Sound monitoring and evaluation (M&E) systems are needed to inform effective biofortification program management and implementation. Despite the existence of M&E frameworks for biofortification programs, the use of indicators, metrics, methods, and tools (IMMT) are currently not harmonized, rendering the tracking of biofortification programs difficult. We aimed to compile IMMT for M&E of existing biofortification programs and recommend a sub-set of high-level indicators (HLI) for a harmonized global M&E framework. We conducted (1) a mapping review to compile IMMT for M&E biofortification programs; (2) semi-structured interviews (SSIs) with biofortification programming experts (and other relevant stakeholders) to contextualize findings from step 1; and (3) compiled a generic biofortification program Theory of Change (ToC) to use it as an analytical framework for selecting the HLI. This study revealed diversity in seed systems and crop value chains across countries and crops, resulting in differences in M&E frameworks. Yet, sufficient commonalities between implementation pathways emerged. A set of 17 HLI for tracking critical results along the biofortification implementation pathway represented in the ToC is recommended for a harmonized global M&E framework. Further research is needed to test, revise, and develop mechanisms to harmonize the M&E framework across programs, institutions, and countries. Micronutrient malnutrition affects ∼2 billion people worldwide , 2; it cUnder the leadership of HarvestPlus, crop-breeding programs at CGIAR centers, national agricultural research systems (NARS), private, public, and community-based seed producers, and farmers have co-developed, tested, and released more than 400 biofortified varieties of 11 different crops worldwide . The effGiven its promise for improving diets, biofortification is at a tipping point to go to scale to replace currently grown staples with low nutrient density , contribSound M&E systems are needed to generate quality data on program performance to inform learning and adaptive program management for effective implementation and evidence-based policymaking . DespiteIn a multi-phase, iterative process, we aimed to review M&E frameworks of biofortification programs implemented to date, and to recommend a subset of high-level indicators (HLI) for a harmonized global M&E framework to track program progress along a generic implementation pathway. We conducted (1) a mapping review to compile IMMT for biofortification programs; (2) semi-structured interviews (SSIs) with biofortification programming experts (and other relevant stakeholders) to contextualize findings from step 1; and (3) compiled a generic biofortification program Theory of Change (ToC) to use it as an analytical framework for selecting the HLI . This stWe focused on published reviews and official program documents that contained detailed descriptions of biofortification programs, M&E frameworks, and IMMT. MEDLINE, Cochrane Library, Web of Science, and Scopus were searched to retrieve reviews that met the inclusion criteria . Six buiTo guide the identification of indicators for M&E from the published and gray literature, we adapted the WHO/CDC logic model for implementing micronutrient interventions in public health  to repreThe SSIs with biofortification programming experts aimed to contextualize the findings from the mapping review by obtaining a generic description of biofortification programs, key factors limiting/enabling their success, M&E frameworks used, and IMMT, as well as methods for assessing coverage and consumption of biofortified foods. SSI guides were developed accordingly with guiding semi-structured questions and detailed probes to gain in-depth information on key topics of inquiry .n = 9) and food systems (n = 1) experts, two experts with extensive food intake assessment experience were interviewed to obtain further details on the challenges and opportunities of conducting dietary intake assessments in LMIC. The latter interviews enabled an understanding of the most suitable methods for assessing consumption of biofortified foods and potential adaptations that could be made to existing diet quality scores. Nine biofortification programming experts and one food systems expert were recruited through snowball sampling  and wereverbatim by two research assistants for subsequent thematic analysis. The content of the transcripts was spot-checked by FMG and SRM with the original audios to ensure content fidelity. Data were collected over five weeks from March to June, 2021 until data saturation was reached among key themes  about the purpose of the study and were informed that the data would be used for research purposes. SSI participants gave verbal consent to record the interviews. As data collection methods were primarily desk-based and contact with participants was minimal (online interviews), approval from an institutional review board was not sought.The mapping review resulted in three published reviews fulfilling the eligibility criteria , 28, 29 From the gray literature, three reports that focused on tracking the progress of biofortification programs in tackling micronutrient deficiencies in the Gambia , 31 and The findings of the SSIs were grouped into three main themes, as described below.Most participants described the biofortification programs in four stages. Those descriptions were also comparable to the biofortification interventions described in the reviews , 28, 29 Stage 1: Breeding and releasing biofortified crop varieties—All participants indicated that the initial development of biofortified varieties of crops was primarily carried out at the CGIAR centers at global and regional levels. In LMIC, the CGIAR shares biofortified parental lines with NARS for inclusion in national breeding programs for further adaptive breeding and field testing. Subsequently, the NARS, or other national varietal release authority, may approve the release of tested biofortified varieties with competitive agronomic traits if they meet predetermined threshold micronutrient levels and other agronomic characteristics as required by the national authorities. The released varieties may then be licensed to public and private companies  for multiplication and subsequent distribution to farmers. Most participants described biofortification breeding as a “dynamic,” “never-ending process,” “constantly searching for high-yielding, pest-resistant, and climate-resilient varieties where breeding for higher micronutrient levels—enough to have a significant impact on micronutrient deficiencies—is mainstreamed into the existing breeding programs.” Most participants considered investing in capacity strengthening at the NARS level for breeding and testing new biofortified varieties crucial for successfully sustaining biofortification in public and private breeding programs over time.Stage 2: Multiplying, introducing, and distributing planting material of biofortified crop varieties to farmers—Most participants explained that multiplication and distribution of planting material are carried out by private, public, or community-based planting material producers, depending on the type of crop. Grain crop seeds for hybrid and open-pollinated varieties (OPV), such as maize and pearl millet, are usually licensed to commercial private and/or public seed companies for subsequent multiplication and marketing. In contrast, vegetatively propagated crops (VPC), such as sweet potato and cassava, are usually multiplied and distributed by community-based stem/vine multipliers.Depending on the competitiveness of the planting material, there is a mixed seed production and distribution system for OPVs and self-pollinating biofortified varieties of crops (SPV), such as beans, rice, and wheat. Private seed companies prefer to produce and market highly competitive varieties , while public sector and NGO support are needed for less competitive varieties with high levels of micronutrients. All participants explained that the crop type and seed systems also define the seed commercialization pattern. Depending on the crop, private seed companies, public multipliers, NGOs, farmer organizations, including women’s groups, or a combination of two or more of these are crucial to scaling the multiplication of biofortified planting material and hence availability thereof to smallholder farmers.Stage 3: Scaling production and utilization of biofortified foods—All participants indicated that scaling will be the focus of most national and global programming in the coming decade. Strengthening all value chain actors, from breeders to farmers, aggregators, processors, retailers, and other service providers, is a crucial cross-cutting aspect of program implementation activities to integrate biofortification into seed and food systems in a sustainable way. Implementing behavior change communication strategies to accelerate awareness and adoption of biofortified crops, fostering good pre and post-harvesting practices, and facilitating access to and promoting utilization of biofortified planting material among farmers are crucial in this stage. Subsidies, partial or complete, and free or low-cost demonstration kits/trial packs can effectively foster the adoption of biofortified crops by farmers. Some biofortification programs also establish linkages between farmers and different market options, such as food processors, to help farmers and aggregators sell their products as ingredients for processed foods.Most participants also highlighted the role of the public sector, NGOs, and humanitarian organizations in scaling access to biofortified planting material and foods and using biofortified foods for emergency response. For example, CIP participants indicated that they work with the World Food Programme to include OFSP in food security programs in refugee camps in northern Ghana, northern Uganda, and northern Kenya. Other examples include involving the public sector in distributing OFSP in school feeding programs in Nigeria and Ghana. Most participants also indicated that behavior change strategies to promote the utilization of biofortified crops and foods among potential consumers in rural and urban settings are crucial in the scaling phase.Stage 4: Integrating biofortification in local food systems—A participant described the mainstreaming of biofortification into food systems as follows:“… biofortification needs to be mainstreamed into national policies, plans, and breeding programs. The new release of competitive biofortified varieties is actively ongoing; the varieties are tested by NARS, released for production by national authorities, and adopted by farmers, and the production of biofortified crops increases continuously. As a result, biofortified foods are mainstreamed into the agricultural and food sectors; consequently, consumption of biofortified food increases, contributing to relieving micronutrient deficiencies and improving the quality of diets.”Interview with senior expert, Washington, DC, March 2021Furthermore, some participants indicated that defining standards with ranges of micronutrient content for biofortified planting material and food manufactured with biofortified ingredients is crucial to ensure that biofortified crop varieties and foods meet the expected micronutrient content in the future.From the SSIs, two application scenarios emerged for M&E of outcome (adoption) and coverage of biofortification programs and consumption of biofortified foods: nationally representative surveys and sentinel site monitoring surveys. All participants indicated that nationally representative surveys are warranted only when the program has reached sufficient maturity and coverage and recommended the integration of biofortified crops and foods into production and consumption modules of existing nationally representative data collection systems  to optimize costs and sustainability of M&E of production, coverage, and consumption of biofortified crops and foods. On the contrary, some participants indicated that sentinel site surveys could be used for monitoring pilot stage or “nascent programs” or in cases of budget constraints for M&E. In a sentinel surveillance system, data are regularly reported from a sample of pre-selected sites  purposefully selected to represent the population of the areas where the programs are implemented . The reqThe following sections discuss the methods and tools to assess the coverage and consumption of biofortified crops described in the SSIs. This section specifically concerned diversity and diet quality scores, as used by CIP and HarvestPlus in biofortification programs (and others in generic nutrition-specific and nutrition-sensitive interventions).A lack of agreement emerged among participants on the most appropriate methods for assessing coverage and consumption of biofortified foods. Some participants indicated a preference for traditional consumption surveys such as 24-hour recalls (24hR) or Food Frequency Questionnaires (FFQ). In contrast, others suggested alternative methods, such as mathematical modeling of Household Consumption and Expenditure Surveys (HCES) data to estimate apparent food consumption and micronutrient intake (before and after biofortification of the staple[s] consumed) based on the adult male equivalent formula, as proposed by the Food and Agriculture Organization (FAO) , 37.Concerning HCES, some participants voiced concern that these may produce inaccurate estimates of individual food consumption and nutrient intakes, primarily because they do not consider intra-household food sharing practices or foods consumed away from home. In contrast, others argued that considering the complexity of conducting 24hR or FFQ, their estimates are also inaccurate. The most salient examples of sources of inaccuracy mentioned for 24hR were:•standardized portion sizes are seldom available for specific LMIC contexts;•extensive training and experience are required to collect, process, and analyze data from 24hR and FFQ. Such training is often lacking, leading to inaccurate data collection processes and poor data quality.