The product presentation videos on E-commerce platforms have a significant influence on consumers' purchase decisions, and enterprises have focused on choosing the type of product presentation videos. Based on the resource matching theory, mental imagery theory and cue utilization theory, this study investigated the influence of product presentation videos type (product appearance video vs. product usage video) on consumers' purchase intention and the moderating effect of product rating (low vs. high). Through three pre-experiments and two formal experiments, the results showed that the product usage video has a stronger effect on consumers' purchase intention more than the product appearance video, which is mediated by perceived diagnosticity and mental imagery. In addition, product rating moderated the influence of product presentation videos type on consumers' purchase intention. The product usage video would improve consumers' purchase intention more than the product appearance video when the product rating is high; however, there is no significant difference in the impact of two types of videos on consumers' purchase intention when the product rating is low. This study supplements the research on product presentation videos and provides a reference for online retailers to select effective product presentation videos. With the rapid development of E-commerce, people are increasingly choosing to shop online. According to the report released by E-marketer , it is eHowever, existing research on product presentation videos is not enough. Prior studies mainly investigated the influence of product presentation videos on product sales  were selected as candidate products. These 6 products were: power strips, pillows, backpacks, electric kettles, smart bracelets, and canvas shoes. A total of 81 participants were recruited for Pre-experiment 1 through the “Wenjuanxing” platform, which is a professional questionnaire advisory body in China. At first, the participants were told that the purpose of this experiment was to classify products. Then, the participants were asked to fill in demographic information. Finally, the participants were asked to score 6 products respectively  based on the definitions of search products and experience products. The lower the score was, the more it indicated that the participant considered this product to be search product. The higher the score was, the more it indicated that the participant considered this product to be an experience product.t-test showed that the average scores of 6 products were consistent with expectation. Specifically, the average scores of canvas shoes , backpacks , and pillows  were higher than the Median 4, indicating that the participants considered them to be experience products. In addition, the average scores of electric kettles , power strips , and smart bracelets  were lower than the Median 4, indicating that the participants considered them to be search products. Among them, the average score of canvas shoes  was higher than that of the other two experience products, and the average score of electric kettles  was lower than that of the other two search products. Therefore, canvas shoes were selected as the experience products, and electric kettles were selected as the search products, which were used for Pre-experiment 2 and formal experiments.The questionnaires of 81 participants  were all valid. The single-samples The purpose of Pre-experiment 2 was the manipulation check of product presentation videos' type, and to determine whether the two types of product presentation videos could be used for Experiment 1 and Experiment 2. According to the experience products and search products selected through Pre-experiment 1, we filmed the appearance video of electric kettles, the usage video of electric kettles, the appearance video of canvas shoes, and the usage video of canvas shoes. The duration of each video was 20 s. Specifically, the appearance video of electric kettles mainly contained the appearance attribute information, such as color, size, and design. The usage video of electric kettles mainly presented the steps and procedure of using electric kettles to boil water by a model. The appearance video of canvas shoes mainly contained the appearance attribute information, such as color, size, and style. The usage video of canvas shoes mainly showed the results of wearing canvas shoes by models. A total of 95 participants were recruited for Pre-experiment 2 through the “Wenjuanxing” platform. At first, the participants were told that the purpose of this experiment was to classify product presentation videos. Then, the participants were asked to fill in demographic information and the item about whether they had watched product videos online before. Finally, the participants were asked to score 4 videos respectively  based on the definitions of appearance video and usage video. The lower the score was, the more it indicated that the participant considered this video to belong to the product appearance video. The higher the score was, the more it indicated that the participant considered this video to belong to the product usage video.t-test. The result revealed that the average score of electric kettles usage video was higher than that of electric kettles' appearance video . In addition, the average score of canvas shoes usage video was higher than that of canvas shoes' appearance video . The manipulation of product presentation videos' type was supported. Therefore, the electric kettles' appearance video and electric kettles' usage video were used for Experiment 1. The canvas shoes' appearance video and canvas shoes' usage video were used for Experiment 2.The questionnaires of 95 participants  were all valid. The manipulation of product presentation videos' type was examined by independent-samples This study used an experimental method. Single factor (videos' type: appearance video vs. usage video) between-group designs were implemented. Two videos that passed the manipulation check through Pre-experiment 2 were adopted, namely, the electric kettles' appearance video and the electric kettles' usage video. The two videos were the same in other aspects  except information content. In addition, brand information was removed to eliminate the influence of product brand. Perceived diagnosticity was measured with three items based on the research of Kempf and Smith , Jiang aTmall.com. After searching for “electric kettles,” you enter the category overview page. Then, you click an electric kettle on the category overview page to enter the product home page. You see the following product video on the product home page. Please complete the items after watching the video.” The third part was the measurement scales of related variables. In addition, the measurement item about product presentation video types was set to test the manipulation effectiveness of this experiment. The fourth part contained demographic information, such as the gender, education, and age of the participants.The “Wenjuanxing” platform was used to design experimental questionnaires and generate links. The participants were also recruited through the “Wenjuanxing” platform. The experimental questionnaire consisted of four parts. The first part told the participants that this experiment was about investigating consumers' behavior. The second part described the experimental scenario, specifically “Imagine that you are shopping on an E-commerce platform like The participants were randomly assigned to one of the two experimental groups (the appearance video group vs. the usage video group). At first, the participants imagined that they were on the product home page of an E-commerce platform by reading descriptions. Then, they would see the product presentation videos corresponding to their experimental groups. Finally, the participants would complete the relevant scales and demographic information. A total of 163 participants participated in the experiment, and 144 participants completed the experiment. The demographic information of participants is shown in t-test. The result showed that the average score of electric kettles' usage video was higher than that of electric kettles' appearance video . The manipulation of product presentation videos' type was supported.The manipulation of product presentation videos' type was examined by independent-samples F = 10.78, p < 0.01], where Mappearancevideo = 4.49, Musagevideo = 5.43. It was indicated that the product usage video improves consumers' purchase intention more than the product appearance video. Therefore, H1 was verified.The test was performed using ANOVAs, and the results are shown in Z = 8.61, p < 0.01), which is consistent with the hypothesis that perceived diagnosticity and mental imagery mediate the effect of product presentation videos' type on consumers' purchase intention. We then examined the mediators individually, and the result showed that a 95% confidence interval for the indirect path through perceived diagnosticity was significant, β = 0.1069 , indicating that the mediation effect of perceived diagnosticity between product presentation videos' type and consumers' purchase intention was significant. Therefore, H2 was supported. In addition, a 95% confidence interval for the indirect path through mental imagery was significant, β = 0.2685 , indicating that the mediation effect of mental imagery between product presentation videos' type and consumers' purchase intention was significant. Therefore, H3 was supported. To determine the relative value of the two mediators, we conducted bias-corrected comparisons between mediators. The 95% confidence intervals for contrasts of perceived diagnosticity with mental imagery did not include zero, indicating that mental imagery was a significantly stronger mediator than perceived diagnosticity.The bootstrapping method was used to test the mediating effect of perceived diagnosticity and mental imagery Hayes, . The anaStudy 2 aimed to provide support for H4 that product rating moderates the effect of product presentation videos' type on consumers' purchase intention.The purpose of Pre-experiment 3 was the manipulation check of product rating, and to determine whether the two types of product rating could be used for Experiment 2. After observing the distribution of product rating on major E-commerce platforms and referring to Chu et al. , the lowt-test. The result showed that the average score of the four-star rating was higher than that of the two-star rating . The manipulation of the product rating was supported. Therefore, the two-star rating was used as the low product rating, and the four-star product rating was used as high the product rating for Experiment 2.The questionnaires of 58 participants  were all valid. The manipulation of product rating was examined by independent-samples This study used an experimental method. About 2 (videos' type: appearance video vs. usage video)- × -2 (product rating: low vs. high) between-group