Regular physical activity provides many health benefits to older adults. As a well-known form of physical activity, cycling can be an appropriate means for older people to meet WHO recommendations and to improve their health. In addition, cycling can help to protect the environment and reduce greenhouse gas emissions. The primary aim of this scoping review is to identify the currently available scientific evidence and gaps of research in this field.A systematic search in seven databases resulted in 7,192 studies. After the exclusion of duplicates, studies were screened by two independent reviewers in a two-stage process. Based on previously defined inclusion criteria, 123 studies were included. Data extraction was based on a descriptive analytical method, and seven categories for the main topics of studies were developed. Data were extracted by three reviewers to analyze different characteristics of included articles such as age range, study design, data type, gender, type of bicycle, and country of origin.The included studies covered the following topics: (1) traffic safety, (2) cycling as physical activity or for transport, (3) health benefits, (4) environmental factors, (5) facilitators and barriers, (6) application of technology and (7) promotion of cycling. Results show that the majority of studies were performed in both younger (60–79 years) and older (80+ years) adults. Most studies had an observational study design, used conventional bicycles, and were based on quantitative methods. Researchers from the United States, Netherlands, and Japan published the highest number of studies related to cycling.Traffic safety was the most prevalent focus of the included studies. Gaps were identified with regard to studies focusing on the promotion of cycling, application of technology, as well as facilitators and barriers of cycling. While research on traffic safety should continue to be a high priority for public health, potentially more research should focus on how to get older people to bicycle more. This is warranted by the proven individual and planetary health benefits of cycling and the urgency of combating climate change. Due to As part of PA recommendations, cycling is often recommended for older adults , 2. ScieAccording to available studies, cycling has multiple benefits. For example, a bicycle-based intervention was shown to positively affect metabolic parameters, such as physical fitness level, total fat-free mass, and fasting plasma insulin levels, in rural Indian men . Other sDespite these benefits, there is still potential to increase the number and proportion of older adults cycling. According to a study, 6% of overall urban transportation globally is currently carried out by bicycle, but this percentage could be increased to over 15% by 2050 . AnotherA primary concern for older individuals has been the safety of cycling in order to avoid injuries and crashes , particuIt has been suggested that psychological , 36, perHowever, there is currently a limited understanding of what research in the interdisciplinary field of cycling looks like in its entirety and how well it aligns with the potential of cycling as a means of PA promotion. Therefore, we conducted a scoping review that intends to complement existing reviews that focus on specific aspects of cycling, such as the links between the physical environment and active travel in older adults .2.This scoping review was conducted based on the framework developed by Arksey and O'Malley  and expa2.1.This review aims (a) to scope the available evidence on cycling in older adults to identify its main topic as well as potential gaps in this field of research and (b) to analyze the included articles in terms of age range, study design, data type, gender, type of bicycle, and country of origin. The review focuses solely on general/outdoor cycling, as stationary indoor cycling is substantially different in terms of environmental conditions, biomechanics of pedaling, safety, feasibility, and physiological or psychological response –52.2.2.We searched for studies related to cycling in older adults published in English and German before December 22nd, 2021. The search for relevant studies was performed in seven databases: PubMed, Web of Science, Scopus, Cochrane library, SportDiscus, CINAHL, and PsychInfo. The search strategy was developed by all authors and consulted with a librarian. The search strategy included the following keywords related to cycling in older adults: (“old people” or “older people” or “elderly” or “elders” or “aging” or “ageing” or “old men” or “old women” or “older persons” or “older adults” or “seniors”) and (“bicycling” or “cycling” or “biking” or “bike” or “bicycle”). A combination of different MeSH terms and free text was used to search databases.2.3.www.covidence.org). Duplicates were removed automatically. The screening process involved two stages based on inclusion and exclusion criteria. In the first stage, articles were screened by title and abstract, while the second stage included selection of studies by reading the full texts. The inclusion criteria were:1.The study includes human subjects aged 60 years and/or older.2.Cycling is one of the main components of the study or the study objective is related to cycling .3.-the health effects of cycling,-injuries and/or risk of injuries caused by cycling (aspects of safety),-factors that determine if a person bicycles outdoors and/or the prevalence of cycling,-the promotion of cycling for health reasons.The study investigates one or more of the following:4.The study was published in a peer-reviewed journal .5.Cycling was not used as a means to investigate a different purpose of study, e.g., to test endurance, heart rate, the training effects of cycling, or as a warm-up.Records were managed in the Covidence systematic review software , and conflicts were discussed until a consensus was reached. To avoid bias, reviewers used the internet-based software Covidence, which provides random access to articles for reviewers.2.4.A descriptive analytical method  was used3.3.1.One review was identified. In this systematic review and meta-analysis, the neighborhood physical environment and active travel in older adults were analyzed based on 42 quantitative studies. The results show that there are strong links between the neighborhood's physical environment and active travel in older adults. In particular, the review identified positive associations with total walking for residential density/urbanization, walkability, street connectivity, access to destinations/services, land use mix, pedestrian-friendly features and access to several types of destinations .3.2.The study characteristics of the 122 single studies are presented in 4.4.1.The primary objective of this scoping review was to identify studies dealing with cycling in older adults. Overall, 123 studies were identified, most of which used observational designs, while there were few intervention studies and only one review. The studies could be categorized as pertaining to seven main topics, with more than two-thirds focusing on traffic safety. Other topics investigated more frequently include cycling as PA or for transport, health benefits, and environmental factors. By country, almost half the studies were conducted by research teams located in the United States, the Netherlands, and Japan. Time series analysis indicates that research interest in cycling among older people increased markedly after 2007.4.2.We observed a heightened interest in the safety aspects of cycling , 25, 54.Evidence has shown a positive association between the extent of cycling paths and non-recreational cycling . EnvironCurrently, prevalence rates of cycling among older people are quite low in many countries, and even in bike-friendly countries only a minority of older people report to cycle regularly . In Fran4.3.The majority of studies were conducted in high-income countries such as the United States, the Netherlands, or Japan. Among these three, the Netherlands is most prominently associated with being a “bicycling country” , hintingHowever, it seems to be highly relevant to conduct more research on cycling among older adults in low- and middle-income countries. It is a general problem of PA-related research that there is a large gap in the number of publications between high- and low-income countries . From a 4.4.The results indicate that research on safety issues regarding cycling is important. Also, from a political perspective, the importance of road safety in the context of PA promotion is reflected in documents such as WHO's Global Action Plan on Physical Activity (WHO 2018) and its European Physical Activity Strategy (WHO 2016). These documents call for the implementation of policy actions to improve the safety of cyclists (WHO 2018) and for identifying linkages between PA promotion and road safety strategies (WHO 2016). In addition, policy documents highlight the importance of a cycling network infrastructure , pre- and in-service training of professionals in the transport sector on PA promotion (WHO 2018), and the removal of barriers for disadvantaged groups (WHO 2016). An in-depth analysis of the identified studies on facilitators and barriers of cycling for older adults could help to identify target group-specific barriers for cycling and develop appropriate strategies to remove them.4.5.This study was limited to published studies in English or German, and including studies written in other languages might have changed the nature of the results. Also, we acknowledge that the categorization of the identified studies by research topic was not always easy, since some studies covered more than just one topic . Furthermore, this review focused exclusively on scientific studies and did not include other types of publications, such as policies and intervention reports, that may also serve to promote cycling among older adults.4.6.To our knowledge, this is the first scoping review in the field of cycling in older adults which covers a broad range of articles in order to identify the state of the evidence on cycling in older adults. Traffic safety was the most prevalent topic of the included studies. The number of studies being published has increased over time, but the rate of increase for each main study topic was different. For some topics, such as the promotion of cycling and health benefits, only a few published studies were identified despite their well-documented importance. The majority of studies were conducted in a small number of countries. Studies from additional countries and world regions may be required to account for different geographical, infrastructural and cultural contexts. Moreover, for some study topics, such as environmental factors, facilitators and barriers, application of technology, and promotion of cycling, only a few published studies were identified, warranting further attention to these topics in future research. The growing tendency towards ownership and use of e-bikes, pedelecs, and recumbent bicycles, also seems to call for conducting more research in these fields. In addition, given the very low numbers of qualitative and review study designs identified in this paper, further research using non-quantitative designs may enrich the evidence on how to promote cycling. Finally, most studies had observational study designs, while only a few interventional studies were conducted. The urgent need to promote cycling requires more interventional studies to produce evidence on how to provide ideal conditions for cycling and maximize the desired effects.