•For FFQ, appropriate food lists tailored to the context and population group are needed, requiring initial formative research and validation against 24hR and is therefore even more rare in LMIC.Other mentioned barriers to undertaking 24hR and FFQ were the time required for data collection, processing, and analysis of data, cost, and complex logistics and the availability of up-to-date and accurate food composition tables in LMIC.In light of the above limitations, one participant explained that apparent food consumption estimated from HCES is sufficient to estimate the coverage and consumption of biofortified foods, as long as biofortified foods are included in the surveys as specific categories of food. The participant also indicated that the advantage of HCES is that food acquisition or consumption data are regularly collected at the household level in multiple LMIC and that the data are publicly available in most cases. Another participant indicated that including biofortified foods in the food acquisition and consumption lists of HCES would allow making sufficiently robust estimates of coverage and consumption of biofortified foods for routine program monitoring.Given the complexity and cost of undertaking dietary intake surveys, some metrics have been developed to simplify diet quality assessment. One of them is the minimum dietary diversity score for women (MDD-W), a dichotomous indicator that assesses dietary diversity and estimates nutrient adequacy among women of reproductive age (WRA) . The MDD“…Diet indicators such as the MDD-W elicits a score: 2, 3, 6. Positive changes in these numbers attributable to a certain intervention will tell at the macro level whether things are improving. However, this information will not contribute to improving the quality of implementation of a program or identify specific actions needed to improve diet quality of target groups…”Interview with biofortification expert, USA, March 2021.Regardless of these limitations, efforts have been made to adapt the MDD-W to capture the contribution of biofortified foods to nutrient intake. CIP participants indicated that they use the MDD-W to assess the change in dietary diversity among WRA attributable to their interventions with OFSP. CIP modified the MDD-W’s scoring system by adding biofortified crops as a unique and independent food group contributing to diet diversity and extending the maximum MDD-W score to 11. Although this modification has not been validated as a proxy measure for assessing vitamin A adequacy, it enables CIP to assess their interventions’ contribution to dietary diversity in specific geographies.Another potential method to assess the coverage and consumption of biofortified foods described in the SSIs was the Global Diet Quality Score (GDQS), a novel food-based metric that calculates nutrient adequacy and the risk of non-communicable diseases associated with dietary intake. The GDQS is calculated based on the consumption of 25 food groups ) . Total sAs mentioned by one participant, the GDQS metric and its data collection tool [the GDQS mobile application ] could bData are collected with a mobile application that stores dietary intake data in an Excel file. The Excel sheet could be easily modified by adding new rows with the foods of interest, uploading the new file to the app, and it would be ready to capture the consumption of specific foods. However, this modification should be validated. Also, the GDQS data collection method is not designed to capture portion sizes of single foods but to estimate quantities of food intake at the food group level.”“… Interview with an expert on dietary assessment methods,USA, June 2021.The two experts on dietary intake methods also explained that modifications to the GDQS metric and data collection method could be used to assess the contribution of biofortified foods to diet quality and to estimate the coverage of biofortified foods, but not to estimate the contribution of foods to micronutrient intake. Yet, some biofortification experts observed that, given the potential variation in micronutrient content of biofortified foods eventually consumed by households, and their coverage, the use of modified diet quality indicators could lead to over-or underestimation of the contribution of biofortified foods to diet quality.Based on the generic description of biofortification programs from the SSI participants (Theme 1) and the internal program documents provided by HarvestPlus and CIP participants , 42, 43,We used the ToC from A generic or global M&E framework for biofortification programs with a comprehensive set of 17 high-level indicators is presented with their respective metrics, methods, and tools for data collection. The framework is developed based on the commonalities of biofortification programs implemented in multiple LMICs in Africa, Asia, Latin America, and the Caribbean regions by collaborations between national and international agricultural research systems and other public, private, NGO, and UN stakeholders. The 17 HLI presented in this paper may not be used all at once. Their use is flexible and can be prioritized, depending on the implementation stage and stakeholders’ information needs, as illustrated in This study highlights crop-related differences in biofortification programming. Competitive planting materials such as grain crop seeds for hybrid and OPV are usually licensed to commercial private or public/private seed companies. They are distributed to farmers through formal commercial channels. VPCs such as OFSP or cassava belong to decentralized informal seed systems, where the planting material is exchanged/shared with other farmers or sold in local markets by traders and vendors . Yet, thSentinel site surveys may be a convenient alternative for M&E of biofortification interventions of formal and informal seed systems. They can generate timely actionable information to improve program implementation at a relatively low cost , 47. SenConcerning the 17 HLI, Most of them have already been tested globally in multiple biofortification projects . Additionally, indicators 1, 3, 4, and 6–16 were anchored to the ToC developed by the MELIAS collective, and hence their definitions are now harmonized across biofortification programs led by HarvestPlus, CIP, and GAIN. Furthermore, the indicators on awareness (indicator 12), coverage, and consumption (indicator 13) were built on approaches previously used to assess large-scale food fortification programs (LSFF) , 49. IndLikewise, indicators 8–11 for assessing market availability of raw, prepared, and processed biofortified foods were recently developed by HarvestPlus and GAIN for the scaling phase of biofortification programs and are not tested. Proposals for studies to test these indicators are being prepared. Indicator 17  can be constructed using a diet quality indicator, e.g., the MDD-W or GDQS. These indicators are most useful once significant coverage of biofortified crops and foods is attained and when consistent data on the quality of biofortified crops and foods  are available. Using this indicator with uncertain data on coverage and biofortification quality may lead to under-or overestimating the contribution of biofortified foods to diet quality.The generic ToC presented in This study presents a generic M&E framework for biofortification programs, including a ToC for a generic or ‘global’ biofortification program impact pathway and a set of 17 HLI and their associated methods, metrics, and tools. The study is based on a thorough review of a wide range of available frameworks from published and gray literature and ground-truthed through interviews with experts in biofortification programming and dietary intake assessment.The generic implementation pathway of biofortification programs described in Theme 1 and represented in Compared to the ToC of the MELIAS collective , the ToCThis study has limitations and strengths. A limitation is that most of the information on the M&E framework and biofortification programming was obtained from program documents provided by HarvestPlus and CIP. Though these two organizations have been spearheading biofortification programming in the past decade, relying on only their points of view may represent a narrow scope. Although we searched for biofortification programs implemented by other organizations, we couldn’t find many, and those we found did not provide significant relevant information for the aims of this study. The joining of GAIN of HarvestPlus’s efforts in 2018 to scale biofortified foods , 52 and The main strengths of this study include (1) compilation of a generic ToC for biofortification programming based on a review and triangulation of tried-and-tested ToCs of various biofortification programs implemented globally; (2) identification of the most pertinent HLI used by biofortification programs and anchoring of these to the ToC above; and (3) review of available IMMT to recommend a sub-set of HLI and ground-truthing of these with experts on biofortification programming. This multi-method iterative approach allowed us to identify rich information on biofortification programs to address our research aims.Further work is required to determine how IMMT for biofortification programs can best be incorporated into existing national data collection systems and integrated into other nutrition and health indicator-based high-level reporting such as Demographic and Health Surveys. Furthermore, implementation research  is warranted to explore barriers and enablers to using the proposed HLI in ongoing biofortification programs, including programs implemented in remote areas with difficult access. This will help to further harmonize this framework across programs, countries, geographies, crops, and institutions; and to optimize planning and funding of monitoring and evaluation activities to ensure that biofortification programs reach the neediest.Another area of research that we suggest implementing is in the artificial intelligence field. Participants unanimously described numerous limitations to implementing food consumption surveys using traditional methods such as 24hR and FFQ. Artificial intelligence applications could help simplify these assessments, for example, by using pictures captured with a mobile phone integrated into an artificial intelligence-based food recognition system and linking them to mega-databases of food composition tables  to estimSR-M participated in research design, data collection and analysis, and conceptualizing the manuscript. FG participated in data collection and analysis and wrote the manuscript with SR-M, BM, and EB shared the gray literature, ToCs, and indicators used by HarvestPlus globally, participated in SSIs, and critically reviewed the manuscript. SK and CL advised on the study design and critically revised the manuscript. TA developed the syntax for the mapping review, participated in the mapping review data analysis, and critically revised the manuscript. AM-B was the current project manager and contributed to the manuscript. KH was the former project manager and contributed to implementing the project. IB and SO developed the proposal to obtain funding for this study. EF critically reviewed the research proposal and manuscript. SR-M and FG had primary responsibility for the final content. All authors read and approved the final version of the manuscript.