designs were implemented. Two videos that passed the manipulation check through Pre-experiment 2 were adopted, namely, canvas shoes' appearance video and canvas shoes' usage video. The two videos were the same in other aspects  except information content. In addition, brand information was removed to eliminate the influence of product brand. Perceived diagnosticity was measured with three items based on the research of Kempf and Smith , Jiang aTmall.com. After searching for “canvas shoes,” you enter the category overview page. Then, you click canvas shoes on the category overview page to enter the product home page. You see the following product video on the product home page.” The third part was also a description, specifically “After watching the product video, you further view the product rating, and find that the product rating is two/four stars, please complete the flowing items.” The fourth part was the measurement scales of related variables. In addition, the measurement items about product presentation video types and product rating were set to test the manipulation effectiveness of this experiment. The last part contained demographic information, such as the gender, education, and age of the participants.The “Wenjuanxing” platform was used to design experimental questionnaires and generate links. The participants were also recruited through the “Wenjuanxing” platform. The experimental questionnaire consisted of five parts. The first part told the participants that this experiment was about investigating consumers' behavior. The second part described the experimental scenario, specifically “Imagine that you are shopping on an E-commerce platform like The participants were randomly assigned to one of the four experimental groups. At first, the participants imagined that they were on the product home page of an E-commerce platform by reading descriptions. Then, they would see the product presentation videos corresponding to their experimental groups. After that, they would be informed of the product rating. Finally, the participants would complete the same scales in Experiment 1 and demographic information. A total of 202 participants participated in the experiment, and 188 participants completed the experiment. The demographic information of the participants is shown in t-test. The result showed that the average score of canvas shoes' usage video was higher than that of canvas shoes' appearance video . The manipulation of product presentation videos' type was supported.The manipulation of product presentation videos' type was examined by independent-samples t-test. The result showed that the average score of the four-star rating was higher than that of the two-star rating . The manipulation of the product rating was also supported.The manipulation of the product rating was also examined by independent-samples F = 13.81, p < 0.01], where Mappearancevideo = 4.43, Musagevideo = 5.84. It was indicated that product usage videos improve consumers' purchase intention more than product appearance videos. Therefore, H1 was verified again.The test was performed using ANOVAs, and the results are shown in Z = 9.38, p < 0.01), which is consistent with the hypothesis that perceived diagnosticity and mental imagery mediate the effect of product presentation videos' type on consumers' purchase intention. We then examined the mediators individually, and the result showed that a 95% confidence interval for the indirect path through perceived diagnosticity was significant, β = 0.1272 , indicating that the mediation effect of perceived diagnosticity between product presentation videos' type and consumers' purchase intention was significant. Therefore, H2 was supported again. In addition, a 95% confidence interval for the indirect path through mental imagery was significant, β = 0.3047 , indicating that the mediation effect of mental imagery between product presentation videos' type and consumers' purchase intention was significant. Therefore, H3 was supported again. To determine the relative value of the two mediators, we conducted bias-corrected comparisons between mediators. The 95% confidence intervals for contrasts of perceived diagnosticity with mental imagery did not include zero, indicating that mental imagery was a significantly stronger mediator than perceived diagnosticity.The bootstrapping method was used to test the mediating effect of perceived diagnosticity and mental imagery Hayes, . In thisF = 12.62, p < 0.01], which indicates that the product rating (low vs. high) moderated the effect of product presentation videos' type on consumers' purchase intention. Furthermore, simple effect analysis showed that the purchase intention of the participants who were assigned to the usage video group (Musagevideo = 5.61) was significantly higher than that of the participants who were assigned to the appearance video group (Mappearancevideo = 4.52) in the condition of the high product rating , as shown in appearancevideo = 3.16,Musagevideo = 3.25, F = 2.01, p >0.1]. Therefore, H4 was supported.With purchase intention as the dependent variable, videos' type and product rating as the independent variables, a 2 (videos' type: appearance video vs. usage video)- × -2 (product rating: low vs. high) ANOVAs revealed a significant interaction effect of videos' type with the product rating [Based on the resource matching theory, mental imagery theory, and cue utilization theory, this study investigated the influence of product presentation videos' type (appearance video vs. usage video) on consumers' purchase intention and examined the moderating effect of the product rating (low vs. high). Moreover, the mediating role of perceived diagnosticity and mental imagery was also verified.There are three findings in this study: First, the product presentation videos' type has a significant effect on consumers' purchase intention. The product usage video improves consumers' purchase intention more than the product appearance video for both search products and experience products. Second, perceived diagnosticity and mental imagery mediate the influence of product presentation videos' type on consumers' purchase intention. The product usage video improves consumers' perceived diagnosticity and mental imagery more than the product appearance video, resulting in higher purchase intention. Third, product rating moderates the influence of product presentation videos' type on consumers' purchase intention. The product usage video improves consumers' purchase intention more than the product appearance video when the product rating is high; however, there is no significant difference in the impact of two types of videos on consumers' purchase intention when the product rating is low.This research has contributed to product presentation videos, product rating, and the resource matching theory. First, this study enriches the classification of product presentation videos. Previous studies mainly classified product presentation videos based on the expressing form of videos, but the information in different videos was kept the same. However, the effect of product presentation videos depends, to a large extent, on the information in videos. Focusing on the information content and referring to the classification of product review information , the Fundamental Research Funds for the Central Universities of Chongqing University, project No. 2019 CDJSK 02 XK 12.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Although the relationship between acute alcohol consumption and injuries is well recognized, studies exploring how the time of day the drinking commences affects alcohol-related injuries have been scarce. This contribution examines the associations between the time at which the drinking began and the duration of the drinking, the volume of alcohol consumed, the injury type, and the blood alcohol concentration (BAC) level.This study employed a cross-sectional survey, which was conducted in two hospital emergency departments (ED) in Chiangmai Province, Thailand. The sample was composed of 519 injured patients aged 18 years and older. Outcome measures included the BAC and type of injury. Exposures included the quantity of alcohol consumed, the time the drinking commenced, and the pattern of drinking involved. The injured patients who drank alcohol within six hours prior to sustaining their injury were more likely to get injured and present themselves at the ED at night (20:00–04:00) compared to those who sustained an injury but did not drink in the hours prior. However, this relationship was only true for unintentional injuries, not intentional ones. The majority of participants consumed their first drink between 16:00 and 20:00. On average, among the 104 patients who drank prior to sustaining an injury, the total amount of alcohol consumed was 6.9 drinks, the duration of drinking was 2.6 h, the rate of drinking was 6.0 drinks/hour, and the BAC was 0.119 gm%. Every drink increased the BAC by 0.012 gm% and each year of increasing age increased the BAC by 0.003 gm%. People who were older, less educated, and drank more frequently tended to have their first drink earlier than other drinkers. An earlier start to their drinking resulted in a faster pace of drinking and a higher BAC.BAC increased with the total amount of alcohol consumed and the age of the drinker. Different groups of people had their first drink at different times of the day, resulting in differences in the rate of drinking, the BAC, the time of injury, and the time they presented to the ED after injury. Injuries can be caused in many ways, including, but not limited to, violence, self-harm, road traffic collisions, burns, drownings, and falls. It can have an immeasurable impact on individuals’ lives and those around them, causing morbidity and financial costs. Injuries were the second leading cause of direct medical costs in Canada  and in tAlcohol consumption, especially heavy drinking, is a clear factor for many chronic health problems and injuries, and creates a great burden to society , 5. ManyAlthough there have been many studies exploring the relationships between alcohol exposure, the amount of alcohol consumed, and the risk of subsequent injuries, as described above, only a small number of studies examined the effects of other factors. Only a handful of studies assessed the effects of the usual drinking patterns  , 22, theStudy design and data collection tools were developed by the World Health Organization (WHO) collaborative study on alcohol and injuries . The preData was collected from patients aged 18 years or older who were admitted to a hospital ED within 6 h of an injury between June and August of 2016, for a total of 519 participants (response rate of 89 %). Every injured patient recorded during the night (0:00–8:00) and morning (8:00–16:00) shifts, and every other injured patient during the evening (16:00–0:00) shift was approached and asked to participate in the study. To correct for different