Diatoms synthesize species-specific exoskeletons inside cells under the control of the cytoskeleton and microtubule center. Previous studies have been conducted with the visualization of the microtubule center; however, its composition has not been studied and reliably established. In the present study, several components of MTOC in diatoms, GCP (gamma complex proteins), Aurora A, and centrins have been identified. Analysis of the predicted amino acid sequences of these proteins revealed structural features typical for diatoms. We analyzed the conserved amino acids and the motives necessary for the functioning of proteins. Phylogenetic analysis of GCP showed that all major groups of diatoms are distributed over phylogenetic trees according to their systematic position. This work is a theoretical study; however, it allows drawing some conclusions about the functioning of the studied components and possible ways to regulate them. Diatoms are a large group of the unicellular autotrophic organisms that belong to the kingdom Chromista . These mThe main direction of diatom study is currently focused on a search of cell and genetic mechanisms providing various symmetry and structure of diatom silica frustules. It was shown that frustule morphogenesis control is carried out by the cytoskeleton; to date the microtubule significance is the most studied ,8,9. BacMicrotubule functions and tubulin polymerization/depolimerization are regulated by a large number of proteins ,21; theiThe eukaryotic MTOC is based on the γ-tubulin with the Gamma-tubulin Complex Proteins (GCP) ,28. CurrThalassiosira pseudonana and Phaeodactylum tricornutum genomic data revealed genes encoding the GCP2 and GCP3, as well as the centrins and protein kinase Aurora A [Earlier, the presence of α-, β- and γ-tubulin in the diatom genomes was shown ,29,30. TAurora A .In this study, we conducted a search for the nucleotide sequences of several MTOC components in well-known databases organized and curated by genomic and transcriptomic projects on the identification of these components in diatoms  iUlnaria acus, P. tricornutum, T. pseudonana, Pseudo-nitzschia multiseries, and Fragilariopsys cylindrus revealed the presence of genes encoding GCP2 and GCP3. Thalassiosira oceanica has the only gene encoding GCP3 , while, in centric species. sequences are more similar .In diatoms, GCP sequence identity within individual genera can be 40% in pennate diatoms , while Phytophthora nicotianae belonging to superphylum Heterokonta has similar GCP2 length  and arginine (R), and the content of these polar positively charged amino acids reaches 26%. Sometimes they are represented by repeats from 2 to 4 K and R in different combinations. Earlier, such motives were described as potential signals for protein translocation to the nucleus [Diatom GCP2 length varied from 274 to 1698 a.a. which exceeds the GCP2 length of  nucleus ,35. Furt nucleus . ProbablSkeletonema, it reaches 86%. The analysis of domain structure revealed that the most part of identified sequences are fragments of C- terminal part. For instance, there are repeats of K and R in C-terminal of centric species Skeletonema and Thalassiosira .The length of predicted amino acid GCP3 sequences varies from 221 to 1092 a.a. which is also longer than the sequences of the model organisms  with GCP4 amino acid sequences of model organisms , threonine (T), and tyrosine (Y), we undertook a search for these conserved residues in diatom sequences. Three conserved residues Y were found in the diatom GCP2—Y484, Y547, and Y724. In addition, conserved S655 and T707 were found. Phosphorylation is possible at histidine (H) in bacteria, fungi, and plants ,38. We fFor human GCP3, 42 sites for post-translational mono-methylation, ubiquitination and phosphorylation are known, but diatom GCPs do not have a single conserved one. Often arginine residues are located at the ubiquitination sites at lysine residues in diatom sequences. Putative ubiquitination sites may be conserved K563 and K761 at the diatom GCP3 C-terminal domain. Furthermore, ten conserved H and three conserved Y may be potential phosphorylation sites in the C-terminal domain . The conGCP4s were found in a small number of diatom species, which makes it impossible to reveal their patterns. We have not identified conserved amino acids that can be putative sites of post-translational modification. Mediophyceae diatoms have conserved histidine corresponding to human GCP4 H561 and S635 that we can suggest as potential diatom GCP4 post-translational modification . EarlierThus, we assume that phosphorylation and ubiquitination are characteristics of diatom GCP post-translational modification; however, these sites do not correspond to human GCP. For every diatom GCP group, we identified several conserved Ks, Hs, and Ys, and these potential sites are located only in the C-terminal domain unlike other well-known model organisms. Perhaps this is due to features of complex formation between diatom γ-tubulin and GCPs and their activity regulation during cell cycle. We have not found any differences between centric and pennate potential post-translational modification sites, possibly because of their similar regulation.H. sapiens, A. thaliana, S. cerevisiae, P. nicotianae) are not grouped together with diatoms, emphasizing the specificity of each diatom. Thus, using the example of the GCP2 and GCP3 group distribution, we can assume that the evolution of the diatom GCPs is similar to the evolution of other elements of the cytoskeleton, such as EB proteins and tubulins, in these organisms [Phylogenetic reconstruction of the GCP of model organisms and diatoms shows that GCP2, GCP3, and GCP4 form separate groups . At the rganisms ,39.Protein-kinases Aurora are a recently discovered family of kinases  that are involved in many mitotic events and are localized in the centrosome  and promSkeletonema. Sequences have an average length of about 310–360 a.a. Aurora A consists of three domains, more variable N- and C-terminal regions and the catalytic kinase domain. The diatom Aurora A structure has similar features described for model organisms. Kinase domain has been identified for all diatom sequences and has a length of about 250–348 a.a. Homology within the kinase domain is high both between diatoms and model organisms (up to 68%). The N-terminal domain is more variable; its structure identity is observed only among several genera  among most of the presented sequences; however, in some sequences its length can reach 130 and 365 a.a.Two genes encoding Aurora A have been identified for six diatom species. We assume that diatoms are characterized by only one isoform of this protein. The presence of two genes for some species may be due to compilation errors in the transcriptome analysis results, since all repeat sequences for six species were found in the MMETSP database. In the published genomes, the sequences of only one isoform of Aurora A have been found for each species. The identity of the predicted amino acid sequences in diatoms of different taxa can vary significantly (20–60%) and increases up to 95% within genera; for example, it can reach 99% for l genera ; for exaIt is known that Aurora A catalytic activity is regulated by phosphorylation of the tyrosine (T288/T287) in its kinase domain and by association with other proteins . The ana2+ and asparagine 274 (D) [2+/calmodulin binding that induces its autophosphorylation at S51, S53/54, S66/67, and S98. These residues are not conserved either; that was predictable since they are all located in the variable N-terminal domain.Active unphosphorylated protein can bind with Mg 274 (D) . AlignmeIn mitosis, Aurora A is activated and autophosphorylated at residue T288 ,47. A coThe interaction between centrins and Aurora A, which provides phosphorylation of centrins and is localized together with them in the centrosome, has been well studied . AccordiS. cerevisiae and Chlamydomonas reinhardtii), one gene-encoding centrin was found [Paramecium caudatum, there were found 22 genes, and in Trichomonas vaginalis, 24 genes [2+.In some unicellular eukaryotes . These Pseudo-nitzschia fraudulenta; however, some of them have a length of less than 110 a.a. and represent only a fragment of the amino acid sequence. Sequence identity with the reference group is more than 40% and, within members of the Mediophyceae, is more than 52%, which is consistent with the literature, in which centrins are described as proteins with high homology [We identified 42 centrin sequences in 22 diatom species. It is noteworthy that most of the sequences (28) belong to the Mediophyceae. Nine species have two or more sequences that can be characterized as centrins. The largest number (eight) of amino acid sequences of centrins was found for the