The authors discuss the therapeutic potential of representative A2AAR antagonists in the frame of experimental and clinical data and point out the need for A2AAR antagonist drug candidates with high binding affinity and for multiparametric optimization of lead compounds in order to develop clinically useful A2AAR antagonists.The human genome encodes more than 800 different G protein-coupled receptors (GPCRs), uncovering their importance in human physiology. These integral membrane proteins sense a diverse spectrum of chemical signals in a highly selective way and mediate a wide array of cellular signaling cascades, resulting in a plethora of homeostatic responses. Understanding the ligand recognition, activation, signaling and regulation of these receptors is of primary importance not only to shed light on several aspects of human physiology but also for developing novel therapeutic approaches. Regarding this concern, GPCRs are the target of more than 30% of the drugs on the market. Activated by external stimuli through coupling to different G-proteins or arrestins, GPCRs elicit a cyclic adenosine 3,5-monophosphate response, calcium mobilization or the phosphorylation of extracellular regulated protein kinases 1/2. However, noncanonical interactions between G proteins and GPCRs that do not result in nucleotide exchange and classical G protein signaling are now recognized. These new layers of functional selectivity have greatly expanded the opportunities for therapeutic interventions and the development of new chemical biology tools, such as advanced structural and computational methods, and have further fostered our understanding of GPCRs’ regulatory mechanisms, paving the way for future drugs. In this frame, the recent developments in the field of protein engineering and the crystallography of membrane proteins are considered major advances in GPCR biology. Although the discovery of natural compounds and/or endogenous ligands molecules on GPCRs is still ongoing, the wide availability of ligand-bound GPCR structures has provided crucial insights into the structure, function, and pharmacology of these receptors, empowering the application of structure-based drug design (SBDD) approaches for the discovery of potent candidates with favorable pharmacological profiles. The evidence of new types of ligand–receptor–effector relationships, such as inverse agonism, positive and negative allosterism, multimeric receptor pharmacology, and ligand-biased signaling has further led to novel methods for the therapeutic potential of GPCRs. With this backdrop, the “GPCRs: Ligands and beyond 2022” Special Issue focuses on recent advances in GPCRs’ biology. This thematic issue consists of five original articles and five reviews covering a broad range of topics related to medicinal chemistry and the therapeutic potential of this integral membrane protein family. The first original article from Bassani and coworkers  focus thWe hope the readers enjoy this Special Issue and are inspired to develop new approaches for the rational design of pharmacological GPCR regulators.


Background:Salvia miltiorrhiza Bunge.  injection classes (SMIC) is widely used in the treatment of unstable angina (UA). However, it is uncertain which SMIC is more effective in terms of UA efficacy. The purpose of this Network Meta-analysis (NMA) was to compare the treatment effects of various SMIC to determine the best SMIC for the treatment of UA.Methods: The China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), Chinese Biomedical Literature Database (CBM), PubMed, Web of Science, and Cochrane Library databases were searched to screen randomized controlled trials (RCTs) of SMIC for UA. The search time frame was all from the establishment of the database to May 2022. RevMan 5.3 and Stata 14.0 software were used for NMA.Results: A total of 148 studies including 14,979 patients, including 7,584 cases in the experimental group and 7,395 cases in the control group were included, and eight SMIC were extracted, namely:Danshen injection, Fufang Danshen injection, Guanxinning injection, Danshenchuanxiongqin injection, Danhong injection, Danshentong IIA Huangsuanna injection, Shenxiong Putaotang injection, and Danshenduofensuanyan injection. The results of NMA showed that, in terms of total effective rate, Shenxiong Putaotang injection and Danshenchuanxiongqin injection have the advantage; In terms of ECG efficiency, Danshentong IIA Huangsuanna injection and Danshen injection have an advantage; Danshenchuanxiongqin injection and Danshenduofensuanyan injection were more effective than other SMIC in improving angina pectoris attacks; Shenxiong Putaotang injection has an advantage in improving hs-CRP; Shenxiong Putaotang injection and Danshentong IIA Huangsuanna injection have advantages in improving TC and TG, respectively.Conclusion: The eight SMIC included in the current study were effective in treating UA, Shenxiong Putaotang injection and Danshentong IIA Huangsuanna injection were both superior in improving all outcome indicators. However, there is still a need for larger samples and high-quality randomized controlled trials for more refined comparisons of various SMIC.Systematic Review Registration: [PROSPERO], identifier [CRD42022350872] The China Cardiovascular Health and Disease Report 2020  shows thSalvia miltiorrhiza Bunge.  is one of the most widely used drugs. Salvia miltiorrhiza is derived from the dried root and rhizome of Salvia miltiorrhiza Bge. and has a long history of use in China as a traditional Chinese medicine .Chinese herbal medicine (CHM) has a 3,000-year-old history with unique theories for concepts of etiology and systems of diagnosis and treatment . It stilmedicine . Salvia mponents . Accordiammatory . It can ammatory . In viewtreat UA . Among tThe results of a previous meta-analysis  demonstrTherefore, we decided to use Network Meta-analysis, which combines direct comparative evidence in randomized controlled trials (RCTs) and indirect comparative evidence based on co-controlled RCTs , to try The present study was proposed to compare eight SMIC widely used in medical units at all levels in China, includin: Danshen injection (DS), Fufang Danshen injection (FFDS), Guanxinning injection (GXN), Danshenchuanxiongqin injection (DSCXQ), Danhong injection (DH), Danshentong IIA Huangsuanna injection (DST IIA HSN), Shenxiong Putaotang injection (SXPTT), Danshenduofensuanyan injection (DSDFSY). Combined treatment with CMI can not only quickly relieve the immediate symptoms such as palpitations, but also effectively relieve other accompanying symptoms such as insomnia, excessive dreaming and fatigue .This programme is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Programme (PRISMA-P) . The PRIThe PICOS (Population-Intervention-Comparators-Outcomes-Study design) framework was adopted as the eligibility criteria for the review as following.RCTs on SMIC for the treatment of unstable angina, blinded and in any language.All patients enrolled were receiving regular treatment for unstable angina /angiotensin receptor blockers (ARBs), Antiplatelet agents, Glycoprotein IIb/IIIa Receptor Inhibitors (GPI), Anticoagulant therapy etc.), No other serious underlying disease, such as acute myocardial infarction, severe heart failure, coagulation disorders or liver or kidney disease, or malignancy, with an expected survival of less than 1 year; Western or Chinese medical diagnostic criteria must meet the accepted diagnostic criteria for unstable angina pectoris in coronary artery disease at the time of study publication; patients were enrolled regardless of age, gender, race, geography, disease duration, or ethnicity.We decided to study the eight most commonly used SMIC through previous studies and actual clinical observations. These eight SMIC are: Danshen injection (DS), Fufang Danshen injection (FFDS), Guanxinning injection (GXN), Danshenchuanxiongqin injection (DSCXQ), Danhong injection (DH), Danshentong IIA Huangsuanna injection (DST IIA HSN), Shenxiong Putaotang injection (SXPTT), Danshenduofensuanyan injection (DSDFSY). For the purpose of data analysis, we defined conventional treatment as the administration of standardized treatment and symptomatic treatment consistent with the guidelines approved at the time the study was conducted. Eligible comparisons are as follows: control group, patients receiving regular treatment for unstable angina, without CMIs or Oral Chinese Medicine (OCM), etc., with unlimited duration of treatment and dose administered; appropriate treatment and symptomatic treatment for the patient’s own underlying disease condition is permitted. In the treatment group, only one of the above SMIC must be used in combination with the corresponding control group, and the dosage and duration of treatment must be in accordance with the specifications for the use of the drugs.Studies that did not meet all of these inclusion criteria were excluded. In addition, the following exclusion criteria were applied:①Repeated publications; ②Personal experience summary, pure theoretical research, and animal experiment; ③In addition to SMIC, the two groups also used traditional Chinese medicine decoction, Chinese patent medicine or acupuncture and moxibustion; ④ The number of reported cases in each group was too small (<20 cases); ⑤Too short treatment course (<7 days); ⑥The data in the literature are incorrect or incomplete.By reviewing clinical trials published in academic journals that evaluated UA, we decided to use evaluation parameters including: Total effective rate, According to the guidelines for UA and ECG efficacy criteria set by the Chinese Medical Association, the efficacy criteria are “significantly effective”, “effective” and “ineffective” . ElectroIn summary, Outcome indicators primary indicators: ① Total effective rate (Significantly effective + Effective), ② ECG efficacy (Significantly effective + Effective), ③ Angina pectoris attacks; secondary indicators: ① hs-CRP (High sensitivity C-reactive protein), ② total cholesterol (TC), ③ triglyceride (TG).