probabilities of sampling and to be representative for ED visits as a whole, weights were introduced, where possible. However, Fisher’s exact test could not be conducted as weight, and thus we report a Chi2 for weighted and Fisher’s exact test for unweighted counts. Trained field staff collected data from study samples using the WHO / National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol & Injury structured interview schedule. The BAC of each participant was obtained using a breathalyzer administered immediately upon the patient’s arrival at the ED. See [We were interested in five sets of variables. (1) The demographic variables consisted of sex, age, education, and place of residence. (2) The time-related alcohol consumption behaviours and their consequences, including the weekday and the time of the first drink, the weekday and time of the last drink, the time of injury, and the time patients presented at the ED. The WHO questionnaire that we used had questions pertaining to the day and time of the first drink, the last drink, the patient recruitment time (the time spent in the ED), the period of time between the last drink and the injury, and the period of time between the injury and arrival at the ED. We constructed the time of the injury and the categorical variables based on the day and time of the first and last drinks. It should be noted—especially for researchers who would like to analyze time-related alcohol consumption behaviour—that the period of time that bridges midnight, and therefore encompasses two different dates when constructing the duration variable, must be taken into account. (3) The variables for alcohol consumption within six hours prior to the injury consist of total alcohol consumption, duration of alcohol consumption, and number of drinks consumed per hour. In this study, alcohol consumption and the amount of alcohol intake for each participant in the 6-hour period prior to the injury were recorded. The volume of alcohol consumed was standardized by converting the number and volume of alcoholic beverages consumed into ml of pure ethanol. A standard drink was assumed to contain 16 ml of ethanol. We constructed a variable for duration of drinking by subtracting the time of the last drink by the time of the first drink, taking into account the dates of both drinking times. The rate-of-drinking variable was constructed by dividing the amount of drinking by the duration of drinking. (4) The usual drinking patterns of the participants are also recorded. (5) Our drinking outcome variables of interest included BAC, type and mode of injury. The types of injury included unintentional injury, intentional injury inflicted to oneself, and intentional injury inflicted by someone else. The modes of injury covered injuries related to vehicle crashes ; blunt force injury; stab, cut, bite; fall, trip; and others . All injury categories that had less then 30 recorded incidents were included in the ‘others’ category. Please note that the types and modes of injuries were derived from the answers patients provided to questions regarding why and how they were injured, respectively. These two questions are independent of each other. No patient answered ‘unknown’ to both questions.Differential sampling probabilities between nurse shifts were adjusted by weights. The patients who arrived during the night (0:00–8:00) and morning (8:00–16:00) shifts were thus assigned half the weight of the patients from the evening shift (16:00–0:00). Our study calculated percentages and means with 95 % Confidence Intervals (CI) to describe the distribution of the categorical and continuous variables, respectively. We employed the tabulation with the chi-square test to explore the relationships between the categorical variables. For cases where Fisher’s exact test was indicated, we used unweighted counts, but report the weighted chi-square tests as well. To examine the relationship between the continuous variables, we calculated means and 95 % CIs for each of the time periods for the first drink and compared them using an ANOVA technique. Lastly, multiple linear regression analyses were utilized to examine which of the 13 factors were likely to influence the BAC. We started by analysing the binary relationships between each of the 13 factors and then sequentially added sets of potential determinants to the regression model. All statistical tests applied a p-value of 0.05 as a statistically significant level. We used STATA software 15.0 for all analyses.The analysis was not pre-registered and the results should be considered exploratory.p-value = 0.002). The BACs were 0.106, 0.144, and 0.153 gm% for patients who drank ≤ 5, > 5 and ≤ 10, and > 10 drinks per hour, respectively . Two patients reported not drinking during the six hours prior to being injured but were found to have BAC readings of 0.030 and 0.180 gm%.Of the 519 injured patients who participated in the study, the majority were male (61 %), 18–44 years of age (67 %), had 7 or more years of education (70 %), and lived in the city (78 %). The prevalence of alcohol exposure during the 6 h prior to sustaining the injury/injuries was 19.5 %  (see details in ). The foTable p-value < 0.001). The majority (80.8 %) of patients with 7 + years of education had their first drink between 16:00 and 24:00, whereas those with lower education levels had their first drink earlier in the day . Similarly, the majority of patients had their first drink between 16:00 and 24:00; however, frequent drinkers had their first drink earlier. Those who had their first drink between 08:00 and 12:00 were drinkers who drank every day or almost every day, while those who had their first drink from 12:00 to 16:00 consisted of drinkers who drank at least once a week  were those who had their first drink between 08:00 and 12:00 and consumed about 9.7 drinks. These morning drinkers were all male, with an average age of 42.3 years old, and had an average 7 years of education (data not shown).Table Table Table This study explored the association between the time of day when drinking was initiated and the outcomes for patients who drank alcohol within six hours prior to sustaining an injury and presenting to an emergency department. We found that study participants who had their first drink at any time during the day were, on average, at the greatest risk of injury about 3.5 h later, and likely to attend the ED 6.3 h after their first drink. However, the patients who drank before sustaining an injury were more likely to present themselves at the ED at night (20:00–04:00) compared to those who did not drink before their injury, regardless of the mode of injury. This relationship was true only for the unintentional injuries. An explanation is that the majority of our study participants (79.1 %) drank from 16:00 to 24:00 with an average duration of drinking of 2.6 h. The average duration between the last drink and the injury was 0.9 h, and 1.4 h elapsed between the time of injury and their presentation at the ED. These average times combined resulted in most study participants getting to the ED at the above-mentioned time, between 20:00 and 04:00. This finding reaffirms the reasoning behind why a night-time car crash is often used as a proxy indicator for an alcohol-related accident .On average, study participants drank 6.9 drinks at a rate of 6.0 drinks/hour before being injured. We found that those who started drinking between 12:00 and 16:00 did so at the highest drinking rate of 11.4 drinks/hour. This may be due to drinkers being in a rush to drink quickly over their lunch period. Our study also observed that the patients who started their first drink between 08:00 and 12:00 tended to be male, older, and have less education. They were likely to be more problematic drinkers: they drank frequently, drank excessively, and had high BAC values. Drinking every day or almost every day is not common in Thai culture. Only 9.5 % of males and 3.7 of females drink every day or almost every day . Only 5.The finding that the total number of drinks increased the BAC level is similar to the findings of many of the other studies mentioned above. Interestingly, our study found that the BAC level increased with age after controlling for other factors, including the total number of drinks consumed. One explanation for this phenomenon is that the activity of the enzymes involved in ethanol metabolism  diminishes with age , 32. MorOur study provides some interesting insights into the public health implications regarding the drinking behaviours of the patients who drink alcohol in the six hours prior to their sustaining their injuries. First, starting the first drink at any time of the day will increase the risk of injury uniformly. Second, most study participants had their first drink between 16:00 and 24:00, finished their last drink, sustained their injury, and then presented themselves to the ED between 20:00 and 04:00. Third, more frequent drinkers, older drinkers, and less educated drinkers seemed to have their first drink earlier in the day. Early-start drinkers seemed to be problematic drinkers who drank the fastest and/or the most. This relationship could be used to identify early drinking as a special risk factor. Fourth, increased age is associated with higher BAC levels. Lowering thresholds of the low-risk alcohol drinking guideline according to age, as done by some European countries, may be a good strategy to prevent alcohol-related harmful effects imposed on consumers.To our knowledge, there are currently no ED studies exploring the effect of the start time of drinking on drinking outcomes. However, some limitations to this study must be mentioned. There are three limitations embedded in this study’s design: no information on the severity of the injury was available, samples were non-representative (they did not include those who did not seek treatment at the ED or who died before reaching the ED), and no information was available regarding other substances which may have been used concurrently . There Different groups of people seem to have their first drink at different times of the day, resulting in differences in the rates of drinking, BAC, the time of injury, and the time patients presented to the ED. To prevent alcohol-related unintentional injuries, government officials and relevant sectors should focus their efforts on intervening for alcohol drinking during evening and the early night-time hours since the majority of alcohol-related unintentionally injured patients drank alcohol from 16:00 to 24:00. More problematic drinkers who were older, less educated, and drank more frequently tended to have their first drink earlier in the day than their counterparts, and these groups may need a specific intervention, such as a brief intervention. BAC levels increased with the total amount of alcohol consumed and with the age of the drinker; hence, heavy drinking among older people might be of concern to public health personnel as well.