species homology . The lenNaegleria gruberi centrins [Chlamydomonas reinhardtii, revealed conserved amino acids common to organisms from different taxonomic groups. Since the analysis of diatom genomes showed an abundance of genes related to green algae [Previously, comparison of centrins  with seqen algae ,56, a se2+-induced polymerization [Thalassiosira and Skeletonema (centrins.fas). Post-translational modifications regulate the activity and subcellular localization of centrins, and, as expected, this may allow organisms with relatively fewer centrins to realize their diversity of functions, similar to organisms with a large number of centrins [Interestingly, diatom centrins in the N-terminal part have a positively charged region enriched in lysine (K) and arginine (R) residues. It is suggested that this region may be significant for Carization . Howevercentrins . Analysi2+ ions [2+, remains conserved in all four motifs. In the third EF-hand motif, the sequence is conserved in diatoms of different taxa and is represented by the DDDETG sequence, while, in the other three EF-hand motifs, it is more variable  by Aboal, Synedra acus subsp. radians (Kützing) by Scabitchevsky [Phaedactylum tricornutum by Bohlin [Thalassiosira pseudonana by Hasle and Heimdal [Thalassisosira oceanica by Hasle [Pseudo-nitzschia multiseries (Hasle) by Hasle, Fragilariopsis cylindrus (Grunow) by Krieger [Homo sapiens, Arabidopsis thaliana, Saccharomyces cerevisiae were used  was performed in the set of amino acid sequences predicted on the basis of published genomic data of tchevsky , Phaedacy Bohlin , Thalass Heimdal , Thalassby Hasle , Pseudo- Krieger , and tra Krieger  using bl Krieger . As a quere used . E-valueAll identified sequences were tested by blasting the NCBI database nr  to removH. sapiens proteins with which they coincide. PhosphoSitePlus v6.6.0.4 data were used to search for and analyze post-translational modification sites in the predicted amino acid sequences. The search for grip-motifs in the structure of GCP and DxDxDG motifs in centrins was carried out using previously published information [Alignments for structural and phylogenetic analyzes were made using Clustal Omega 1.2.4  and corrormation ,54,58,71For GCP phylogenetic analysis protein sequences, protein sequences were aligned using muscle  with deFor phylogenetic analysis of centrins, the Maximum Likelihood method was performed with IQ-Tree v1.6.12 . The repIn this study, sequences of different diatom taxa—the MTOC components GCP2, GCP3, GCP4, GCP5, and GCP6—were identified. All systematic groups are characterized by the presence of genes encoding GCP2 and GCP3 in their genomes. Both classes of proteins in the predicted sequences have conserved amino acids characteristic only for diatoms, which indicates their importance for this taxon. Since the diatom consensus amino acids of grip-motifs are similar to those in other organisms, it can be assumed that the mechanisms of GCPs binding to each other and to γ-tubulin also have much in common. Previously, GCP4–6 were not found in diatoms; however, we were able to identify GCP4 sequences in centric diatoms. The existence of diatoms GCP5 and GCP6 has not yet been confirmed, and, despite the fact that in this study we found only single sequences for them, it might be speculated that these genes are present in diatom genomes. This observation will be investigated in further studies. It was possible to establish the high conservation level of several a.a., which may be the sites of post-translational modification, ubiquitination, and phosphorylation. In contrast to model organisms, where the sites are located along the entire length of the sequences, in diatoms, they are concentrated in the C-terminal domain. It is possible that this is due to the peculiarities of the formation of the complex between γ-tubulin and these proteins, the regulation of their activity, and the limitation of the protein activity at certain stages of the cell cycle. There are no differences in potential modification sites between centric and pennate species, which allows us to conclude that GCP in each class of diatoms has a similar regulation.In the diatoms’ Aurora A-predicted sequences, the general patterns of the protein kinase structure described for model organisms are observed. T288 is conserved in all identified sequences. It is noteworthy that it is a part of the motif that serves as a substrate for the Aurora A activity self-regulation through autophosphorylation. This motif is conserved in evolutionarily distant species and, therefore, is necessary for protein function. The analysis of centrins showed that these proteins are conserved for diatoms and other organisms. The presence of R/K-x-T/S-I/L/V/F or R/K/N-R-X-S/T-B motifs which are substrates for phosphorylation by Aurora A indicates the existence of regulatory pathway centrins with Aurora A. The conservation of the third EF-hand motif of centrins in different diatom classes may indicate in favor of a common ancestral form of the protein, and its preservation in both older and younger species.Thalassiosira and Skeletonema  attracts special attention. Previously, the same fact was noted for EB-proteins for these genera [The special sequence structure studied in this work in representatives of the genera e genera . Both ge


Background: Previous observational studies have suggested that circulating adipokine concentrations are related to a greater risk of venous thromboembolism (VTE). However, it remained unclear whether these observations reflect causality.Objective: This study aimed to investigate the causal relationship between circulating adipokine concentrations  and the risk of VTE and its subtypes (DVT and PE) and to determine whether circulating adipokine concentrations are a mediator of venous thromboembolic events in obese patients.Methods: We used Mendelian randomization (MR) analyses to determine the effects of the body mass index (BMI), adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN levels on VTE, DVT, and PE in a cohort of 11,288 VTE cases, 5,632 DVT cases, 5,130 PE cases, and 254,771 controls. We then assessed the proportion of the effect of obesity on VTE, DVT, and PE explained by circulating leptin levels.Result: Genetically predicted higher BMI was related to increased VTE , DVT , and PE  risk, and higher circulating leptin levels increase odds of VTE , DVT , and PE . In addition, we found that the causal effect between elevated serum adiponectin and the decreased risk of VTE  and PE  and between MCP-1 and the reduced risk of VTE  is no longer significant after FDR adjustment. In MR mediation analysis, the mediation effect of circulating leptin levels in the causal pathway from BMI to PE was estimated to be 1.28 , accounting for 39.14% of the total effect.Conclusion: The circulating leptin level is a risk factor for VTE, DVT, and PE, but it might be a potential mediator of BMI on the risk of PE, and thus, interventions on the circulating leptin level in obesity might reduce the risk of PE. Adiponectin is a potential protective factor for both VTE and PE. Venous thromboembolism (VTE) is a chronic cardiovascular disease that mainly consists of deep vein thrombosis (DVT) and pulmonary embolism (PE). Each year, VTE affects roughly 10 million individuals of all races globally and significantly contributes to the burden of illness worldwide . Medical2 (High body mass index (BMI) has been identified as a risk factor of VTE in several major observational studies . Accordi2 . Recent 2 .The molecular processes associating adiposity and the development of VTE have not yet been elucidated, which may be relevant to insulin resistance, adipocyte hypertrophy, and increased production of inflammatory adipocytokines and free fatty acids . As a hiConventional observational epidemiological studies are susceptible to residual confounding and reverse causality and are consequently incapable of drawing causal inferences. Mendelian randomization (MR) is an epidemiological methodology based on germline genetic data that increases causal inference in association by employing genetic variations as the exposed instrumental variables . As a reWe used a two-sample MR framework to examine the association of six adipokines  with the risk of VTE and its two subtypes (DVT and PE) using genetic variants associated with adipokine concentrations from published genome-wide association studies (GWAS). In addition, we used the mediation analysis method based on multivariable Mendelian randomization (MVMR) to explore the proportion mediated by adipokines for the effect between BMI and VTE, DVT, and PE.With publicly accessible datasets that yielded genome-wide association results for BMI, adipokines, and outcomes , we conducted two-step two-sample MR. The two-sample