#1 Coronary Diseases [MeSH Terms]#2 Coronary Diseases [Title/Abstract]#3 Coronary Heart Disease [MeSH Terms]#4 Coronary Heart Disease [Title/Abstract]#5 #1 OR #2 OR #3 OR #4#6 Unstable angina [MeSH Terms]#7 Unstable angina [Title/Abstract]#8 #6 OR #7#9 Traditional Chinese medicine [MeSH Terms]#10 Traditional Chinese medicine [Title/Abstract]#11 Injection [MeSH Terms]#12 Injection [Title/Abstract]#13 Injectable [MeSH Terms]#14 Injectable [Title/Abstract]#15 Danshen Injection [MeSH Terms]#16 Danshen Injection [Title/Abstract]#17 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16#18 Randomized Controlled Trial [Publication Type]#19 Controlled Clinical Trial [Publication Type]#20 random [All Fields]#21 #18 OR #19 OR #20#22 #5AND #8 AND #17 AND #21Computer search of seven databases: The China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), Chinese Biomedical Literature Database (CBM), PubMed, Web of Science, and Cochrane Library databases. The search time of each database is built until May 2022. In addition, references to the literature were incorporated retrospectively to supplement access to relevant literature. The search was conducted with a combination of subject terms and free terms. English search terms included: “Coronary Diseases”, “Coronary Heart Disease”, “Unstable angina”, “Traditional Chinese medicine”, “Injection”, “Injectable”, “Danshen Injection”, “Randomized Controlled Trial” etc. Take PubMed as an example, the search terms and strategies are as follows. The search strategies of other databases were adjusted according to their search rules.Two investigators (LMX and LHD) performed the literature screening and data extraction. After excluding duplicates, the titles and abstracts were read to exclude literature that clearly did not meet the requirements, and then the remaining literature was read in its entirety to clarify whether it met the inclusion criteria, and if there was disagreement, it was determined by discussion or consultation with a third investigators (XWL). Use Microsoft Excel 2019 to perform data extraction and collect relevant information. Data extraction included: ① Basic information: article title, first author, publication date, country/region, etc.; ② Tudy characteristics: interventions in the trial and control groups, number of study subjects, age, duration of intervention, adverse effects; ③ Key information required for risk of bias evaluation in the literature; ④ Outcome indicators included in the trial and control groups.The study quality of the RCTs was assessed by two investigators using the tool for assessing risk of bias recommended in the Cochrane systematic reviewers’ handbook 5.1 . The folCI and the p value of its Z test were calculated, and when p > 0.05 and the lower limit of the 95% CI of IF value was equal to 0 were considered as good consistency between the results of direct and indirect comparisons, otherwise the closed loop was considered to have significant inconsistency, but according to this case there is no closed loop, so the consistency model was used. The efficacy was ranked according to surface under the cumulativeranking curve (SUCRA)  software was used to implement the statistical process. The mean difference (MD) was used as the effect analysis statistic for the measures, and the risk ratio (RR) was used as the effect analysis statistic for the dichotomous variables, with each effect providing its 95% confidence interval (CI). NMA was performed using the network group command in Stata 14.0 for data preprocessing, and evidence network plots were drawn to demonstrate the network relationships of different interventions, with the larger area of the dot in the plot indicating the greater number of patients for that intervention, and the thickness of the line connecting the two interventions representing the number of included studies . Two-by- (SUCRA) , and theConsidering the inclusion of multiple observations, we combined the individual observations two by two and used a multivariate approach to determine the dependencies between the results. Clustering methods and two-dimensional graphs are used to generate the processing clusters . Using tA total of 4,904 literature were obtained by searching relevant databases. After excluding duplicate literature, 1,071 articles were obtained. By reading the titles and abstracts of the literature, 753 articles that obviously did not meet the inclusion criteria were excluded; for the remaining 318 articles, by reading the full text, 170 articles that did not meet the inclusion criteria in terms of study subjects, design types, and intervention conditions were excluded, and 148 RCTs studies were finally included . The litA detailed assessment of the risk of bias for the 148 RCTs studies  is summaThe reticulation between the eight included SMIC is shown in All interventions involved in this study did not form a closed loop and did not require consistency testing.p < 0.05). See A total of 140 studies  were incp < 0.05). A total of 61 studies  comparinp > 0.05) change in angina episodes with CT versus the addition of SMIC, with weeks as the time observation unit or with days as the time observation unit. See 23 studies  with weep < 0.05) for the improvement of hs-CRP compared with CT. See A total of 20 studies  comparinp < 0.05). See A total of 17 studies  comparinp < 0.05) for the improvement of TG. See The addition of Danshenchuanxiongqin injection, Danhong injection, Danshentong IIA Huangsuanna injection, Shenxiong Putaotang injection, and Danshenduofensuanyan injection was statistically significant ; ECG efficacy (Significantly effective + Effective); Angina pectoris attack; hs- CRP (High sensitivity C-reactive protein); TC ; and TG (triglyceride) as evaluation metrics to produce comparative corrected funnel plots for studies to assess small sample effects, see A total of 63 studies  mentioneIn this NMA, A comprehensive summary of the efficacy and safety of different SMIC in patients with UA was presented. The results showed that 1) All SMIC combined with CT were superior to CT alone in terms of total efficiency, ECG efficiency, angina attack, hs-CRP, TC, and TG; 2) Shenxiong Putaotang, Danshentong IIA Huangsuanna, Danshenchuanxiongqin (time observation unit in weeks), Danshenduofensuanyan (time observation unit in days), Shenxiong Putaotang, Shenxiong Putaotang and Danshentong IIA Huangsuanna performed best as measured by total efficiency, ECG efficiency, angina attack, hs-CRP, TC, and TG, respectively; 3) Shenxiong Putaotang performed best in terms of overall efficiency, better than other SMIC, but only better than CT in terms of ECG efficacy; 4) Both Shenxiong Putaotang and Danhong performed better than most SMIC in the measure of Angina pectoris attacks; 5) Shenxiong Putaotang and Danshentong IIA Huangsuanna were the two best performing treatments in terms of lipid markers (TC and TG); 6) Shenxiong Putaotang and Danshentong IIA Huangsuanna, which outperformed other SMICs in several study metrics. Combining the results of each index, Shenxiong Putaotang injection and Danshentong IIA Huangsuanna injection have better improvement for major and minor indexes, and can be preferentially selected for patient treatment.In addition, based on the results, we noted that Shenxiong Putaotang outperformed other SMICs in three indicators  and ranked second in improving TG, suggesting that Shenxiong Putaotang injection is superior in improving symptoms, slowing inflammatory response and optimizing lipids. Previous studies on Shenxiong Putaotang injection have shown its role in protecting cardiomyocytes and reducing the inflammatory response. The present results suggest that the optimization of lipid levels by Shenxiong Putaotang injection is also one of its benefits, and a deeper mechanism in this direction can be explored. Danshentong IIA Huangsuanna injection performed best in both indices: ECG efficacy and TC. The improvement in ECG may be related to enhanced coronary blood flow, which restores collateral circulation and local blood supply in the ischemic region, while the control of TC needs to be explained by further studies.In the clinical setting, therapeutic effects and safety are the two aspects of CMIs applications that receive the most attention. The evaluation of safety not only helps to avoid the occurrence of adverse reactions and find solutions to deal with them, but also summarizes the mechanism of the occurrence of adverse reactions. A total of 62 studies in this NMA included adverse reactions as an observation, 24 of which mentioned specific symptoms and the number of people experiencing them, and the remaining studies did not report any serious adverse events see . AccordiThese symptoms can be effectively relieved by reducing the application, discontinuing the medication, or treating the symptoms. Nevertheless, clinicians should be aware of the possibility of adverse reactions when applying SMIC treatment.Regarding the causes of adverse reactions to injections, on the one hand, the use of CMIs is not standardized, such as the dose or dosing concentration exceeds the routine, and the drip rate is not strictly controlled; on the other hand, the mixing of CMIs with chemical drugs and other combinations greatly increases the incidence of adverse reactions to CMIs, because the thermogenic and allergic superimposed effects of drugs amplify the incidence of adverse reactions, and most adverse reactions that occur when CMIs and CT are combined are generally counted on CMIs . StudiesChinese medicine is rich in philosophical ideas and diagnostic concepts, including holistic, systematic and balanced views, and there is a complementary and reciprocal relationship between these philosophical concepts and biomedical sciences, which can often be used in dealing with the concept of disease in modern medicine . Angina The Chinese Pharmacopoeia 2020 edition records (Salvia miltiorrhiza Bge. contains a variety of pharmacological components, mainly including Salvia miltiorrhiza IIA, Salvinone, Salvianolic acid, Salvianolic acid B and Salvianolin, which have the effects of inhibiting platelet aggregation, anti-myocardial ischemia and anti-atherosclerosis. SMIC can alter blood flow velocity and viscosity, improve the local circulatory capacity of