Video-based teaching has been part of medical education for some time but 360° videos using a virtual reality (VR) device are a new medium that offer extended possibilities. We investigated whether adding a 360° VR video to the internship curriculum leads to an improvement of long-term recall of specific knowledge on a gentle Caesarean Sections (gCS) and on general obstetric knowledge.Two weeks prior to their Obstetrics and Gynaecology (O&G) internship, medical students were divided in teaching groups, that did or did not have access to a VR-video of a gCS. Six weeks after their O&G internship, potentially having observed one or multiple real-life CSs, knowledge on the gCS was assessed with an open questionnaire, and knowledge on general obstetrics with a multiple-choice questionnaire. Furthermore we assessed experienced anxiety during in-person attendance of CSs, and we asked whether the interns would have wanted to attend more CSs in-person. The 360° VR video group was questioned about their experience directly after they watched the video. We used linear regression analyses to determine significant effects on outcomes.p = 0.04) that they would have liked to attend more CSs in-person as compared to the conventional study group.A total of 89 medical students participated, 41 in the 360° VR video group and 48 in the conventional study group. Watching the 360° VR video did not result in a difference in either specific or general knowledge retention between the intervention group and the conventional study group. This was both true for the grade received for the internship, the open-ended questions as well as the multiple-choice questions and this did not change after adjustment for confounding factors. Still, 83.4% of the 360° VR video-group reported that more videos should be used in training to prepare for surgical procedures. In the 360° VR video-group 56.7% reported side effects like nausea or dizziness. After adjustment for the number of attended CSs during the practical internship, students in the 360° VR video-group stated less often (Even though the use of 360° VR video did not increase knowledge, it did offer a potential alternative for attending a CS in-person and a new way to prepare the students for their first operating room experiences.The online version contains supplementary material available at 10.1186/s12909-021-02628-5. Video-based teaching has been part of medical education for a reasonable time –3. An esCommonly students watch operating videos on a computer, laptop, telephone or tablet, all on a 2D screen. However, today, more realistic options are available. With 360° Virtual Reality (VR) videos, the viewer has control over the viewing direction and has the possibility to stand in a 3D space. As this results in a more immersive experience than a traditional 2D video, this might lead to better learning outcomes .Different studies have shown the benefits of 360° VR videos over traditional video in  education –15. It hIn the medical curriculum, the use of 360° VR video could prepare students for attending new real-life situations. In a 6-week obstetrics and gynaecology (O&G) internship, students are able to attend one or more (gentle) caesarean sections (gCSs). However, this is not guaranteed since it depends on patient availability and patient preferences. Attending a CS can be impressive for a student and lead to anxiety and stress. Also as many caregivers are involved, and understanding everyone’s role and the specific organisation in the operation theatre can be perceived as complex.We investigated if adding a 360° VR video prior to the internship curriculum leads to an improvement of long-term recall of specific knowledge about a gCS procedure and general knowledge about obstetrics. Furthermore we studied whether use of this video is appreciated by the students, whether it had an effect on anxiety during the first attendance of a CS in-person, and whether it could replace the attending of a CS in-person.During the master phase of their medical education students of the Vrije University Amsterdam, the Netherlands, have to follow different practical internships for most of the medical specialisms. Prior their practical O&G internship of 6 weeks, they have a 2-week clinical training course (CTC) at one out of five different locations. After the 2-week CTC, the students have the practical part of their O&G internship in different hospitals over the region or abroad . Apart from the internships abroad, assignments to the locations take place at random by the University. During their practical O&G internship they are supposed to attend one of more CSs. During a CSs they are present in the operating room as an observer and depending on the situation they can assist the surgeon.We performed a prospective quasi-experimental study. To avoid a crossover effect, we used a temporal design by CTC location; first the complete CTC group did not see the video, and subsequently the complete CTC group did see the video. The moment the CTC groups did see the video differed between the 5 locations. In total, 18 CTC groups of on average eight O&G interns, were assigned to either; (1) the 360° VR video-group or (2) the conventional study group.All students in the CTC groups were included in the study. A reminder was send after 1 and 3 weeks if the students did not complete the CS Knowledge Quiz. Students who took part in the study all agreed and signed informed consent. Participating students received a €7.50 gift voucher when they completed the CS Knowledge Quiz. According to Dutch law (Wet medisch-wetenschappelijk onderzoek met mensen) no formal ethical review was required. This study was performed according to the declaration of Helsinki and the study protocol and data analyses plan were approved by the Spaarne Gasthuis review board, approval October 15, 2018 (2018.0086).Between September 2018 and November 2018, students from the CTC groups were enrolled for the conventional study group. They received the regular education program at their CTC location. They were approached after the O&G internship and were asked to complete a web-based electronic survey  was present during the 360° VR video to allow for questions on the use of the device. Immediately after seeing the 360° VR video, the participants received a short questionnaire related to their satisfaction . Participants received 1 point for each correct answer and in total, a score between 0 and 10 could be achieved, where a higher score indicated better performance.To measure general knowledge about obstetrics ten multiple-choice questions, with four possible answers, were used. These questions were developed by the Progress Test Medicine, a national test organisation testing the progress of medical during their medical education  was asked (grade 1–10), as a crude indication of the students general performance. Students were asked how their internship at the O&G department was graded (grade 1–10), as well as their anxiety level on a 7 point Likert scale (from − 3 which means “strongly disagree” to + 3 which means “strongly agree”) when they first were present at a CS procedure. It was also asked whether they had prior experience of VR, and whether they had watched other educational video’s. Finally, demographic information such as age and gender was collected.P-values smaller than .05 were considered statistically significant. To analyse the data, SPSS version 24 was used.VA and KvS conducted a statistical analysis of the survey and internship grades using SPSS software. Continues variables are presented as medians and interquartile ranges (IQR), while nominal and ordinal variables are presented in percentages. Linear regression was performed while controlling for possible confounders . In total, 109 students attended the CTCs. Out of 56 CTC students who participated in the conventional education group, 48 (85.7%) completed the study. In the CTC groups who watched the 360° VR video-group, 53 students were present. From them, 41 (77%) completed the CS knowledge questionnaire and were included in the analysis.Participants ages mean 23 years), starting year of the bachelor median 2014) and master (median 2017) were similar between the conventional education and 360° VR video groups, see Table 4 and mas3 years, Tables There was no significant effect of the 360° VR video on all different measurements of knowledge Table . This wap = 0.09, Fig. p = 0.04). There was no significant difference between the two groups in anxiety the first time they visited a CS in-person (Table The median number of attended CS’s was 2 (IQR 1–4). Three participants (2 from the 360° VR video-group) had their internship in a hospital in Aruba, and attended many more CSs . The ten participants who attended six CS or more did not indicate that they would like to attend more CSs during their internship. From the 76 participants who attended 5 or less CS’s, 65.8% indicated that they would have liked to attend more CSs, which was inversely correlated with the number of attended CSs. Overall, more participants in the conventional study group (68.8%) indicated that they would have liked to attend more CS, as compared to the 360° VR video-group  of information (known as a split-attention effect) may have reduced the learning capacity due to increased cognitive workload , 29.TherSometimes learners get lost or are unable to navigate through the VR interface . TherefoIt is important to note that technology itself does not improve learning. The content is far more important. The students indicated that they would have liked to receive more theoretical information during the 360° VR video even though a voice-over was included in the movie . However, it remains that the strength of the use of video over real-life provides the opportunity to emphasize or point out important information, which we might not have fully utilized.There were several limitations to this study; first of all the CTC groups and thus the participants are not randomly assigned to either the conventional study or the experimental group. We did not want to have any cross-over effects, and therefore decided to have a temporal design. The CTC groups receive teaching according to the same protocol, but the practical part depends on the circumstances. Given that all students have equal chances to go to different locations, and this was independent of the VR video, we assume that the effect on our results will have been small. However, groups were not identical with respect to practicing gynaecology questions as well as the number of attended CSs. Even though we adjusted for these factors, we cannot rule out any residual confounding.Secondly, students were not rewarded for good performance on the knowledge questions, nor did it count towards their grade. Therefore students may not have been fully motivated to answer the questions, however we do not believe that this will have differed between the groups. Finally, although 360° VR videos are widely regarded as a virtual reality, it should be noted that the location of the viewer is fixed and it is not possible to walk through, or interact with the environment.Although addition of the 360° VR video to the medical curriculum did not lead to better information retention it was highly appreciated by the medical students. It might provide an alternative for those who were not able to attend a CS in-person. Therefore, especially among situations where the number of procedures are unpredictable, such as a CS, addition of a 360° VR video to the curriculum can be a useful, low-cost tool to fulfil the learning needs of students.Additional file 1. Questions regarding the VR experience.Additional file 2. Questions to test the knowledge of the medical students.