MR refers to the use of various datasets (samples) to determine the relationship between genes and risk factors (like BMI and adipokines) and outcomes (like VTE). We used two-step MR to first examine the effects of BMI and adipokines on outcomes. The first step was to determine the causal effect of BMI and adipokines on outcomes. In the second step, we figured out the causal effect between BMI and the significant adipokines (q < 0.05) found in the first step.p-values at the genome-wide significance level (p < 5 × 10−8). SNPs with R2 > 0.01 and within 5,000 kb distance were identified to be in linkage disequilibrium and were excluded from the study. In total, six adipokines were chosen for this study.The genetic association for adipokines was retrieved from a previously published genome-wide association study (GWAS). Single-nucleotide polymorphisms (SNPs) were identified to be associated with exposures with The summary-level data related to the serum adiponectin level from a GWAS in 39,883 individuals of European ancestry, and a total of 12 SNPs were selected as instrumental variables (IVs) . The sump-values at a genome-wide significance level (p < 5 × 10–8). SNPs with R2 > 0.01 and within 5,000 kb distance were identified to be in linkage disequilibrium and were subsequently excluded from the analysis. Eventually, 84 SNPs were extracted for BMI and were used as instrumental variables (IVs).The genetic association for BMI was retrieved from a GWAS study reported by the genetic investigation of anthropometric trait (GIANT) consortium . This sthttps://r6.finngen.fi/), which encompass 11,288 VTE cases, 5,130 PE cases, 5,632 DVT cases, and up to 254,771 controls, and all participants were of European descent. Association tests in FinnGen had been adjusted for age, sex, first 10 genetic principal components, and the genotyping batch.We obtained summary-level data on VTE and its subtypes (PE and DVT) from the FinnGen study , where β is the estimated coefficient of the IV in BMI and all mediators like GWAS, and EAF is the effect allele frequency. The F-statistic can be calculated by the following formula: F = βexposure2/SEexposure2  are robustly related to the risk factor of interest.2. There is no relationship between any confounders of the risk factor and outcome and the genetic instrumental variable.3. There is no path from the genetic instrument to the outcome other than through its relationship with the risk factor.The basic assumptions of MR are as follows :1. The gp-value < 0.05, we deem these SNPs have horizontal pleiotropy; the MR-PRESSO  method was used to detect and correct the potential outliers  method is used as the main method to assess the causal association between exposures and outcomes; if between-SNP heterogeneity is present, we used the IVW method with the fixed-effects model; if not, we used IVW with the multiplicative random effects model. MR-Egger, weighted median, and weighted mode methods were used in sensitivity analyses to evaluate the robustness of the MR results. Finally, the leave-one-out analysis was conducted to detect the influential SNPs. To account for multiple comparisons (seven exposures and three outcomes), a Benjamini–Hochberg (FDR) correction was employed. k with outcomes adjusted for genetically determined BMI, and β3 is the MR effect of BMI on outcomes adjusted for the genetically determined potential mediator  and the TwoSampleMR R package version 0.5.6.For MR analysis, the number of included SNPs ranged from 3 to 84, explaining 0.0038%–17% of the total variance in exposures , and thep < 0.001; q < 0.001), DVT , and PE   and PE , and between MCP-1 and the decreased risk of VTE  was no longer significant after FDR adjustment  . Notablyjustment . For theAs shown in p < 0.001), DVT , and PE . High BMI was found to be associated with elevated circulating leptin levels   . Consist IVW-FE) .p = 2.93e-01) was no longer significant and reduction in significance was observed for the effect on VTE  and DVT  (p = 0.10), accounting for 39.14% of the total effect  . The grel effect .p > 0.05).In this large-scale MR analysis, we found a causal relationship between genetically determined circulating leptin levels and the risk of VTE, DVT, and PE. In addition, it was acknowledged that adiponectin may be a protective factor for VTE and PE. Simultaneously, MCP-1 may be a protective factor for VTE. However, we found no evidence supporting the causal associations between genetically determined levels of the other three adipokines  and the risk of VTE, DVT, and PE. These findings implied that adiponectin, PAI-1, MCP-1, leptin receptor, and RETN might have no significance in the pathogenesis of VTE, DVT, and PE. Although the difference between univariate Mendelian randomization and multivariate Mendelian randomization results suggests that leptin may mediate the effect of BMI on PE, the results of the mediation analysis suggest that this mediating effect of leptin did not reach statistical differences , suggesting leptin may not be a strong mediator of BMI on the risk of PE.Leptin is a 16-kDa hormone released by adipocytes, the secretion of which is dependent on the fat depot. Additionally, leptin production is greater in the subcutaneous fat depot than that in the visceral depot. The blood levels of leptin show a proportional distribution pattern in adipose tissue mass, which also manifests the instantaneous changes in nutritional status, as reflected by a sharp decrease after the onset of fasting . Previouar cells . It is war cells . A prospar cells . A prospar cells . Howeverar cells . This isp = 0.013; q = 0.053) and PE . Although the FDR-corrected significance threshold was not met, adiponectin could be considered a potential protective factor for VTE and PE when combined with previous findings.Adiponectin is primarily released by the visceral adipose tissue and is the most abundant adipokine, with quantities in the bloodstream inversely associated with obesity, which specifically exerts anti-apoptotic, anti-inflammatory/anti-fibrotic, and insulin-sensitizing effects . In a rap = 0.048). However, this association was no longer significant after FDR correction (q = 0.14), suggesting the association observed in the initial analysis may have been false positive, and further research would be needed to determine if there is a true association between MCP-1 and VTE. Although there are some distinctions in the processes of formation and pathological alterations for arterial and venous thrombosis, there are many similarities in the pathogenesis . The primary sources of monocyte chemoattractant protein-1 are epithelial cells, endothelial cells, smooth muscle cells, monocytes/macrophages, fibroblasts, astrocytes, and microglial cells . Obesityogenesis . Given tHere, we found no association between the genetically determined PAI-1 concentration and the risk of VTE, DVT, and PE. Several aspects of our research study make it superior to others. 1) Statistical data summary of exposure and outcomes was from the largest and latest GWAS in related fields, and there was no overlapping sample in our study. 2) Strict criteria were established to select IVs which may strengthen the statistical power. 3) Since genetic variants were scattered over multiple chromosomes, it is possible that potential gene–gene interactions will not have much effect on the results. 4) To enhance the accuracy of the estimation, we utilized different methods for sensitivity analysis. 5) A mediation analysis based on MVMR was used to investigate the mediating role of adipokines in the risk of obesity and VTE. This study does have some limitations. 1) GWAS used included only the European ancestry population. Thus, additional studies should be performed to explore the intermediated effect in the non-European population. 2) There were some heterogeneities in the analysis. Because meta-GWAS data were used, it was impossible to investigate the possibility of non-linear connections or stratification effects that varied according to age, health status, or gender. 3) Since the GWAS research employed as an endpoint was not stratified by gender, it could not elucidate if adipokines’ influence on VTE was subjected to the gender differences. 4) Limited adipokines were included in the current study. 5) Further research studies were required to determine if the adipokines that showed negative results in current investigation can trigger the formation of DVT, VTE, or PE on their own or contribute to the pathogenesis of DVT, VTE, or PE in collaboration with other adipokines. 6)Our MR investigation revealed that the circulating leptin level was a risk factor for VTE, DVT, and PE, but it may not be a mediator of BMI on the risk of VTE, DVT, and PE and that adiponectin was a potential protective factor for both VTE and PE.