patients, improve myocardial function, reduce myocardial cell apoptosis, regulate the expression of apoptosis-related proteins, and modulate the levels of myocardial inflammatory cytokines and oxidative stress products (UA belongs to the category of “thoracic paralysis” in TCM, and its core pathogenesis is paralysis of the heart veins , while T records  that Salproducts . Fufang products . Guanxinproducts . Danshenproducts . Danhongproducts , scavengproducts , and alsproducts . Danshenproducts . Shenxioproducts . Danshenproducts .Cluster analysis suggested that Danshentong IIA Huangsuanna injection performed better in terms of total effective rate and ECG efficacy, while Danshenchuanxiongqin injection performed better in terms of total effective rate and angina pectoris attacks with weeks as the unit of observation, and Danshenduofensuanyan injection performed better with days as the unit of observation; Shenxiong Putaotang injection performed better in terms of total effective rate and improvement of hs-CRP; Danshentong IIA Huangsuanna injection performed better in terms of improvement of TC and TG.We noticed that Shenxiong Putaotang has better effect in total effective rate and angina pectoris attacks, total effective rate and hs-CRP improvement and improvement of TC and TG. It showed a better effect of Shenxiong Putaotang on the improvement of each index, and whether this result is related to the fact that Shenxiong Putaotang consists of a variety of native herbs or to the fact that the specific clinical application of Shenxiong Putaotang is more standardized and mature could be an idea for subsequent exploration. The results of the two-by-two comparison suggest that the eight SMIC are better than CT in terms of total effective rate, and the addition of Danshenchuanxiongqin injection and Danhong injection are better than CT treatment in terms of other evaluation indexes.Our sensitivity analysis showed that the overall results were more robust with 2 weeks as the experimental observation point, and most of the injections were similar to or better than the original results. The addition of Danshenchuanxiongqin injection or Danhong injection was opposite to the original NMA, in addition to the effect of intervention time on the analysis results, it may also be related to the number of included patients, different underlying disease status, etc. It is worth noting that when TC or TG is used as an observation, the results obtained are different from the original results. This led us to note that for lipid-related indicators the results can vary or even appear opposite depending on the time of the intervention; is such a phenomenon only related to the time of onset of SMIC on lipid indicators? Is it possible to follow up this result with a guideline to specify the treatment cycle? It is worth thinking about.When the trial was limited to a case number ≥90, several results differed from the original meta-analysis, especially regarding blood indicators, including hs-CRP, TC, and TG, and Danshenchuanxiongqin injection and Danhong injection performed differently in these aspects than the original results, possibly because of differences in the number of cases included in each injection and the timing of the intervention. It also suggests that the number of cases is significant for the robustness of the experimental results, and the experimental population should be expanded to obtain results close to the real situation.This NMA took eight SMIC in clinical practice as a starting point and analyzed and compared their therapeutic effects on patients with unstable angina pectoris. In recent years, the ideology of TCM has become increasingly influential not only in countries around China, but also in countries on other continents. CMI can serve as a good vehicle to inherit and develop the theory and application of TCM. Facing the unstable angina pectoris discussed in this paper, Chinese medicine treatment has certain advantages. Through the summary of the study in this paper, it conveys that SMIC has important value for the treatment of unstable angina, and it is worth to be further promoted to countries where non-Chinese medicine is commonly used, which can become compatible and complementary to modern medicine, and play a role in broadening clinical diagnosis and treatment decisions and providing ideas for new drug development.The current study provides clues to continue our thinking: in terms of basic research, do different injections do differ in their therapeutic effects, and is it possible to identify the main components that cause the differences? Is the cause of the adverse reaction due to certain ingredients in the injection, the dose used or other reasons? etc. Clinical studies could continue to address these questions: Are there any differences in treatment outcomes between these injections for patients with different severity of disease, and can they be further differentiated for use according to disease? Can it be applied to patients with comorbid other systemic diseases? Can refined evaluation metrics be determined? Etc. All of these issues may become directions for further research at SMIC in the future. The exact therapeutic effect of SMIC deserves more reliable evidence through more in-depth basic research or higher quality clinical studies. We look forward to having more high-quality clinical studies in the future and using NMA to make greater contributions to the research of evidence-based Chinese medicine.There are some limitations in this study. ① The average quality of the literature included in this paper, the small amount of literature corresponding to individual injections and the insufficient data bring unavoidable data bias. Another part of the reason is that some of the included studies have some methodological shortcomings: no specific methods for random sequence generation and allocation hiding implementations are addressed. ② The RCT studies included in this study were of poor quality in terms of random sequence generation, allocation concealment, and blinding of investigators and subjects, which may have contributed to the presence of selection and measurement bias. ③ The evaluation of adverse reactions in the literature is mostly in terms of symptoms, with fewer reports on safety indicators. ④ The severity of the included patients varied between studies and may have influenced the final outcome metrics. ⑤ Most of the literature has a low number of reports on adverse reactions, which may influence the judgment of adverse reactions.In this study, we evaluated eight commonly used SMIC from different outcome metrics and summarized the efficacy of each SMIC in a probabilistic ranking. This NMA showed that Danshenchuanxiongqin injection was the most effective for angina pectoris with a time observation unit of weeks compared to CT. danshentong IIA Huangsuanna injection significantly improved ECG efficacy and, in addition, was the most effective for TG reduction. Shenxiong Putaotang injection was associated with better total effective rate, hs-CRP and TC. Danshenduofensuanyan injection was associated with the efficacy of angina pectoris attacks with days as the time unit of measurement.In a two-by-two comparison, the addition of Danshenchuanxiongqin injection and Danhong injection outperformed CT treatment alone in all study parameters. Using cluster analysis, the addition of Danshentong IIA Huangsuanna injection performed better when both total effective rate and ECG efficacy were considered; when total effective rate and angina pectoris attacks were considered, Danshenchuanxiongqin injection, Danshenduofensuanyan When considering clinical efficacy and angina pectoris, Danshenchuanxiongqin injection and Danshenduofensuanyan injection were recommended; Shenxiong Putaotang injection performed better in terms of total effective rate and improvement of hs-CRP; regarding the improvement of blood lipids, Danshentong IIA Huangsuanna injection performed better.Although current studies have confirmed the unique advantages and efficacy of TCM in the treatment of unstable angina, the standardization, safety, and efficacy of clinical applications still need to be studied in depth. In the future, we expect to strengthen the requirements for trial methods; differentiate the degree of patients’ conditions, unify drug doses and more specific safety indicators; and complete higher quality RCT studies so as to further validate the cardioprotective effects of SMIC in UA patients and make efforts for a more standardized and widespread application of SMIC.


Older adults engage in approximately 7.1 hours/day in leisure activities; however, much of the leisure activity engagement comprises of passive activity engagement . An increasing amount of literature suggests that regular engagement in cognitively and physically stimulating activities, rather than strictly passive activity engagement, is associated with better physical and mental health as well as maintenance of social networks. As the aging population continues to increase and levels and types of activity engagement are shifting across our more diverse older adult populations, it is imperative to understand levels and types of activities older adults are participating in, as well as the psychosocial and contextual factors related to leisure activity engagement. This symposium will include presentations from studies that explore the following: (1) leisure activity interests, engagement, and constraints; and (2) determinants and/or consequences of leisure activity engagement. Specifically, Sardina and colleagues examined daily variability between affect and leisure engagement, and explored potential sociodemographic moderators for these associations. Tian and colleagues explored the association between leisure activities and modes of transportation. Tian and colleagues explored leisure activity engagement with prospective daily diary methods, and examined associations between leisure activities and physical health. Janke and colleagues explored associations between facilitators, constraints, and constraint negotiation and self-reported physical activity levels for older adults with arthritis.