In aqueoussolution, two chelation geometries predominate, distinguished by bidentateand tridentate Mg2+–phosphate coordination. Theseare approximately isoenergetic but separated by a high energy barrier.Force field-based atomistic simulation studies of this complex requirean accurate representation of its structure and energetics. Here wefocused on the energetics of ATP·Mg2+ coordination.Applying an enhanced sampling scheme to circumvent prohibitively slowsampling of transitions between coordination modes, we observed strikingcontradictions between Amber and CHARMM force field descriptions,most prominently in opposing predictions of the favored coordinationmode. Through further configurational free energy calculations, conductedagainst a diverse set of ATP·Mg2+–protein complexstructures to supplement otherwise limited experimental data, we quantifiedsystematic biases for each force field. The force field calculationswere strongly predictive of experimentally observed coordination modes,enabling additive corrections to the coordination free energy thatdeliver close agreement with experiment. We reassessed the applicabilityof the thus corrected force field descriptions of ATP·Mg2+ for biomolecular simulation and observed that, while theCHARMM parameters display an erroneous preference for overextendedtriphosphate configurations that will affect many common biomolecularsimulation applications involving ATP, the force field energy landscapesbroadly agree with experimental measurements of solution geometryand the distribution of ATP·Mg2+ structures foundin the Protein Data Bank. Our force field evaluation and correctionapproach, based on maximizing consistency with the large and heterogeneouscollection of structural information encoded in the PDB, should bebroadly applicable to many other systems.In the numerous molecular recognition and catalytic processes acrossbiochemistry involving adenosine triphosphate (ATP), the common bioactiveform is its magnesium chelate, ATP·Mg Givenits ubiquity, an accurate steric and energetic description of theATP·Mg2+ complex, including its cation–phosphateinteractions, is key to theoretical studies and atomistic simulationsof many ATP-consuming processes.Hydrolysis of adenosine triphosphate (ATP) serves as a source ofchemical energy across all domains of life, driving essentially allenergy-consuming cellular processes. Both unbound in cellular surroundingsand as enzyme substrates, nucleotide triphosphates occur predominantlywith divalent cations, most commonly Mg4–·Mg2+ coordination modes insolution.4 These are defined by their coordinationof the Mg2+ ion by either all three phosphate groups  contains many complexes in both C2 and C3 configurations.Both are observed as bound substrates of ATP-consuming enzymes, consistentwith quantum chemical studies of solvated ATP·Mg2+–triphosphate coordinationin solution similarly indicate both states are energetically accessible,notwithstanding the well-known challenges posed by strong chargesand metal ions in atomistic simulations.8 Employing the CHARMM force field description of ATP·Mg2+,9 Liao et al.10 calculated a free energy difference between C2 and C3 closeto zero, while Branduardi et al.11 reporteda 2.9 kcal/mol preference for the C2 state. Although the transitionbetween C2 and C3 involves only relatively small geometrical changes,both studies documented energy barriers high enough to preclude adequatesampling of coordination state transitions in unbiased molecular simulations.We are not aware of similar studies for other force fields, such asthe ATP·Mg2+ Amber force field-compatible parametrizationof Meagher et al.12Computational studies of Mg2+, focusing on the configurational equilibria of Mg2+–phosphate coordination both in solution and bound to proteins.Applying an enhanced sampling protocol, we found substantial discrepancies,both between Amber and CHARMM force fields as well as with experiment.To resolve the disagreement, we combined the distribution of ATP·Mg2+ configurations in the PDB and configurational free energycalculations to derive quantitative corrections for both force fields.Here we assess the accuracy of force field descriptions of ATP·Mg2+. The CHARMM22 force field parameters9 are those employed in previous studies directly addressing ATP–Mg2+ coordination.11 As described below,we separately evaluated the CHARMM angle and dihedral parameter modificationsderived by Komuro et al.,13 listed in Tables1 and 2 therein. For the Amber force field, we used the parametrizationof Meagher et al.,12 which is providedthrough a developer-endorsed collection of contributed parametersand has been widely adopted in combination with this force field.18We examined two force field representations of ATP·Mg2+ ion,we first retrieved all PDB structures containing both Mg2+ and ATP. From this selection, we discarded instances with more thanone divalent cation within 8 Å of the ATP molecule and retainedthose with one Mg2+ ion within 3 Å of any phosphateoxygen. Redundant entries, as commonly arise from identical or homologousproteins or binding motifs, or multiple equivalent binding sites withincrystal structures, were not removed, because they provide additionalinformation on the structural flexibility. We thus obtained a sampleof 2123 biomolecule-complexed configurations of ATP·Mg2+.Aiming to collect all instancesof ATP and analogues with exactly one coordinated Mg2+–phosphateconfigurations, we performed a principal component analysis (PCA)using the coordinates of only the α-, β-, and γ-phosphateatoms, their two bridging oxygen atoms, and the Mg2+ ion,on the PDB data set. By averaging over the remaining configurationaldegrees of freedom, this analysis captures Mg2+–triphosphatecoordination variance independently of the configurational diversityof the nucleotide.To aid spatial analysis of MgSupplementary S1).For an initial estimate of the rate of spontaneouscoordination state transitions, we counted instances of simulationsdeparting from their initial coordination mode in 200 unbiased moleculardynamics simulations, each of 1 μs length, comprising 50 simulationseach starting from C2 and C3 configurations, under both Amber andCHARMM. The starting structures for these simulations were chosenfrom the PDB set for maximal configurational diversity, by maximizingthe sum of mutual distances in the PCA space defined above  to enable propagationof diverse configurations from rapidly exchanging reduced-charge statesto the native state with correct thermodynamic weighting, therebygreatly accelerating sampling of the native ensemble.To couple this nonphysical alchemicalstate,e states 1b. Simul4–·Mg2+) subensembles, respectivelyconfined to seven permutations of single, double, and triple coordinationof Mg2+ to the α-, β-, and γ-phosphategroups, and to a further 11 barrier regions of interest. Each restrainedstate was coupled to the single common unrestrained reduced-chargestate by a chain of 20 intermediates, spaced to equalize mutual phasespace overlap along the chain as previously described,22 yielding average acceptance rates of 0.5 andregular end-to-end exchanges of configurations. The correspondingset of subensembles is enumerated in Supplementary S4, along with further simulation details.To enforce sampling of higher-energy configurational regions ofinterest, we further defined 18 geometrically restrained native (ATP23 (MBAR) estimator. In addition, we applied MBARto reweight configurational samples collected across all subensemblesof differing restraint potential and charge scaling to their correctthermodynamic weighting in the unrestrained, fully charged nativeensemble. This protocol yields broad sampling covering both free energyminima and selected regions of higher-energy configurational space,from which arbitrary observables of interest may be extracted.To calculate free energy differences across all states of the extendedensemble, we applied the Multistate Bennett Acceptance Ratio2+–protein complexstructures. Selecting these structures, we excluded proteins largerthan 250 kDa, structures containing nonstandard protein residues ornonprotein cofactors , and structureswith protonatable side chains in the ATP·Mg2+ bindingregion whose protonation state could not confidently be assigned.The otherwise arbitrarily selected set contained 17 C3 and 13 C2 complexes.Configurational free energies were calculated analogously to the solutionprotocol detailed above, with use of the same artificial ATP2.5–·Mg0.5+ intermediate, but incorporating only tworestrained native (ATP4–·Mg2+) endstates corresponding to C2 and C3 coordination. Further simulationdetails are reported in Supplementary S3.To calibrate force field free energiesagainst the wealth of additional structural data points availablefrom the PDB, we calculated free energy differences between coordinationstates for a set of 30 ATP·Mg2+–phosphate configurations, the high intervening electrostaticenergy barrier24 renders sampling of the equilibriumin unbiased simulation quite challenging. Indeed, in 200 unbiased1-μs simulations as detailed under Despitethe simple geometry and small structural difference between the C2/C3Mg2+ ion to the nearestα-phosphate–oxygen distance (Mg−αO), revealinga substantial disagreement between the two force fields. Where experimentaldata suggest a slight preference for C2 over C3,4 the Amber ensemble shows C2 disfavored by 6.4 ± 0.1kcal/mol, while CHARMM shows C2 favored by 5.3 ± 0.2 kcal/mol.On this measure, the two force fields thus disagree by a remarkable11.7 ± 0.2 kcal/mol and predict opposing trends.Applying the RE/MBAR enhancedsampling protocol see , we firs2+, we next used ATP·Mg2+ configurations from the PDB as an additional source of informationabout the actual free energy difference between the C2 and C3 configurations.To this end, we initially assumed that this sample of ATP·Mg2+ configurations, although exposed to quite different surroundingscompared to the solution ensemble, is governed by the same strongintracomplex electrostatic interactions as in solution and shouldthus exhibit similar configurations.To reconcilethis discrepancy, and in the absence of further experimental datafor solvated ATP·Mg2+ instances in the PDB here provides initial support: of the2123 retrieved configurations, 77.2% are found in the C2 (β–γ)and C3 (α–β–γ) coordination states,with 49.7% C2 and 27.5% C3, which is indeed consistent with the experimentalfinding that these forms predominate in solution and are approximatelyisoenergetic. The populations of all observed forms are enumeratedin Supplementary S5.To test if this is actuallythe case, we examined whether regions of configurational space mostdensely populated with PDB structures overlap with low free energyregions observed in the simulations. The raw count of C2 and C3 ATP·MgA more detailed picture is provided by a PCA projection 3a of theTo compare the simulated solution ensembles with the PDB set 3a, we reBeyond these aspects of qualitative agreement, the comparison reaffirmsour finding that Amber disfavors the C2 subform (clusters I and II).This contradicts the CHARMM force field and is inconsistent with thePDB set, unless the majority of biomolecular complexes was to selecta coordination mode that is substantially disfavored in solution,which is unlikely.Further, the CHARMM ensemble shows a free energy minimum betweenclusters I and II of the PCA projection, which is absent in the Amberlandscape and barely represented among PDB Configurations. Again,this result would imply that, for the CHARMM force field, the mostfavorable configuration in solution almost never occurs among knownbiomolecular complexes. Additionally, a substantial fraction of themost-populated PDB cluster II (eigenvector 1 > 0.1) is assessed tobe energetically inaccessible  in this projection ofthe solution free energy landscape, contradicting the Amber forcefield and implying that PDB structures observed in this region mustovercome a large energy penalty.Notwithstanding the different energetics expected for solvent andprotein environments, the above disparities between the simulatedsolution ensembles and the protein-complexed PDB set are concerning.Further, the outright contradictions between the two simulated solutionensembles show that one or even both force fields describe the energetics,and possibly the structures, of the C2 and C3 coordination statesinaccurately.2+ configurations for both force fields, wenext harnessed the diversity of biomolecular surroundings in the PDBsample. Because each PDB structure represents an energetic minimumof an ATP–protein complex, a free energy calculation comparingthe two configurations should, with an accurate force field, alwaysevaluate the experimentally observed coordination state as lower infree energy than the alternative state. Applied to a set of complexessufficiently large to sample a broad range of free energy differencesbetween C2 and C3 configurations, this principle permits measurementsof force field accuracy and, in turn, quantification of the systematicmispredictions that the above analysis strongly suggests. In contrastto the qualitative analysis above, this approach does not assume directcomparability of the solution ensemble and the PDB distribution.For a closer, quantitative assessment of the energetics of the twoATP·Mg2+–protein complexes, as describedunder To this end, we calculated the free energy difference between C2and C3 configurations using both force fields for a selected set of30 ATP·MgOverall, both CHARMM (filled circles) and Amber (open circles)are able to differentiate the coordination mode in most instances,with C3 (blue) points mostly showing a more positive free energy differencethan the C2 (red) ones. Indeed, for Amber, 16 of the 17 most positivefree energy values correspond to C3 PDB structures, and 12 of the13 most negative correspond to C2 PDB structures. Likewise for CHARMM,14 of the 17 most positive values are C3, and 10 of the 13 most negativeare C2.However, the calculated free energies from both force fields areoffset both with respect to each other as well as to the zero freeenergy line, in accordance with our observation above for the solutionfree energies. Amber systematically mispredicts C3 coordination forC2 PDB structures, with only 4 of 13 C2 structures correctly predicted,whereas CHARMM appears biased toward C2, predicting only 10 of 17C3 structures correctly.The very good relative performance of both force fields suggestsa simple additive correction that can be extracted from the calculatedfree energies of the selected protein complexes by shifting both setsof free energy values up or down, as shown in Next, we asked if these forcefield corrections also improve the description of the C2/C3 populationin solution. The unmodified force fields predicted C3 → C2free energy differences in solution of +6.4 ± 0.1 kcal/mol (Amber)and −5.3 ± 0.2 kcal/mol (CHARMM). Applying the respectivelower and upper bounds of the offset ranges determined above , and with the assumption that these offsets, derivedin a diverse set of partially solvated biomolecular environments,are applicable to condensed-phase simulations in general, these differencesreduce to −0.7 ± 0.1 kcal/mol (Amber) and −2.0± 0.2 kcal/mol (CHARMM). Within sampling and experimental uncertainty,these free energy differences are consistent with the populationsobserved by NMR. Considering the large initial disagreement  and, more broadly, the challenges inherent toforce field simulation of strongly charged chemical entities and metalions, we consider this result remarkably accurate.2+–αP distance greater than 3.75 Å)of each force field ensemble, yielding revised solution free energylandscapes for each force field. Further,we asked if these corrections also produce structural ensembles thatbetter agree with the PDB sample. To this end, we applied the respectiveC2/C3 offsets as weighting factors to all C2 frames  and C3 (tridentate) coordination,revealed a pronounced disagreement between the two parameter sets.CHARMM and Amber each predicted substantial preferences in oppositedirections, with neither reproducing the experimental finding thatthese configurations are close to isoenergetic in solution.Our accuracy assessment of two broadly applied force field descriptionsof ATP·Mg2+ configurationsfound among biomolecular complexes in the PDB. Configurational freeenergy calculations for 30 structurally diverse ATP–proteincomplexes served to quantify systematic force field biases that ledto mispredictions of the PDB coordination mode and enabled correctionsto the relative free energy of the C2 and C3 coordination modes foreach force field.Addressing this discrepancy, we compared simulated solution freeenergy landscapes to the distribution of ATP·Mg2+ coordination modeneeds to be sampled, no correction of the C2/C3 equilibrium is required.In rarer cases where this criterion is not fulfilled, our correctionand the resulting reweighting enable a straightforward a posteriori correction of the sampled ensembles, without much additional computationaleffort. The enhanced sampling protocol we described presents a robustsolution to sampling across the high electrostatic barriers that separatecoordination states.For the Amber force field, our subsequent evaluation showed anencouraging degree of overlap between regions of low free energy insolution and the most common configurations observed among proteincomplexes in the PDB, suggesting that the underlying physical andsimulated energy landscapes are similar. For biomolecular simulationsin which only a single ATP·Mg13 This extended configuration is separated from the more compact C2subconfigurations found in the PDB only by low energy barriers, whichcan readily be crossed in equilibrium simulations. Contrasting withthe high energy barriers that separate C3 configurations from thisoverextended region, which permit equilibrium sampling under CHARMMof a C3 region that broadly reflects the distribution of configurationsfound in the PDB, CHARMM ensembles of C2 ATP·Mg2+ willthus sample a region that matches neither the PDB nor the predictionsof the Amber force field. The force field modifications of Komuroet al.13 alleviate but do not eliminatethis tendency.By contrast, we observed a pronounced tendency toward overextensionof the triphosphate group under CHARMM, in line with earlier observations.2+, C2 configurationscomprise the majority of PDB structures. Accordingly, many typicalbiomolecular simulation applications incorporating ATP·Mg2+ will sample a distorted equilibrium under CHARMM. In particular,the single largest cluster in the PDB (25 and which binds ATP·Mg2+ in its C2 configuration.Underscoring the importance of more accurate theoretical representationsof both structure and energetics of ATP·MgAssuming that the free energy of any structural property observedin a PDB structure is lower than that of alternative configurations,we have demonstrated how the wealth of free energy information containedwithin the many available protein structures in the PDB can be harnessedto assess and improve biomolecular force fields. We think this approachis quite general and should be applicable to many other molecularproperties for which experimental data are scarce or hard to obtainbut where a diverse sample of instances can be obtained from the PDB.