This study examined the effects of different prenatal nutrition treatments on pregnant cows and their calves. The cows were divided into three groups: NP (no supplementation), PP (supplementation during the last three months of pregnancy), and FP (supplementation throughout pregnancy). After calving, all cows and calves received the same environmental and nutritional conditions. Measurements such as body weight, body condition score, ribeye area, backfat thickness, and rump fat thickness were taken at various stages. The results showed some differences in cow weight, fat thickness, and body condition during pregnancy and postpartum. However, the effects of prenatal nutrition on the calves’ weaning weight and growth rates were minimal. Overall, the study concluded that prenatal nutrition had a limited impact on postnatal performance in beef cattle.p < 0.05) using a linear model . The BW, RFT, and BCS from the cows showed significant differences in the middle third of pregnancy and pre-delivery and RFT postpartum (p < 0.05). For the offspring, the weaning weight showed a tendency (NP lighter than others). In terms of gain, the PP group tended to be higher in RFT at calving (p = 0.06), in REA at finishing (p = 0.09), and in ADG in the same period (p = 0.09). The prenatal nutrition strategies had little or no effect on the beef cattle postnatal performance.This study aimed to evaluate the effects of different prenatal nutrition treatments on pregnant cows and their progeny. One hundred and twenty-six pregnant Nellore cows (455.3 ± 8.1 kg) were allocated in three different nutritional treatments during pregnancy: NP—control, PP—protein-energy supplementation in the last 3 months of pregnancy, and FP—the same supplementation throughout pregnancy. After parturition, all cows and calves received the same environmental and nutrition condition. The body condition score (BCS), body weight (BW), ribeye area (REA), backfat thickness (BFT), and rumpfat thickness (RFT) were collected on four occasions during pregnancy in the cows and from birth to finishing in calves. All data  were submitted to an analysis of variance ( Maternal nutritional status is of great importance during pregnancy, as stimuli or insults during this period can lead to phenotypic and metabolic changes in the developing individual ,2,3. DurThus, prenatal nutrition is of great importance in the meat industry, since its impacts can influence the animal’s physiology in several aspects . In cattAdipose tissue, in turn, is formed primarily during fetal life and early postnatal life, ending its development in puberty . The onsRelated to this, several studies have already shown the effects of maternal nutrition on muscle and adipose tissue development ,13,14,15In this study, it was hypothesized that different protein-energy supplementation strategies during pregnancy in beef cattle alter the growth performance of their progeny. Thus, the objective of this study was to evaluate whether the different nutritional plans produced impacts on the muscular, adipose, and body development of the animals throughout their life, from the calving period to the finishing in feedlot.This study was approved by the Research Ethics Committee of the Faculty of Food Engineering and Animal Sciences from the University of São Paulo under protocol No. 1843241117, according to the National Council for the Control of Animal Experimentation guidelines.A total of 150 Nellore cows were fixed-time-artificially-inseminated (FTAI) with the semen of four bulls. At day 30 after FTAI pregnancy, diagnosis occurred (126 pregnant cows), and the animals were separated into three treatments: NP (control)—Not Programmed, without protein-energy supplementation; PP—Partial Programmed, protein-energy supplementation in the final third of pregnancy; and FP—Full Programmed, protein-energy supplementation during all of the gestation. Protein-energy supplementation was at the level of 0.3% BW. All groups received 0.03% BW mineral supplementation, included in protein-energy supplementation. More details about the groups and supplementation can be found in Schalch Jr. et al. .Brachiaria brizantha cv. Marandu with access to the supplement and water ad libitum. After calving, the protein-energy supplementation was discontinued, and all the animals were kept together until the weaning stage, which occurred when they reached an average age of 220 days. The offspring received identical sanitary, vaccination, and feeding procedures, which were previously established on the Campus farm. Following weaning, the animals were segregated by their sex, without consideration for the previous treatments , and were placed in distinct pastures. They continued to reside in their respective pastures throughout the rearing period. A total of 63 male offspring were used in this study . More details about the rearing phase can be found in Polizel et al. [Cows were blocked based on their age, BW, and body condition score and kept in pasture paddocks of l et al. .At 19 months, young bulls initiated the finishing phase in the feedlot system lasting 106 days . During this period, they received three different diets: an adaptation diet provided in the first 15 days (Dry matter (DM) = 48.1%; TDN = 71.0%; CP = 15.0%; NDF = 36.5%; Fat = 3.2%; Dry matter intake (DMI) = 2.21% of BW); a second diet during 35 days ; and a third diet for 56 days .Longissimus thoracis muscle, between the 12th and 13th ribs, were taken to measure REA and BFT, while the RFT was measured by positioning the transducer in the final portion of the ileum, between the junction of the Biceps femoris and the Gluteus medius muscle [Ultrasound measurements of the ribeye area (REA), backfat thickness (BFT), and rump fat thickness (RFT) were conducted using an Aloka SSD-500 ultrasound machine. The ultrasound device was equipped with a 17 cm linear transducer operating at a frequency of 3.5 MHz, manufactured by Aloka Co., Ltd. . To ensure proper contact between the transducer and the animals’ skin, vegetable oil was utilized as a coupling agent during the measurements. Images in sections of the s muscle . The imaRegarding the ribeye area gain (REAg), backfat thickness gain (BFTg), and rump fat thickness gain (RFTg), the differences were calculated individually and inside each period, i.e., the gain in the rearing phase was obtained by subtracting the last measure collected in the rearing phase from the last measured in calving.Weights were obtained using an electronic scale from Coimma  coupled to the cattle crush, where, regularly from birth to slaughter, the animals had their weight recorded. To obtain the average daily gain (ADG), a linear regression between age in days and weight was performed individually for the calving, rearing, and finishing phases. The body condition score (BCS) from the cows was performed in the FTAI and pre-delivery phases  on a scale with values from one to nine, according to Richards et al. .® version 9.4 . To assess the normality of the residuals obtained from the data, the Shapiro–Wilk test was applied, utilizing the UNIVARIATE procedure. In cases where the measurements deviated from normality, a logarithmic transformation ) was employed. The homoscedasticity of residuals for principal effects was tested in the groups using Levene’s test. To evaluate the effects of treatments on phenotypes, analysis of variance was used, and the means were compared by the Tukey–Kramer test, with differences between treatments considered significant when p ≤ 0.05. The ages of the animal, cow, and sire were also considered in the linear model. Concerning the repeated measures, the same variables as those of the linear model were considered, and the time of data collection was also included. The covariance structure for the residuals was tested for each variable and chosen based on the Akaike information criterion (AIC). The variables REA, REAg, BFT, BFTg, RFTg, and weight used an unstructured analytic (un), while ADG used a first-order factor analytic (fa(1)). For this analysis, the model was as follows:All analyses were conducted using the MIXED procedure of the statistical package SASp < 0.01), with BW values in the FP group higher than in the others. Postpartum BW had no difference between the groups (p = 0.13). There were no differences in RFT in the early and middle thirds of gestation (p < 0.01). In the postpartum period, FP showed a higher RFT than NP (p = 0.04); however, PP did not show any difference from the others. The initial BCS was not different between treatments , and the PP group did not show any difference between the other two treatments.The initial BW did not show any significant difference . Howeverestation , and prep = 0.08), where the NP group tended to be different from the others, and in the other periods, all treatments were similar (p > 0.05). When analyzing repeated measures over time, a trend in time x treatment interaction was shown (p = 0.07). In terms of ADG, a trend in the difference between treatments was identified for the finishing phase (p = 0.09), but there were no impacts of supplementation kind over time or any other period . When the REAg was analyzed, there was a trend for difference at the finishing phase (p = 0.09); however, no differences appeared at other periods or when it was carried over time  in all periods evaluated, for repeated measures over time, and for BFTg, showing a BFT similar for all three groups in a lifelong period (No differences between treatments were found for backfat deposition (g period .p > 0.05). When the analysis was carried over time, a trend in time x treatment interaction appeared (p = 0.06), i.e., the effect of time may depend on which treatment animals received. Relating to RFTg, there was a trend at the cow-calf phase (p = 0.06), where the PP group tended to be different from NP and FP and over time (p = 0.09), but at the rearing phase and feedlot, all treatments were similar , no significant differences were found between treatments , but trends towards difference appeared at interesting points evaluated, indicating the presence of processes that can be studied further.Stalker et al.  and WarnSome recent studies have evaluated the effects of energy-protein supplementation in pregnant Nellore cows ,31,32,33During pregnancy, the nutrients ingested by the mother and sent to the fetus prioritize the formation of vital organs, such as the heart, brain, and kidneys , leavingFollowing this idea, we also measured the gains that occurred between the periods in an attempt to detect if there was a compensatory gain in postnatal life. A trend towards a difference in REAg during confinement was identified, where the PP treatment, which received protein-energy supplementation only in the final third, had a lower increase in REA compared to the others. Despite being only a trend in the treatment effect, important questions can be raised for future investigations.The FP group may have received good levels of nutrition during their fetal formation and thus managed to maintain satisfactory muscle development. The NP group, which was considered our control and a good representative of beef cattle that undergo an extensive system in tropical regions, tolerates maintaining the same levels of muscle development as the FP since they are zebu animals, a naturally more rustic species, and perhaps, after generations of developing in Brazilian production, it has adapted and is able to overcome the adversities of this system. Still following this thought, and taking into account the primary window of muscle fiber formation that occurs only from the first third to the middle of the second third of pregnancy , it is pThe similarity between treatments for REA was also observed by Mohrhauser et al.  and RamíThere was no difference in BFT, but some trends emerged in RFT and its gain. There was a trend in the interaction time x treatment, and when analyzing the RFTg, there was a trend in the calving period, where the PP group was superior to the others, and also over time. This trend towards a greater gain in fat thickness for the PP, coupled with the increase observed in some studies in groups that underwent restriction, reinforces the idea presented for the treatments previously when we talked about REAg.Regarding weight, we observed a trend at weaning, where the control group had a lower weight compared to the others; however, no other trend was observed throughout life. In some studies, where the cows passed the pregnancy to pasture but received protein supplementation, the calves did not show differences in weight at birth; however, at weaning, there was an increase in weight when compared to the non-supplemented group ,46,47. AAlthough there were no differences for ADG between treatments, a trend was observed in the feedlot, where the PP group tended to have a weight increase above the others. When searching for studies in the literature, once again, scattered results were found. Some studies suggest there is no difference between treatments for ADG in the feedlot ,44, whilGiven the results found in this work and in a search of the literature, it is possible to perceive the need for further studies on the effects of prenatal nutrition, it being the restriction or supplementation of cows. Still, some of our results tended to differ, which may become significant if the experiment is repeated and the conditions of the extensive system cause a more severe restriction in animals that do not receive protein-energy supplementation.Maternal energy protein supplementation had little or no effect on the animal’s postnatal growth performance for the traits evaluated. However, we found some trends toward the difference between treatments in the characteristics , suggesting that the three different prenatal nutrition strategies  may discreetly affect interest productive traits. The large number of phenotypic results brought by this article during the complete production cycle of beef cattle contribute to clarifying the long-term effects on male bovine progeny.