The domestic sex trafficking of minors is occurring across Canada and the UnitedStates. Understanding the routes into sex trafficking, including the waytraffickers target, recruit and enmesh youth in the sex trade is invaluableinformation for service providers and law makers developing prevention andintervention initiatives. This review synthesized research on the exploitationprocesses and tactics employed by traffickers in the sex trafficking of domesticminors in Canada and the US. The authors comprehensively and systematicallysearched five electronic databases and obtained additional publications and greyliterature through a backward search of the references cited in articlesreviewed for inclusion.  Inclusionary criteria included: Studies published inthe English language between January 1990 and June 2020 containing originalresearch with quantitative or qualitative data on the recruitment or pathwaysinto sex trafficking for minors trafficked within the US and Canada. The searchyielded 23 eligible studies. The synthesis of the studies in the reviewconverged on the notion of sexual exploitation occurring on a continuumcomprising of three components; the recruitment context, entrapment strategiesutilized by traffickers, and enmeshment tactics used to prolong exploitation.Findings highlight the significant physical, psychological and emotional hurdlesfaced by youth victims of sex trafficking and point to the importance ofcomprehensive and holistic approaches to prevention and interventionpractices. Human trafficking is a global problem that has garnered significant international andnational attention over the past 2 decades. In 2000, 140 countries signed onto thePalermo protocol agreeing that human trafficking is a significant human rightsviolation and a criminal offense that requires prevention, the protection ofvulnerable populations, and the prosecution of violators of the protocol. In NorthAmerica, both Canada and the United States signed this protocol and have sincepassed legislation and policies to combat human trafficking. Sex trafficking becamecriminalized in Canada in 2005 when human trafficking entered the criminal codeunder section 279.01 and in the United States in 2000 with the passing of theTrafficking Victims Protection Act (TVPA). Sex trafficking is one of the most commonforms of human trafficking consisting of the recruitment and exploitation of anindividual through the use of threats, force, coercion, deception, or abuse of powerfor the purpose of a commercial sex act . A commeMinors (under the age of 18) are overrepresented among victims of sextrafficking, with the majority of victims recruited between 12 and 14 years ofage . Given tOn the basis of age, youth from all sectors of society are at risk forrecruitment into sex trafficking. Developmental vulnerabilities such as identityformation, the need for belonging, desire for autonomy, desire for romanticrelationships, and evolving problem-solving skills make them easily exploitableby traffickers who appeal to these vulnerabilities . Based oSimply being a girl places a youth at an elevated risk status relative to boys, with 98Based on the differential needs and situations of youth, the recruitment andexploitation of underage populations are thought to differ from adultpopulations . While iThere have been few attempts to estimate the prevalence of the STM in NorthAmerica; however, available statistics are often “guesstimates” rather thanreliable rates .AvailabWhile STM defies geographic borders, a country’s economic environment, geographicpositioning, laws, employment rates, per capita income, and historical eventsshape the industry and individual risk for recruitment . Asa reThe domestic STM is of major concern within Canada and the United States .While byouth for commercial sexual exploitation.Recent research has also shifted to focusing on domestic trafficking rather thaninternational trafficking from other countries, expanding our understanding ofSTM in North America. Understanding the process of recruitment for youth intosex trafficking is invaluable information for service providers and lawmakersdeveloping prevention and intervention initiatives. The goal of this study wasto systematically synthesize the research on the recruitment process employed bytraffickers in the sex trafficking of domestic minors in the United States andCanada. Based on this synthesis, an overarching framework that explains thebroader process of recruitment of domestic minors into sex trafficking isproposed.Given emergent issues of domestic STM in North America, federal and localgovernments wish to develop evidence-based approaches to combat sex traffickingand protect domestic youth. For example, a provincial government in Canadainvested 307 million dollars toward antihuman trafficking initiatives, and theAmerican federal government awarded over 100 million dollars for humantrafficking initiatives and survivor supports. Research on STM has increasedover the last decade, including the specific ways in which traffickers target,recruit, and exploit This systematic review included articles that examine the recruitment process ofdomestic youth into sex trafficking within the American and Canadian context.Inclusion criteria were predetermined and documented in a protocol guiding thereview process. The protocol was developed and agreed upon by both authors. To beeligible for inclusion in the present review, studies were required to be originalresearch studies with quantitative and/or qualitative data and analysis, publishedin English between January 1990 and June 1, 2020. Articles published from 1990onward were selected as these articles would be reflective of the changes thatensued with the international agreement and signing of the United Nations Conventionon the Rights of the Child on the definition of the sexual exploitation of children.The selected period also represents the time frame when the majority of research onsex trafficking were published. Based on the geographical, social, and politicalsimilarities that impact criminal patterns of sex trafficking, the current studyincluded studies focusing on minors trafficked within the United States and Canada.Studies were required to include data pertaining specifically to the recruitment andgrooming of minors (youth under the age of 18), as previous research has highlightedthat the recruitment of adults is different from minors . StudiesA comprehensive search was conducted in five electronic databases: PsycINFO,Sociological Abstracts, Social Services Abstracts, Applied Social Sciences Indexand Abstracts, and Nursing and Allied Health Database. Alternate terms for sextrafficking were used in order to capture articles using delinquency language and consensual or transactional language . Likewise, several terms were used to capture the concepts oftrafficker recruitment and grooming strategies. Boolean operators “AND” and “OR”were used to combine sex trafficking, recruitment, and age terms. The searchstrategy comprised of the following key words:  AND  AND (“youngperson” OR juvenile OR “young people” OR minor* OR child* OR teen* OR adolescen*OR youth* OR “under 18” OR “at risk populations” OR “predelinquent youth”).Additional publications and gray literature were identified through a backwardsearch of the references cited in articles reviewed for inclusion.The initial screening of titles and abstracts was completed by the first author.Articles were excluded during this phase if obviously ineligible. Full-textscreening was completed by two reviewers independently. Both reviewers screenedthe full text of articles retrieved to assess eligibility. Reviewer decisionswere compared, and discrepancies were resolved through discussion. A thirdreviewer was included when consensus was not reached.n = 567). The initialtitle and abstract screen eliminated 953 articles; 180 articles were retrievedfor full-text screening, and an additional 23 articles from the gray literaturewere included for the full-text screen. After the two reviewers independentlyreviewed the remaining 203 articles, 180 were excluded due to not meeting one ormore of the following eligibility criteria: did not speak about sex trafficking or recruitment andentrapment strategies (n = 117), adult and minor victim sampleswere grouped in the study (n = 9), study grouped internationaland domestic trafficking samples (n = 21), the study sampleswere not Canadian or American (n = 8), or were duplicatereports (n = 2). Book and movie reviews, opinion pieces,systematic and scoping reviews, and all other study designs that did not involvethe analysis of primary or secondary data were excluded (n =23). While many studies were excluded for failing to meet several eligibilitycriteria , if thearticle did not study sex trafficking or recruitment and entrapment strategies,it was excluded primarily on these criteria alone. In total, 23 studies met ourinclusion criteria , and theremaining studies were published in 2002 (n = 1), 2009(n = 2), and 2010 (n = 1). The 23 studiesincluded data from individuals trafficked as minors (n = 18),stakeholders (n = 7), and active or previously self-identifiedpimps (n = 2), with some studies using data from two of theaforementioned three categories. Stakeholders included government agency, lawenforcement, nongovernmental organization (NGO) representatives, and adolescentswith knowledge about the domestic STM .Eighteen peer-reviewed articles, two government reports, and three dissertationsmet inclusion criteria. Twenty of twenty-three studies utilized Americansamples, and three used Canadian samples. Thirteen studies used qualitativemethods, nine of which involved retrospective interviewing. Seven articlesinvolved mixed method designs, and three utilized secondary data analysis. Seen = 13 studies), Caucasian or White (n= 13), Hispanic (n = 7), Asian American (n =2), South Asian (n = 1), Indigenous or Native(n = 3), mixed race (n = 8), and other (n= 1). Eleven articles reported on the gender of victims. Samples werepredominantly all female (seven of 11 studies), with only four studies includingmale or transgendered participants. Only two articles provided data on sexualorientation.Eighteen of the 23 studies include demographic information on victims orsurvivors of sex trafficking. Overall, studies included African American orBlack  who initiallyintroduce the minor into the sex trade. Traffickers or pimps are describedto either take on the recruiting role themselves or use recruiters to seekout vulnerable youth .WilliamSeveral different types of relationships between the trafficker/recruiter andyouth are cited by the reviewed articles, the most commonly citedrelationship being a romantic one as cited among 18 of the 24 reviewedstudies . Three sSix studies reference the significance of sex-trafficked youth coming fromimpoverished households with unmet financial needs . In addin = 7) than other recruitment locations among all trafficker entrapment methods isthe “boyfriend” scheme, also referred to as “romancing” or “Romeo pimping”.SeveralNumerous articles (10 of 23 studies) reference “befriending” tactics utilizedin the entrapment of youth into sex trafficking . Two stuLess commonly referenced are biological family or foster-parent traffickers(five of 24 studies) who utilize their position of authority in entrappingthe youth in sex trafficking . TwostuAccording to Fifteen of the reviewed articles make reference to control factors wherebyyouth feels unable to leave their exploitive situation due to feeling fear,shame, or like they are “owned” by their trafficker . Marcus Eight studies make reference to dependency factors that serve as barriers toyouth exiting the sex trade and leaving their trafficker  with goals to build partnerships between sectors, coordinate care,and include improve community capacity and responses to sex trafficking. However,effective survivor interventions do not only require capacity for service; rather, adeep understanding of the psychological complexity of sex trafficking enmeshment canallow service providers to approach youth with empathy in their efforts to keep themsafe and prevent reentry. Indeed, the present review offers this understanding,highlighting the barriers to exiting in financial, emotional, and psychologicaldomains.This review was conducted systematically and rigorously and followed the PreferredReporting Items for Systematic Reviews and Meta-Analyses guidelines for systematicreviews; however, there are limitations to be considered. First, while the authorsof this review conducted an extensive, multistrategy, high-sensitivity search toattain all possible studies, it is possible that not all available studies werefound and included in this review due to terms not used in our search or databasesunexplored. Second, during the