as the decreased number of T and B cells. At the same time, under normal circumstances, IgG antibodies in maternal blood can be passed to the fetus through the placental barrier, allowing fetus to obtain passive immunity. Therefore, the positive result of fetal IgG may be due to the vertical transmission from the mother. In a study focusing on infants delivered by mothers with SARS, the lack of vertical transmission is considered to be the result of the development of passive immunity in late pregnancy, as evidenced by the presence of SARS-CoV-1 antibodies in the cord blood and breast milk of some pregnant woman.After the first exposure to the virus, the patients with better immunity exhibit stronger body reactions. Innate immune cells play a vital role in effectively and proactively responding to various pathogens.Considering the importance of this ongoing global public health emergency, although our conclusion is limited by the sample size, we believe that the findings of this case report are conducive for understanding the possible clinical features of COVID-19 infection in pregnant women, the duration of the antibody, and passive immunity of the fetus.The authors thank the obstetricians and radiologists for the diagnosis and treatment of pregnant women.Conceptualization: Min Li, Yun Zhao.Data curation: Jing Peng, Ruobing Li, Heng Yin, Fei Tang, Hui Xie, Min Li, Yun Zhao.Visualization: Hui Xie, Min Li.Writing – original draft: Jing Peng, Ruobing Li, Min Li, Yun Zhao.Writing – review & editing: Min Li, Yun Zhao.


Acromesomelic dysplasia, Maroteaux type (AMDM) is an autosomal recessive form of acromesomelic dysplasia characterized by disproportionately short stature, shortening of the middle and distal segments of the limbs as well as vertebral involvement. AMDM is the result of a mutation in the natriuretic peptide receptor 2 (NPR2) genes which impairs skeletal growth ,2,3.nd pregnancy, was referred to the endocrine and metabolic center of the Nemazee Hospital, located in southwestern Iran, for evaluation of short stature. The patient was born at 38 weeks of gestation by cesarean section and was healthy by Apgar scoring. Birth weight was 3100 g, length 45 cm and head circumference 35 cm. He had no dysmorphic features and general physical examination revealed no pathology. There was no satisfactory length gain after birth, as noticed by his parents. At the referral time at age 2 years the patient had a weight of 8200 g (-4 SD), a length of 71 cm [-4 standard deviation (SD)]. Head circumference was 48 cm (0.3 SD). Fingers of the hand were extremely short and broad with small nails; there was no redundant skin on the fingers (A 2- years old boy, offspring of non-consanguineous parents and of a 2 fingers . His feeRadiographic findings showed curved radius, relatively short ulna, and broad metacarps with wide phalanges. The vertebrae were of normal size and showed no beaking. Iliac wings and metatarsal bones were normal . DNA wasThe mutation of the case was displayed in NPR2 with cytogenic location of 9p13.3. This mutation overlaps with two diseases: firstly, autosomal dominant epiphyseal chondrodysplasia, miura type which is characterized by tall stature, long hands and feet with arachnodactyly, and secondly, short-rib thoracic dysplasia 5 with or without polydactyly ,5. Both In summary, considering the skeletal changes, radiological findings and sequence analysis of the mutation, this patient is the first AMDM case reported from Iran. The patient had severe short stature, but no obvious abnormality in the distal segment of his lower limb. We suggest that this patient may represent a new variant form of AMDM.