We aimed to use network meta-analysis to compare the impact of infection risk factors of close contacts with COVID-19, identify the most influential factors and rank their subgroups. It can provide a theoretical basis for the rapid and accurate tracking and management of close contacts.We searched nine databases from December 1, 2019 to August 2, 2023, which only took Chinese and English studies into consideration. Odd ratios (ORs) were calculated from traditional meta-estimated secondary attack rates (SARs) for different risk factors, and risk ranking of these risk factors was calculated by the surface under the cumulative ranking curve (SUCRA).25 studies with 152647 participants identified. Among all risk factors, the SUCRA of type of contact was 69.6 % and ranked first. Among six types of contact, compared with transportation contact, medical contact, social contact and other, daily contact increased risk of infection by 12.11 : 6.51–22.55), 7.76 , 4.65  and 8.23 OR: 8.23, 95 % CI: 4.23–16.01) times, respectively. Overall, SUCRA ranks from highest to lowest as daily contact (94.7 %), contact with pollution subjects (78.4 %), social contact (60.8 %), medical contact (31.8 %), other (27.9 %), transportation contact (6.4 %).The type of contact had the greatest impact on COVID-19 close contacts infection among the risk factors we included. Daily contact carried the greatest risk of infection among six types of contact, followed by contact with pollution subjects, social contact, other, medical contact and transportation contact. The results can provide scientific basis for rapid assess the risk of infection among close contacts based on fewer risk factors and pay attention to high-risk close contacts during management, thereby reducing tracking and management costs. As ofDuring the outbreak of the epidemic, with the continuous detection of infected individuals and the large number of close contacts being tracked, enormous work pressure was placed on the transportation and isolation work of close contacts ,14. In pWe can quickly assess the risk level of close contact infection based on fewer risk factors that are easily collected and have a significant impact on infection, and pay attention to high-risk close contacts in the management process, thereby reducing the time and cost of tracking and management, therefore, understanding the SARs of various infection risk factors and identifying important risk factors is crucial for rapid and accurate identification and management of close contacts ,19. PrevThere is an appropriate approach to address this issue. Compared to traditional meta-analysis, network meta-analysis can produce indirect comparisons via a common comparator . Secondly, it can directly and indirectly compare multiple treatments and interventions, more accurately assessing the relative effects of different control groups to draw conclusions . ThirdlyTherefore, the purpose of this study is to comprehensively compare and rank the impact of various risk factors of infection in close contacts with COVID-19, determine the most influential factors of close contact infection, and rank its subgroups by using network meta-analysis. This study provides a provide scientific basis for the rapid and accurate identification and management of close contacts, effectively optimizes epidemic prevention resources, and provides reference for the prevention and control of similar emerging respiratory infectious diseases in the future.22.1The network meta-analysis was performed using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). This study was registered with PROSPERO, number CRD 42022336859.2.2The classification of the type of contact was defined according to the Guideline of COVID-19 Control and Prevention-Close Contact Management Procedure (9th ed.) and was adjusted by included studies . The typ2.3For this network meta-analysis, we searched PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), WangFang Database, VIP, China Biology Medicine disc (CBM), medrixv and biorixv from December 1, 2019 to August 2, 2023, which only took Chinese and English studies into consideration. We developed and adapted a modified search algorithm for PubMed with combination of subject words and free words (in title and abstract) and then modified for other databases. The literature searching was completed by two reviewers. The search strategies for each database were in 2.4Studies meeting the following criteria were included: (1) Participants of study: close contacts of COVID-19 without medical workers; (2) Exposure: the article involves risk factors or prediction models of COVID-19 close contacts infected with SARS-CoV-2; (3) Outcome: SARS-CoV-2 infection; (4) Two or more risk factors of COVID-19 close contacts infection should be involved. The exclusion criteria were as follows: (1) Duplicate reports (in which case the study with the largest sample size or longest follow-up period was included); (2) Studies about epidemiological model for predicting the epidemic trend of COVID-19 and the case fatality rate; (3) Outcome indicators were not available or could be calculated by manual statistics; (4) Reviews, meeting abstracts, expert consensus and suggestions. The study selection was completed by two reviewers. Conflicts were resolved by a third reviewer.2.5The primary outcome of network meta-analysis was the SARs of COVID-19 close contacts. SARs were defined as the probability that close contacts of index cases become confirmed cases of a disease . The cal2.6The data extracted from each report included title, the first author, publication time, study site, source of data, definition of close contacts, sample size, risk factors, number of contacts infected, number of contacts. Data abstraction was completed by independent pairs of reviewers. Conflicts were resolved by a third reviewer. Risk factors of COVID-19 close contacts infected in each study were classified into four categories based on the three keys to the epidemic of infectious diseases: source of infection, route of transmission and susceptible population. Finally, four categories of risk factors without overlap were included in our study: factors about index cases, factors about contact, factors about close contacts and factors about prevention and control measures. The risk factors were classified by two researchers independently. Disagreement was resolved by discussion to reach a third reviewer.2.7The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included cohort and case‒control studies . Each st2.82) metrics were used to evaluate the heterogeneity of the studies. Subgroup analysis was based on the study regions, investigation time, study type, literature quality, and sample size to analyze the sources of heterogeneity; For the sensitivity analysis, we remove included studies one by one to observe stability of results. Publication bias was examined by funnel plots and Egger's test. Network meta-analysis was performed by STATA version 14.0.We conducted network meta-analysis based on a random effects model. We used a network plot to show the relationship between the risk factors we included, calculated the relative rankings of risk factors and presented the surface under the cumulative ranking curve (SUCRA) percentages for both groups and subgroups. We selected and analyzed the type of contact based on the result of network plots and SUCRA. A network plot was used to compare the evidence among the type of contact, compared the type of contact by calculating the OR, and indicated which type of contact had the greatest impact on the infection of COVID-19 contacts according to SUCRA. To estimate inconsistency, we calculated the difference between indirect and direct estimates whenever indirect estimates could be constructed with a single common comparator. The Q test and I-squared , and a random effects model was used to merge the SARs . Sensitivity analysis showed robust results after excluding four studies. According to the study region, study data time, study type, literature quality, and sample size, no heterogeneity sources were found in subgroup analysis. The funnel plot and Egger method were used to test publication bias for all included studies, and the results showed the presence of publication bias (P < 0.001). The results of the trim and filling method showed that there is not much difference in the results before and after pruning, and the results are relatively stable. The inconsistency test showed the difference between direct and indirect evidence was not statistically significant (p > 0.05). There was no clear evidence suggesting inconsistency between direct and indirect network effects.The fixed effects model showed differences  and direct contact with contaminated surfaces and fomites . During There are some confounding factors in our study, which may lead to inaccurate result in the overall study analysis. First of all, different countries have different population densities, different criteria for judging COVID-19 close contacts and different national prevention and control policies. These regional factors will influence the infection risk of close contacts and may increase the heterogeneity of our study . Secondl4.2The epidemic prevention and control policies in China were different from other countries, so subgroup analysis was carried out by region. After excluding studies from non-Chinese regions, the result of subgroup analysis suggested that OR for different types of contact changes. There may be several reasons. Most of study sites we included were from China, which was possibly because mainland China had more detailed and unified management and classification of close contacts than many other countries. After excluding studies from non-Chinese regions, estimates became significant and more accurate as the 95 % CIs narrowed, indicating stability and reliability of results increased. These differences may be caused by different standards for the definition and management of close contacts in China and other regions.The types of contact classification varied and often simplified in some other countries and changed depending on the situation. China has conducted strict and detailed epidemiological investigations on close contacts, and divided all types of contact into six categories according to national guidelines. There have not been much changes in types of contact classification thus far. The World Health Organization guidelines for contact tracing classification were similar to Chinese guidelines, including household contacts, closed environment contacts, medical contacts, transportation contacts, and other well-defined contacts, but the latest criteria for close contacts do not have a clear type of contact classification . The US In addition, the Chinese government adopted strict social distancing measures in the early days of the epidemic, people were not allowed to go out unless necessary. Compared with one-off contact and certain social distance between social members in public places, living environment and long-term living conditions provide repeated, frequent, and close contact opportunities with each other, resulting in high recurrence, high