review process, the authors emailed the authors ofstudies where the sample was unclear ; however, if noresponse was attained, those articles were excluded from the present review. Third,the review only included studies published in the English language due to a lack oftranslation resources.This review presents the first synthesis of research on the recruitment process ofdomestic North American youth for sex trafficking. Importantly, the review fills asignificant gap in the literature by identifying a framework for the exploitationcontinuum that involves a series of entrapment and enmeshment tactics that intersectwith youths’ vulnerabilities and circumstances. Information derived from the studiesdraws attention to the vast and brutal experiences of victimized youth and thecircumstances, making it challenging for youth to leave their trafficker. This studyshould serve as a call to action for governments, agencies, NGOs, and frontlineworkers to use empirical evidence to support their programs, policies, andpractices. Illuminated by this study are the large hurdles faced by victimized youthto exit the sex trade and the multifaceted needs of survivors from the most basic,such as shelter, money, food, and clothing, to more complex psychological, medical,and emotional needs. Indeed, the unmet needs of survivors were the circumstancesleaving them vulnerable to traffickers’ recruitment tactics in the first place.Therefore, policies and postexit programs need to support youth systematically andholistically in order to truly support their exiting.An important backdrop to the issue of STM in North America is the shift in discoursefrom sex-trafficked youth as criminals  tosurvivors/victims of a crime which followed the criminalization of sex traffickingand federal consent laws between 2000 and 2008 in Canada and the United States. Witha change in legislation came a shift in the way policy makers, law enforcement, andresearchers began to view victimized youth as needing protection rather thanpunishment. While beyond the scope of the current article, it is interesting to notea clear acceleration of research on the recruitment and enmeshment of minorsinvolved in sex trafficking following the legislative changes promoting thedecriminalization of victims. In fact, all articles included in the present reviewwere published 2002 and later, after the passing of the TVPA in 2000. Futureresearch should further examine the political and practical implications of thisshift in discourse.While research on risk and vulnerability have highlighted the enhanced risk forLGBTQIA+ youth for recruitment into sex trafficking e.g., , the revGiven the significance of online platforms for recruitment, preventioninitiatives should take place online.Prevention initiatives should involve knowledge dissemination with youth,families, school staff, law enforcement, child welfare agencies, andhomeless shelters about pathways into sex trafficking, internet safety,and red flags.Youth education on unhealthy and exploitive romantic relationships shouldbe an important piece of academic curriculum in early adolescence.Interagency communication and collaboration is necessary to ensuresurvivors receive coordinated services.Policy attention is needed in efforts to provide victimized youth withfinancial stability, housing, childcare, and mental health support.Regional law enforcement agencies should develop specific humantrafficking divisions that are well educated and equipped to support theextraction of youth from sex trafficking.Policy attention and funding are needed to support the development oftrauma-informed aftercare for youth survivors of sex trafficking.We call on researchers to study the pathways to exploitation andexperiences of LGBTQIA+ youth involved in sex trafficking.Future studies need to further delineate the route of exploitation byfamilial traffickers and identify similarities and differences in therecruitment of adults and minors as well as domestic and internationalvictims.


An ensemble of 29 wheat crop models simulates seasonal wheat growth well under locally recommended sowing conditions, but needs improvements to capture the yield response to early sowing, especially under high sowing density. Crop multi-model ensembles (MME) have proven to be effective in increasing the accuracy of simulations in modelling experiments. However, the ability of MME to capture crop responses to changes in sowing dates and densities has not yet been investigated. These management interventions are some of the main levers for adapting cropping systems to climate change. Here, we explore the performance of a MME of 29 wheat crop models to predict the effect of changing sowing dates and rates on yield and yield components, on two sites located in a high-yielding environment in New Zealand. The experiment was conducted for 6 years and provided 50 combinations of sowing date, sowing density and growing season. We show that the MME simulates seasonal growth of wheat well under standard sowing conditions, but fails under early sowing and high sowing rates. The comparison between observed and simulated in-season fraction of intercepted photosynthetically active radiation (FIPAR) for early sown wheat shows that the MME does not capture the decrease of crop above ground biomass during winter months due to senescence. Models need to better account for tiller competition for light, nutrients, and water during vegetative growth, and early tiller senescence and tiller mortality, which are exacerbated by early sowing, high sowing densities, and warmer winter temperatures. Wheat is the most traded crop commodity at the global scale and provides more than 20% of calories and protein in human diets . For decAdapting sowing conditions to climate change requires an understanding of how crop growth and yield development are affected by sowing date and density. Increased temperature shortens the growing season of wheat and shifts optimal sowing dates . The abiProcess-based crop growth models were developed to study the multiple interacting factors affecting crop growth, development, and yield formation under field conditions  are used to simulate the effect of climate variability and change on cropping systems  and Wakanui  in the Canterbury Region of the South Island of New Zealand . ‘Wakanu−2, while at Wakanui, only the locally recommended sowing density was used (150 seeds m−2).In the Canterbury region of New Zealand, winter wheat is usually sown between early April and mid-May, with some farmers sowing in late March in recent years . At LeesThe objective of the Leeston trials was to increase wheat production in a high yielding environment without water and nitrogen stress. The trials investigated the complex interaction between tiller development, ear population, and grain yield, with the goal of finding the optimal sowing density for an early sowing date. The experiments consisted of a split-plot design with sowing dates as the main plots and sowing rates as the subplots, with four replicates. The Wakanui trials used a single sowing density and investigated different cultivars, sowing dates, and the use of plant growth regulators (2015–2016) or defoliation (2016–2017 and 2017–2018), at different sowing dates. The experiments were designed as randomized blocks with sowing dates as the main plots and cultivar by plant growth regulation or defoliation as the subplots, replicated four times. In our study, we considered only the data of the ‘Wakanui’ cultivar grown under standard growth regulation and without defoliation.−1 and irrigation up to 210 mm of water.The field management was adapted each year to obtain ideal growth conditions: crops received a yearly N fertilization of between 122 and 284 kg N haIndividual plots (12 m×1.65 m) were drilled into a top worked seed bed. At both sites, the soil type was Temuka clay loam (Fluventic Endoaquents in the USDA classification), a deep, low permeability soil with high plant available water capacity  participated in this study and contributed to the MME output  Wheat group  anthesis (Zadoks 65) and physiological maturity (Zadoks 87). In addition, the grain, stem, chaff, and leaf dry weight at maturity, ear number and grain number, grain unit dry weight, and harvest index were provided. Also, time series of measurements of total above ground dry biomass, leaf number per stem, and LAI were provided, as well as NDVI and FIPAR.After calibration, simulations were conducted by each model for all combinations of sowing date, sowing density, and growing season , for a tGY) to the mean , was quantified with the coefficient of variation (CV), which is the ratio of the standard deviation  and the simulated (S) values and is given as:The root mean square error (RMSE) is the standard deviation of the residuals and is calculated as the squared root of the mean squared difference between the observed (The model accuracy was quantified using the relative RMSE (RRMSE), expressed as a percentage, which is useful to compare outputs with different units. RRMSE is obtained by dividing RMSE by the mean of the observations  was performed to test if year, sowing date, and sowing rate had significant main or interaction effects on grain yield. We considered only the Leeston trials, where both sowing date and rate were tested . The anaP>0.05) but the ANOVA showed a significant variation of measured grain yield with year (P<0.001) and sowing date (P<0.01). The sowing density had no significant effect on measured grain yield , the MME performance was good for simulating the in-season development of the total above ground biomass, LAI and FIPAR, as well as the final grain yield measured in the field  to excellent (RRMSE of 5.75 for harvest index) ; Fig. 2.The simulated interannual variability of grain yield increased with increasing RRMSE , meaning−2 in the simulations, while in the measurements we observed a slight decrease between 150 and 200 seeds m−2. Conversely, average grain dry mass and harvest index showed little change with sowing density , under earlier sowing the final total above ground biomass and grain yield increased for both measurements and MME simulations , the effect of sowing date on final above ground biomass and grain yield initially showed a decrease between February and early March sowing and then an increase  the decrease of NDVI and FIPAR during winter was also observed for March sowings, highlighting that the decrease could be observed in later sowings , final total above ground biomass and grain yield increased with earlier sowing (−2), early sowing increased tillering, and thus increased competition and tiller mortality  simulated a decrease in FIPAR after the rapid increase with the February sowing in 2015 and only two  with the February sowing in 2014, while none of the models simulated the decrease measured with the March sowing in 2014. Interestingly, the models that were more successful in simulating the FIPAR response represent different modelling approaches, SQ being a very sophisticated model that represents tillering, grain number, and size explicitly, while HE is based on a one-leaf and one-grain approach. Furthermore, the models that captured the decrease in FIPAR did not show better performance in simulating yield . This shThe comparison of the MME and experimental data highlighted that the MME was not able to correctly represent the response of yield to increasing sowing rate at early sowing dates and the response to sowing date at the currently recommended sowing rate. Some of the models showed better performance than the MME in predicting grain yield at an early sowing date, but none was more accurate than the MME at a low sowing rate .Although previous studies have shown that MMEs were effective in reducing uncertainty in predicting yield .Fig. S2. Measured normalized difference vegetation index, measured and simulated fraction of intercepted PAR, and total above ground biomass and grain yield versus days after sowing for wheat crops sown on 20 February, 10 March, 26 March, and 23 April 2014 at the locally recommended density (150 seeds mTable S1. List of the 29 wheat crop models used in the AgMIP Wheat Phase 4 studyTable S2. Statistical evaluation of model error and interannual variability of measured and simulated grain yield, considering wheat sown at the locally recommended sowing date and plant density.Table S3. Statistical evaluation of model error in grain yield, considering wheat sown at the locally recommended plant density vs low sowing density.Table S4. Statistical evaluation of model error in grain yield, considering wheat sown at the locally recommended date versus early sowing.Protocol S1. Crop model performance and evaluation metrics.erac221_suppl_Supplementary_MaterialsClick here for additional data file.