To describe the incidence and main causes of maternal near-miss events in middle-income countries using the World Health Organization’s (WHO) maternal near-miss tool and to evaluate its applicability in these settings.We did a systematic review of studies on maternal near misses in middle-income countries published over 2009–2020. We extracted data on number of live births, number of maternal near misses, major causes of maternal near miss and most frequent organ dysfunction. We extracted, or calculated, the maternal near-miss ratio, maternal mortality ratio and mortality index. We also noted descriptions of researchers’ experiences and modifications of the WHO tool for local use.We included 69 studies from 26 countries (12 lower-middle- and 14 upper-middle-income countries). Studies reported a total of 50 552 maternal near misses out of 10 450 482 live births. Median number of cases of maternal near miss per 1000 live births was 15.9  in lower-middle- and 7.8 (IQR: 5.0–9.6) in upper-middle-income countries, with considerable variation between and within countries. The most frequent causes of near miss were obstetric haemorrhage in 19/40 studies in lower-middle-income countries and hypertensive disorders in 15/29 studies in upper-middle-income countries. Around half the studies recommended adaptations to the laboratory and management criteria to avoid underestimation of cases of near miss, as well as clearer guidance to avoid different interpretations of the tool.In several countries, adaptations of the WHO near-miss tool to the local context were suggested, possibly hampering international comparisons, but facilitating locally relevant audits to learn lessons. Women are at risk of developing severe morbidity and mortality during pregnancy, childbirth and postpartum, especially in low-income and middle-income countries where 99% of all maternal deaths occur.,,––,In addition to maternal mortality, severe maternal morbidity is used as an indicator of quality of maternity care.–,Several studies, however, have demonstrated difficulties in applying the tool.Box 1Cardiovascular dysfunction: shock; cardiac arrest (absence of pulse or heartbeat and loss of consciousness); use of continuous vasoactive drugs; cardiopulmonary resuscitation; severe hypoperfusion (lactate > 5 mmol/L or > 45 mg/dL); severe acidosis (pH < 7.1)2/FiO2 < 200)Respiratory dysfunction: acute cyanosis; gasping; severe tachypnoea (respiratory rate > 40 breaths per minute); severe bradypnoea (respiratory rate < 6 breaths per minute); intubation and ventilation not related to anaesthesia; severe hypoxaemia Coagulation or haematological dysfunction: failure to form clots; massive transfusion of blood or red cells (≥ 5 units of blood); severe acute thrombocytopenia (< 50 000 platelets/mL)Hepatic dysfunction: jaundice in the presence of pre-eclampsia; severe acute hyperbilirubinaemia (bilirubin > 100 μmol/L or > 6.0 mg/dL)Neurological dysfunction: prolonged unconsciousness (lasting ≥ 12 hours) or coma (including metabolic coma); stroke; uncontrollable fits or status epilepticus; total paralysisUterine dysfunction: uterine haemorrhage or infection leading to hysterectomySevere postpartum haemorrhageSevere pre-eclampsiaEclampsiaSepsis or severe systemic infectionRuptured uterusSevere complications of abortionAdmission to intensive care unitInterventional radiologyLaparotomy Use of blood products2/FiO2: ratio of arterial oxygen partial pressure to fractional inspired oxygen; WHO: World Health Organization.PaOSource: WHO, 2011.Reports about the incidence of maternal near miss have been published for several high- and low-income countries, and the applicability of the WHO maternal near-miss tool has been evaluated in several of these. However, data are lacking about maternal near miss in middle-income countries. We therefore made a systematic review of the incidence and main causes of maternal near miss in middle-income countries. We also aimed to evaluate qualitative findings documented by researchers with regard to applicability of the tool and suggest possible adaptations of the WHO maternal near-miss approach for middle-income settings.We conducted the review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline,,We performed a search of online databases for articles on maternal near miss in middle-income countries published between 1 January 2009 and 12 November 2020 without language restrictions. The earlier date was chosen since 2009 is the year when the WHO maternal near-miss approach was first published.We used the keywords “severe acute maternal morbidity,” “maternal near miss” and “middle income country.” Since PubMed® does not provide medical subject headings terms for country income groups, we first determined which countries were classified as middle-income and inserted each country name as a separate term in the search strategy. The search was last run in November 2020 in the online databases PubMed®, Embase®, Web of Science, Cochrane Library, Emcare and Academic Search Premier. In addition, we searched the following regional databases: Index Medicus for the Eastern Mediterranean Region; Index Medicus for South-East Asia Region, Latin America and the Caribbean; African Index Medicus; IndMED; and Global Health Library. More details of the search strategy are in the data repository.,,We included studies that met all four inclusion criteria: (i) articles about maternal near miss as defined by WHO; (ii) data on the incidence of maternal near miss per 1000 live births and the main causes; (iii) describing countries meeting the World Bank classification for middle income;We excluded studies that: (i) did not apply WHO maternal near miss definitions; (ii) only focused on one specific disease or risk factor without providing overall data on maternal near miss; (iii) were comments, abstracts, secondary analysis or surveys of existing studies; (iv) only focused on neonatal outcomes; or (v) only described the process of health care or methods of identifying maternal near miss without providing incidence or most frequent causes, and without providing qualitative findings with regard to applicability and adaptations of the tool.Two independent researchers screened all citations initially for relevance based on title and abstract and selected studies for inclusion after reading the full-text papers. Disagreements were resolved in a discussion between these two reviewers to reach a consensus. In case no consensus could be reached, the reviewers consulted a third researcher to reach an agreement on inclusion of articles. We extracted data on the number of live births, number of cases of maternal near miss and number of maternal deaths. Where available, we noted the following indicators: maternal near-miss ratio , maternal mortality ratio , ratio of maternal near miss to maternal death  and mortality index [number of maternal deaths ÷  × 100]. If indicators were missing for any study, we calculated the values from the available data. We also extracted data on the most frequent organ dysfunction and the most frequent cause of maternal near miss. When studies included qualitative comments on the methods of using the WHO maternal near-miss approach, we noted any modifications to the WHO tool applied in the studies and any problems reported by the study researchers. When articles described the use of multiple methods to identify maternal near miss, we only reported data concerning use of the WHO maternal near-miss tool. ,We subdivided the countries for analysis into lower-middle income and upper-middle income according to the World Bank categories.We estimated risk of bias in individual studies by quality assessment of studies. Studies were considered to be of acceptable quality if: (i) there was a clear description of the study population with a minimum of 100 live births over a period of at least 3 months; (ii) new cases of maternal near miss were identified in daily audits or rounds by trained medical staff; and (iii) the setting was an entire hospital rather than only one intensive care unit. The two reviewers who selected the studies did the quality assessment. We amended the Newcastle–Ottawa scaleEthical approvals were obtained from the Health Research Ethics Committee (HREC), Faculty of Health Sciences, Stellenbosch University, on 3 October 2018  and from the Provincial Health Authority, the chief executive officer of Tygerberg Hospital and the heads of respective departments. –The search resulted in 996 records. After removal of duplicates, we screened 973 articles based on title and abstract, after which 138 articles were retrieved for full-text evaluation. Of these, we excluded 76 articles . Four retrospective studies described data from before 2009 using the WHO definition for maternal near miss.–The included articles reported data from 69 studies in 26 countries (12 lower-middle-income countries and 14 upper-middle-income countries). Two of the articlesThe incidence and causes of maternal near miss in middle-income countries are presented in Studies reported a total of 2917 maternal deaths. The median maternal mortality ratio for all middle-income countries was 163 per 100 000 live births (IQR: 52–367), with a median of 306 per 100 000 live births (IQR: 162–666) in lower-middle-income countries versus 62 per 100 000 live births (IQR: 9–105) in upper-middle-income countries. The median mortality index in middle-income countries was 13.5% (IQR: 8.4–24.0%), ranging from 15.8% (IQR: 9.0–28.5%) for lower-middle-income countries to 10.7% (IQR: 7.3–15.4%) for upper-middle-income countries. Hypertensive disorders of pregnancy and obstetric haemorrhage were the commonest causes of maternal near miss. In the lower-middle-income countries, the most frequent cause of near misses was haemorrhage , reported in 18 out of 40 studies (45%) from 10 countries. Hypertensive disorders of pregnancy (including severe pre-eclampsia and eclampsia) were the cause of near miss in 15 studies (38%) from four countries. In the upper-middle-income countries, hypertensive disorders of pregnancy were the commonest cause of maternal near miss in 15 out of 29 studies (52%) from six countries. Obstetric haemorrhage was reported as the commonest cause in eight studies (29%) from seven countries. In both lower-middle- and upper-middle-income countries, the main identified organ failure was coagulation or haematological dysfunction (which included haemorrhage with a minimum of 5 units of blood for transfusion and a platelet count < 50 000 platelets/mL). Cardiovascular organ dysfunction  was the second most common organ failure.,,,,,,,,,,,Adaptations to the maternal near-miss tool were suggested in 33 out of 69 (48%) studies. These modifications and difficulties in applying the WHO maternal near-miss tool are described in ,Some studies reported problems with applying the tool, including underestimation of maternal near miss by using only criteria based on organ dysfunction;The WHO maternal near-miss tool facilitated evaluation of the maternal near-miss ratio in 26 middle-income countries. The main reported causes of maternal near miss were hypertensive disorders in pregnancy and obstetric haemorrhage. The maternal near-miss ratios were considerably higher in lower-middle- than upper-middle-income countries (median: 15.9 versus 7.8 per 1000 live births). This finding is not unexpected due to differences in countries’ resources, but is an important finding about the validity of the maternal near-miss approach. Lower-middle-income countries also had considerably higher maternal mortality ratios and mortality indices than upper-middle-income countries.,,,The median maternal near-miss ratios per 1000 live births in middle-income countries in our study were higher than those in previous studies of high-income countries ,Monitoring maternal near misses and maternal deaths showed differences not only among middle-income countries but also across different settings of the same countries. Differences between rich and poor or urban versus rural populations are often large in middle-income countries. Outcomes will differ depending on the quality of care and socioeconomic circumstances in different regions.–,,,Adaptations to the WHO maternal near-miss tool have previously been considered for high- and low-income countries.The issues mentioned above show that the maternal near-miss tool is helpful in recognizing severe morbidity, but may benefit from adaptations to be locally applicable. The major aim of the tool is that lessons for clinical care are drawn. Only including cases of maternal near miss that occur in tertiary level hospitals does not provide a comprehensive picture of maternal near miss in a country. Especially in middle-income countries, differences in quality of care in facilities are large between richer and poorer populations, those living in urban versus rural areas and those using public versus private facilities.,,,A limitation of our study is that small differences in methods of identification of maternal near miss between countries could result in major differences in outcomes. Moreover, we had to exclude a considerable proportion of studies that used different criteria to identify maternal near miss. This underlines the complexity of the challenge when aiming to compare maternal near miss across different countries and settings. An additional list of diagnoses would be a valuable contribution to reflect actual health problems in different settings.–A strength of our study was the relatively large number of publications that allowed us to obtain a comprehensive overview of maternal near miss in middle-income countries and to make robust comparisons between different regions and countries. We only report data about maternal near miss from 26 of the world’s 105 middle-income countries. We excluded some studies of near miss from our review because they used different criteria from the WHO near-miss criteria or did not clearly report the criteria used. Nevertheless, the countries analysed here reported large numbers of live births as denominator populations, providing a relatively robust and comprehensive overview of maternal near-miss ratios. We found multiple studies for Brazil and India, with India showing a particularly broad range of outcomes. These data for India reflect the large differences within this large country, indicating that smaller studies might not be representative for the entire territory.We conclude that instead of adapting the WHO maternal near-miss tool, the foremost important aim of the tool should be to improve the quality of maternity care from lessons learnt by performing audits of cases of maternal near miss.