infection, and high incidence of family members , which mWe found that daily contact has the highest risk of SARS-CoV-2 infection, this contact is unavoidable. When people want to resume their previous social life, vaccines can help susceptible populations gain immunity, so vaccination may be a great way to reduce the risk of infection . For thoThis network meta-analysis has some limitations. First of all, due to language limitations, our study only included Chinese and English studies, and there was a selection bias in selection of included studies. Secondly, vaccination factors were not analyzed in the included studies. Although the protection of population by COVID-19 vaccine is not complete, it is also an important factor affecting close infection, which may be an important confounding factor. Homologous booster vaccination and sequential vaccination will make the COVID-19 vaccine more effective ,54. Ther5The type of contact had the greatest impact on COVID-19 close contacts infection among risk factors we included. Daily contact carried the greatest risk of infection among six types of contact, followed by contact with pollution subjects, social contact, other, medical contact and transportation contact. The ORs of daily contact were significantly higher than other types of contact, supported by more accurate results using studies from China. Therefore, analyzing and ranking the infection risk factors of close contacts will tend to quickly make a decision according to one or several risk factors when tracing or managing, so as to take different management measures, reduce the waste of resources and the cost of tracking and management. In situations of resource scarcity, it is advisable to focus on close contacts with high infection risk levels, monitor their progression and take measures in time. It can also avoid the spread of epidemics due to loose management. This study is the foundation of our ongoing research. We are constructing an infection risk assessment model for close contacts of COVID-19, estimating the probability of close contacts based on factors that have a significant impact on infection, and dividing the risk level. This also has guiding significance for similar emerging respiratory infectious diseases in the future.This article does not contain any studies with human participants or animals performed by any of the authors.This work was supported by Financial Science and Technology Project of the Corps : The XPCC developed and demonstrated the application of a decision support platform for the precise prevention and control of major outbreaks.Data included in article/supp. material/referenced in article.Wei-wen Zhang: Writing – original draft, Methodology, Data curation. Chen-xi Li: Writing – review & editing, Methodology. Shu-jing Cao: Software, Data curation. Yu-yuan Wang: Software, Data curation. Ze-xi Lu: Software, Data curation. Jia-lin Sun: Writing – review & editing, Methodology, Conceptualization. Ming -xia Jing: Writing – review & editing, Conceptualization.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mingxia Jing reports financial support was provided by Financial Science and Technology Project of the Corps .


Although an increased usage and development of 3D technologies is observed in healthcare over the last decades, full integration of these technologies remains challenging. The goal of this project is to qualitatively explore challenges, pearls, and pitfalls of AR/VR/3D printing applications usage in the medical field of a university medical center. Two rounds of face-to-face interviews were conducted using a semi-structured protocol. First an explorative round was held, interviewing medical specialists (8), PhD students (7), 3D technology specialists (5), and university teachers (3). In the second round, twenty employees in high executive functions of relevant departments were interviewed on seven statements that resulted from the first interviewing round. Data analysis was performed using direct content analyses. The first interviewing round resulted in challenges and opportunities in 3D technology usage that were grouped in 5 themes: aims of using AR/VR/3D printing (1), data acquisition (2), data management plans (3), software packages and segmentation tools (4), and output data and reaching end-user (5). The second interviewing round resulted in an overview of ideas and insights on centralization of knowledge, improving implementation of 3D technology in daily healthcare, reimbursement of 3D technologies, recommendations for further studies, and requirement of using certified software. An overview of challenges and opportunities of 3D technologies in healthcare was provided. Well-designed studies on clinical effectiveness, implementation and cost-effectiveness are warranted for further implementation into the clinical setting. Since the early 1990s, innovative visualization techniques including augmented reality (AR) and virtual reality (VR) have been slowly but progressively introduced in modern medicine. Popular applications focused on visualizing complex anatomical structures and combine these online models with virtual training and operation planning features. For a review on AR/VR in anatomy education, see –5. The dDespite the rapid developments and the promising results of AR/VR/3D printing in research over many decades, full integration of these new techniques remains unaccomplished; AR/VR/3D printing is still not standard practice and is not regularly used in daily healthcare. This article qualitatively investigates the challenges, pearls, and pitfalls of AR/VR/3D printing applications in the medical field. Considering both the achievements and the remaining challenges, this study aims to identify trends towards possible future developments.This study was conducted at the Radboud University Medical Center in Nijmegen, the Netherlands. After consultation of the local ethical review board, ethical approval for this study was waived. To recruit participants, various online advertisements were placed with a 2-week interval. Also, to ensure that all eligible participants were identified, two recruiting e-mails were sent to all chairs of the departments of our university medical center. Between these two e-mails, there was an interval of 4 weeks. In these recruiting advertisements and e-mails, the researchers explained the methodology and goal of this study. Two rounds of qualitative interviewing were conducted. No strict inclusion or exclusion criteria were defined by the researchers, allowing for anyone with an interest in AR/VR/3D printing to be interviewed.The first round of interviewing concerned an exploratory round in which residents, practicing medical doctors, PhD students, 3D technology software specialists (employees Radboudumc 3Dlab), and university faculty, both junior and senior, were interviewed to express their thoughts, wishes, expectations, and views on possible challenges. Eligible participants were contacted by e-mail containing more detailed information on the purpose of the interviews and the research methodology. Participation was voluntary. After agreeing to participate, an online interview setting was arranged by using Skype. Audio-recorded informed consent to be interviewed and recorded was obtained from all participants prior to the start of the interview. Semi-structured interviews were conducted to obtain detailed descriptions and extensive data of the participants’ perspectives on AR/VR/3D printing applications. The interview schedule of the first round was structured by using topics suggested by discussion between three investigators. These topics were enriched by seemingly important topics derived from the literature . Intervihttp://atlasti.com; ATLAS.ti Scientific Software Development GmbH, Berlin, Germany). The constant comparative method was carried out after finishing the first interview following an inductive iterative process. This means that data analysis started after the first interview was completed. Codes derived from the previous interview were used as a starting point for coding the next one, adding additional codes whenever needed. This process was carried out until saturation was achieved, i.e., when no new codes arrived during an interview. Thereafter, two additional interviews were held.The data from the interviews were independently analyzed using direct content analysis by two researchers . This waAxial coding, in which codes were linked together and combined into categories, was also started and was continued throughout the first interviewing round. Out of the identified categories themes were derived.The second round of interviewing was based on the recommendations and outcomes of the first round of interviewing. By recommendation, the chairs of departments with relevant experiences with AR, VR, and/or 3D printing were contacted in which the goals and aims of this study were explained. Chairs were asked to recommend specific employees in high executive functions (including themselves) with a vision of the future of AR, VR, and/or 3D printing to take part. For this round, executives were chosen because they are the ones deciding whether or not and in what way to implant 3D technologies in daily healthcare.Reminding e-mails were sent up to three times after the initial e-mail. All interviews in the second round of interviewing were audio-recorded, and again, audio-recorded informed consent was obtained from all subjects. Based on the codes and themes resulting from the first round of interviewing, seven statements on the implementation and centralization of 3D technologies in a healthcare setting were extracted by two researchers. These statements can be viewed in Fig. http://atlasti.com; ATLAS.ti Scientific Software Development GmbH, Berlin, Germany) by two investigators.Data analysis was identical to qualitative data analysis for the first round of interviewing as described above see “” sectionTwenty-three participants, including residents, practicing medical doctors, PhD students, 3D technology software specialists, and university faculty, were interviewed during the first round of interviewing. Twenty participants were interviewed during the second round of interviewing. These employees in high executive office were appointed to several departments . Details can be viewed in Table Interviewees expressed that their goals regarding AR/VR/3D printing were threefold. With regard to educational purposes, it was reported that residents used either technique to learn specific skills, especially regarding laparoscopic surgery  could provide insight in radiomics of tissue. When aligned with artificial intelligence, these developments could predict outcomes which are directly relevant for patients. More particularly, patient education by the use of AR/VR/3D printing was discussed as an important goal. It was expressed that these new techniques were believed to enhance patient understanding of a specific disease or treatment. Besides, when comprehension was increased, interviewees expressed that this could improve therapy compliance. Including patients in this process could help to construct patient-friendly, useful, and more