Emergency medicine (EM) is at an inflection point: The specialty’s response to the projected workforce surplus will shape the specialty for decades. Emergency physician (EP) educators, especially residency and clerkship leadership, have a duty to address the pipeline into EM, specifically the marked growth of EM residency positions via program expansion and creation. The pipeline problem is complex: How does the specialty slow or reverse the growth of EM residency positions while so many emergency departments (ED) and EPs could provide exceptional education if given the opportunity?The answers will be just as complex. They will require open, honest, and respectful discussion; and they will require nuance, introspection, and a focus on the greater good. Both the search for answers and the potential solutions will be uncomfortable:Established EM residency programs need to consider harms of expansion and potential benefits of contraction;Planned residencies need to weigh their impact on the greater EM community given the predicted oversaturated job market; andProfessional organizations need to directly address the rapid expansion of EM residency positions.If educators, clerkships, residency programs, and professional organizations take urgent and appropriately aggressive actions, potentially drastic workforce sequelae may be averted.The workforce numbers appear grim. Projections suggest an over-supply of 7,845 EPs by 2030.3The number of EM residency programs increased from 222 to 273 (23%) between 2014–2021 after accounting for the SAS.4Of the 42 EM residency programs currently on initial ACGME accreditation, nearly a quarter (10) are accredited “with warning”; for comparison, only six of 236 programs on continued accreditation are accredited “with warning.”5The proportion of EM education delivered at for-profit hospitals has also changed considerably. Before 2016, only 4% of new training sites were located at for-profit hospitals, but from 2016 to 2021, 37% of new sites were located at for-profit hospitals.2The data from the 2022 EM match was not much better. Of the 277 EM residency programs participating in the Match, 69 did not fill (25%), and of the 2,921 EM residency positions offered, 219 did not fill (7.5%). For comparison, there were 14 unfilled EM positions in the 2021 Match (0.5%).6While EM programs that filled in 2021 ranked an average of 5.8 applicants per position, this year EM programs that filled ranked an average of 8.8 applicants per position. The only specialties that ranked more applicants per position in order to fill were internal medicine and pediatrics. This year only 1.1% of seniors graduating from allopathic medical schools applying solely to EM went unmatched, and the only specialties with lower unmatched rates were pediatrics and child neurology. Additionally, 25 EM residency programs did not fill more than half their quota of spots in 2022; three programs filled only one spot; and two programs did not fill any spots.6Some EM educators believe that market forces will bring the supply side of the EM workforce back into balance, suggesting that the overall number of EM residency positions offered will decrease because of poor Match results.Hospitals and EDs may have financial incentives to develop new EM residency positions, especially when creating training programs at hospitals without established graduate medical education (GME) programs. In 2018, Medicare paid teaching hospitals an average of $171,000 per funded resident.9While identifying the multitude of factors underlying the rapid growth of EM residency positions is vitally important to developing and implementing solutions, attributing blame with a goal of punishment or retaliation prevents collaboration and removes the nuance necessary to find answers.Potential solutions may not satisfy all stakeholders. Dr. Gillian Schmitz, president of the American College of Emergency Physicians (ACEP), said: “We need to start having some difficult conversations on how we control [residency] growth in a responsible manner and put the needs of the specialty ahead of any individual residency program’s best interests.”Finding and implementing solutions will take thoughtful and potentially aggressive action by EM educators, residency programs, clerkships, and national organizations.While EM faculty may feel sheltered from workforce issues because of a modicum of job security and some level of insulation provided by the academic orb, EM educators must still work to understand the problem, its scope, and potential solutions. Faculty should feel empowered to create the space and time necessary to respectfully discuss the problem and the uncertainty and angst surrounding it, both with colleagues and with learners.Forums like the Council of Residency Directors in EM (CORD) list-serv or the Clerkship Directors in EM (CDEM) list-serv may be great venues for advancing the discussions, proposing potential solutions, and pushing one another to think outside the box. The power of the “CORD collective” has often been cheered for addressing challenges together. Additionally, EM educators should not shun potential solutions, even if they disagree.Given current workforce projections, it is important for residency program leaders to be introspective regarding the short- and long-term plans for their residencies. It may be useful for leaders at established or planned programs to answer the key questions listed in Clerkship directors and EM specialty advisors should provide robust education to prospective EM residency applicants regarding the workforce and the 2022 Match, and they should help students craft respectful but probing questions for residency interviews to tease out a variety of issues, including the potential influence of business interests on resident education.Professional organizations have and will continue to play a significant role in EM’s response to the predicted workforce crisis because they wield powers that individuals, residency programs, and departments do not have. These organizations can elevate the standards required of EM residency programs, formulate consensus statements, research best practices, and even lobby for potential solutions.A working group with representatives from CORD, ACEP, American Academy of Emergency Medicine (AAEM), the Society for Academic Emergency Medicine (SAEM), American College of Osteopathic Emergency Physicians, Association of Academic Chairs of Emergency Medicine (AACEM), Emergency Medicine Residents’ Association, AAEM Resident and Student Association, and SAEM Residents and Medical Students convened to strategize solutions to the predicted oversupply of EPs.In March, these organizations published a joint statement addressing the 2022 Match, highlighting the growth in EM residency positions, the utility of continuing to study workforce dynamics, and the importance of working together toward solutions.Emergency medicine organizations could even more directly address the supply side of the workforce by developing guidelines aimed at reducing program creation and complement increases, except in exceptional circumstances. While these guidelines would not be enforceable, they would still tighten the reins on workforce expansion; for example, organizations ignoring such guidelines would have to share their reasoning when interviewing prospective residents. CORD appears to be in a bind when it comes to making statements or guidelines regarding the Match and the EM workforce. To some extent, both SAEM and AACEM find themselves in similar positions. Although not explicitly stated in its mission, vision, and purpose statements,In addition to making guidelines and advocating to strengthen residency standards, EM professional organizations can address the supply side of the workforce in a variety of other ways as well. Educators in EM have the opportunity to help guide the specialty through an inevitable inflection point. Proactively addressing the supply side of the EM workforce risks creating near-term pain points, including a temporary decrease in EM residency applicants. Simultaneously, however, having uncomfortable discussions, exploring potential solutions, and making difficult decisions now could strengthen and fortify the specialty for decades.