effective AR and/or VR applications. However, it was also expressed that AR/VR/3D printing was probably not useful in every disease; some disorders were deemed more appropriate than others. More elusive and complex diseases, as well as those conditions not visible from the external surface , were believed to benefit more from the combination of standard patient consultation and AR/VR/3D printing. Finally, it was reported that AR/VR/3D printing could help patients to explain their disease to their relatives and improve awareness and understanding.In general, interviewees used serial radiological data (computed tomography (CT) and magnetic resonance imaging (MRI) scans). In some cases, a 3D camera system, sometimes equipped with infrared light, was used. Radiological data was obtained as DICOM files, which is the standard data file for these types of images. To further process the data, the DICOM files were converted to NIfTI files. Data concerned both in vivo and ex vivo data.Data management plans needed to adhere to good clinical practice, ethical guidelines, and (inter)national jurisdiction. Privacy officers and data management specialists needed to be consulted according to most interviewees in order to ensure that data was stored safely and properly. Nevertheless, the most important factor for successful data management was the effectuation of a pipeline between the data storage space and the imaging visualization software and/or post-processing software.http://www.itksnap.org) and MeshLab (https://www.meshlab.net/)). In-house written software was also reported by the 3D technology software specialists to be used. Residents and university faculty used clinically approved software packages. All interviewees reported struggling at the beginning of their first AR/VR/3D printing project due to the vast number of possible options with regard to software and analysis techniques. In addition, highly protected computer systems within the university medical center environment did not allow for free installation of software. Only “approved” software could be installed, which complicated the pipeline from data storage spaces and the further processing of the retrieved data. In response to that, well-protected stand-alone devices are bought independently by different departments. On these stand-alone devices, the department downloads and installs the necessary software packages which are not allowed to be installed on computer systems which are part of the hospital network. Thereby, various interviewees reported to have paid for and installed identical software packages independently.A diverse variety of freeware applications was used by the PhD students and the 3D technology software specialists (mostly ITK Snap (The obtained output data comprises electronic 3D models (AR/VR) and/or the 3D-printed models. Depending on the purpose of these models, the output could differ. Electronic 3D models comprised StandardTessellationLanguage files (.stl-files) and Wavefront OBJ files (.obj-files).Regarding the question whether the AR/VR/3D printing models reach the end-users, the interviewees were divided. When the end-user was defined as the scientist or practicing medical doctors, the interviewees expressed that these end-users were enabled to see and interact with the acquired models. However, regarding patients, students, and residents, substantial improvements could still be made. The AR/VR models could not be incorporated into the electronic patient file and thereby could not be interacted with by the patients. Furthermore, AR, VR, and 3D-printed models were primarily made in experimental settings. With regard to the sparsely created 3D-printed models, most models are distributed to the patients. However, to implement this on a larger scale, a fitting reimbursement needs to be effectuated to cover the costs of production.When discussing student education, it was noted that the AR applications were finding their way towards the individuals’ devices to be used following the anytime and anywhere learning principle. The same, however, was not the case for the VR model. On the other hand, 3D models already form a cornerstone of anatomy education. The use of 3D printing to create models that are unavailable but are required according to the university faculty is being implemented progressively over time.The seven statements, as shown in Fig. When discussing centralizing all knowledge and expertise on AR, VR, and 3D printing, interviewees were in favor of this idea, but only if certain conditions would apply. The central hub would need to be a service rather than a selection committee that decides on which projects will be supported and which will not, especially if the hub itself is financed by overhead funding  and materials used, several scenarios were heard. First, if research shows that the use of AR, VR, and/or 3D prints was considered a functional, evidence-based technique that improves patients’ understanding of their disease, it would be necessary that insurance companies reimburse the costs. Second, if research, however, reports these techniques to be an add-on modality that does not result in lower costs of the healthcare processes or improved patient satisfaction, outcome, or safety, it should not be reimbursed by insurance companies. More extremely, it was said that if research shows no evidence for the use of AR, VR, and/or 3D printing, it should be avoided. However, an alternative view on this latter scenario was that when patients wanted to have a 3D model of their illness even though research had not shown an additional value, the service could still be offered. The costs, however, should be reimbursed by the patients themselves. Concerning the use of AR/VR/3D prints in educational settings, program directors were enthusiastic to aid further integration of these techniques in (bio)medical curricula. When focusing further on recommendations for future studies to help investigate the effectiveness of AR/VR/3D prints, it was stated that future clinical studies should also focus on the implementation process of the interventions to increase the effectiveness of these applications in practice. Feasibility and adequacy in the clinical setting should be assessed to elucidate which method is favorable in each setting. Additionally, the costs of creating AR, VR, and 3D prints should also be investigated, and cost-effectiveness studies are needed to elucidate whether these costs outweigh the benefits.When discussing specially designed consultation rooms in the out-patient departments, all interviewees were critical. If it were found that these techniques could be useful, the interviewees stated that the necessary changes would have to be carried out. However, as long as evidence was lacking, such permanent changes were not considered to be necessary. However, three participants wondered whether medical professionals were equipped to teach their patients by the use of such innovative models. They proposed to design special educational programs for medical professionals on how to use such models effectively to optimize patient education by the use of AR, VR, and/or 3D prints.Furthermore, all interviewees believed that well-designed, well-protected electronic environments were needed to reach the end-users of these technologies, whether they were students or patients. In addition, five interviewees stated that when patients could use the models on their own devices, no special changes were needed in the consultation rooms of the out-patient departments.The final statement regarding the use of certified software was reported to be two-sided. All interviewees agreed that for clinical practices, especially when basing healthcare decisions on 3D models, the post-processing software legally needed to be tested and approved by the relevant institutions  approved; Conformité Européenne (CE) marked). For research or educational purposes, the interviewees were less strict. They admitted that in these settings, more freedom with regard to the creation of well-designed models would be preferable.This paper provided an overview of the challenges and opportunities experienced by experienced users of AR/VR/3D prints in a university medical center in the Netherlands and used these insights to qualitatively investigate the views and opinions of employees in high executive functions with affinity to the topic to identify trends towards possible future developments. Regarding the educational and research purposes of AR/VR/3D prints, the interviewees expressed that these implementations were ongoing and extensively investigated. More specifically when focusing on the use of AR/VR/3D prints in educational settings, university faculty and program directors were enthusiastic about aiding further integration of these techniques in (bio)medical curricula. It was found that although the technological possibilities have rapidly developed over the course of 30 years, studies on clinical effectiveness, clinical implementation, and cost-effectiveness are lacking.Various papers reported improved knowledge retention in patients suffering from specific disorders –27. NeveAnother important understudied field of research concerns the cost-effectiveness of AR/VR/3D prints in medicine. This remains an important omission of the scientific literature . It has One of the strengths of the current paper is the qualitative design and the use of two rounds of interviews to include experienced users of AR/VR/3D print technologies as well as professors and visionaries with affinity about this subject. One limitation concerns the method used to select subjects for the second round of interviews, as asking single individuals in leadership roles for recommendations could have led to selection bias. Another limitation of this study is the limited generalizability of the results and recommendations regarding specific institutions, as this study was conducted in only one university medical center in the Netherlands. Nevertheless, the reported recommendations can also be useful for other institutes to improve their infrastructure with regard to AR, VR, and/or 3D printing. Furthermore, the most important omissions of the field of AR, VR, and/or 3D prints have been identified. Along with the reported trends, some suggestions for possible future developments have been made to help accelerate the integration of AR/VR/3D prints into the daily practice of modern medicine. However, to increase the likelihood of successful and relevant implementation of these new techniques in modern medicine, the patient’s perspective should not be forgotten. Although beyond the scope of the current study, more research should be conducted regarding patients’ expectations of AR/VR/3D printing in modern medicine.Qualitative exploration has provided an overview of the challenges and opportunities of AR, VR, and/or 3D prints in modern medicine and education. Especially concerning clinical usability and implementation, further developments are warranted. For further implementation into the clinical setting, well-designed studies on the clinical effectiveness, clinical implementation, and cost-effectiveness are obligatory.