Background and Objectives: We investigated the non-inferiority of patient-controlled analgesia (PCA), using either nefopam alone or combined nefopam-fentanyl for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Materials and Methods: In this prospective, randomized, controlled study, 78 patients were allocated to receive nefopam 240 mg (Group N240) or nefopam 120 mg with fentanyl 600 μg (Group NF), equivalent to fentanyl 1200 μg, with a total PCA volume of 120 mL. Patients were given a loading dose (0.1 mL/kg) from the PCA device along with ramosetron (0.3 mg) and connected to a PCA device with a background infusion rate of 2 mL/h, bolus dose amount set at 2 mL, and lockout interval set at 15 min. Pain scores were obtained using the numeric rating scale (NRS) at 30 min after recovery room (RR) admission, as well as 8 and 24 h postoperatively. The primary outcome was analgesic efficacy evaluated using NRS-rated 8 h postoperatively. Other evaluated outcomes included the incidence rate of bolus demand, rescue analgesic and antiemetic requirements, and postoperative adverse effects. Results: NRS scores were not significantly different between the groups throughout the postoperative period (p = 0.539). NRS scores of group N240 were not inferior to those of group NF at 30 min after RR admission, or at 8 and 24 h postoperatively . Postoperative adverse effects were not significantly different between the two groups (p = 1.000) and other outcomes were also not significantly different between the two groups (p ≥ 0.225). Conclusions: PCA using nefopam alone has a non-inferior and effective analgesic efficacy and produces a lower incidence of postoperative adverse effects compared to a combination of fentanyl and nefopam after laparoscopic cholecystectomy. Laparoscopic surgical procedures are preferred over open surgery because of their advantages, such as less postoperative pain, early recovery, and reduced postoperative complications; however, patients often complain of moderate to severe pain after laparoscopic surgery  and effeOpioid-based patient-controlled analgesia (PCA) is still commonly used for postoperative pain control in many countries and hospitals; however, it is associated with adverse effects, such as nausea and vomiting, respiratory depression, constipation, urinary retention, opioid tolerance, opioid resistance, and opioid-related hyperalgesia ,4,5. PosPostoperative pain management regimens need to minimize or completely avoid the use of opioids whenever possible ,10. To mNefopam is a centrally acting non-opioid, non-steroidal analgesic that has been used as an alternative to opioids for analgesia in patients with moderate to severe pain . NefopamWe hypothesized that PCA using nefopam alone could control postoperative laparoscopic pain as effectively as PCA using a nefopam-fentanyl combination. Therefore, we investigated the non-inferiority of PCA, using either nefopam alone or combined nefopam-fentanyl using fentanyl-equivalent doses for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. The primary outcome of this study was whether the non-inferiority margin of the numeric rating scale (NRS) exceeded 1.0 at 8 h postoperatively in the group receiving PCA using nefopam alone (group N240), compared to that using a nefopam-fentanyl combination (group NF). https://cris.nih.go.kr/, ref: KCT0002777) accessed on 12 June 2019. It was conducted according to the Declaration of Helsinki of 1964 and all its subsequent revisions.This prospective, randomized, controlled, double-blind non-inferiority study was approved by the Institutional Review Board of Chosun University Hospital (Chosun 2019-05-006) on 6 June 2019, and was prospectively registered with the Clinical Research Information Service (CRIS: The subjects included patients aged 20 to 70 years with an American Society of Anesthesiologists (ASA) physical status of I-III who were scheduled to undergo elective laparoscopic cholecystectomy under general anesthesia between 7 June 2020 and 16 December 2020. Written informed consent was obtained from all participants or their legal surrogates after a thorough explanation of the purpose of this study. Participants were instructed to push the “demand” button of the PAINSTOP device  whenever they experienced pain of >4 points on the NRS . We excluded patients with renal, hepatic, or thyroid functional abnormalities, neuromuscular disorders, convulsive disorder, moderate to severe respiratory depression, glaucoma, urinary retention, a history of opioid or nefopam medication within 24 h, or a history of opioid- or nefopam-related complications.n = 39) or nefopam 240 mg alone . Randomization was performed using a computer-generated table of random numbers with a 1:1 allocation ratio. This randomization was performed using an online website .Seventy-eight patients were randomly assigned to two groups that received PCA with either a combination of fentanyl 600 μg and nefopam 120 mg  was responsible for obtaining informed consent from participants, as well as gathering and recording data from the participants and PCA devices. The researcher who managed the PCAs (RP) was responsible for assigning the correct drugs to each PCA device according to the randomization scheme. For blinding, RP recorded the drug assignment on anesthetic charts after the anesthesia was completely finished, and RA finally collated the data from patient medical records, as well as data generated through the trial for at least 24 h postoperatively. Neither RA nor RP participated in the statistical analysis. The nurses in the recovery room (RR) or ward recorded data on postoperative pain and postoperative nausea and vomiting (PONV) using the NRS; these nurses were not part of the investigating team and were trained by the hospital to assess pain intensity and PONV using the NRS, visual analogue score , or Woong–Baker faces pain ratings scale . After premedication with intramuscular midazolam (0.05 mg/kg), the patients were transported to an operating room. RA anesthetized the patients using total intravenous anesthesia with propofol and remifentanil, during which the entropy or bispectral scores were controlled between 40−60 and the hemodynamics were controlled to a maximum of 20% change from baseline values; optimal neuromuscular paralysis was maintained with rocuronium under acceleromyography monitoring. Consistent hypotension was managed with intermittent bolus dosing of either phenylephrine 100 µg or ephedrine 10 mg. Bradycardia below 50 beats/min was managed with intermittent bolus dosing of atropine 0.5 mg. Intraoperative hypothermia was prevented through the application of an air-forced blanket warmer. Incisions were made at the infraumbilical, subxyphoid, and right midclavicular subcostal regions to create access for laparoscopic cholecystectomy. At the end of surgery, patients did not receive any wound anesthetic infiltration with local anesthetics or any regional analgesia. The patients were transferred to the RR after complete reversal of the rocuronium-induced neuromuscular paralysis and when they were fully awake.Ten minutes before the end of surgery, RP started the PCA device according to the group allocation after administration of a loading dose (0.1 mL/kg) from the PCA device along with ramosetron (0.3 mg). In group FN, the total PCA volume used was 120 mL, which was comprised of normal saline, fentanyl (600 μg), nefopam (120 mg), and ramosetron (1.2 mg). In group N240, the total PCA volume used was 120 mL, which was comprised of normal saline, nefopam (240 mg), and ramosetron (1.2 mg). The PCA devices were set to administer a bolus of 2 mL , with a lockout interval of 15 min and a background infusion rate of 2 mL/h . All drug doses were based on the ideal body weight of patients. The PCA devices were locked using a password to ensure the safe injection of drugs and to prevent changes in device settings.When patients experienced pain of >4 points on the NRS or >40 points on the VAS, nurses or patients were allowed to push the button for administration of a bolus dose. When patients required additional rescue analgesics within the lockout interval, we permitted the intravenous injection of opioids, NSAIDs, or tramadol as a rescue analgesic to treat pain of >4 points on NRS. These rescue analgesics were selected by surgeons. When there was no consistency in the degree of pain complaints between the NRS and VAS in the RR and the ward, the patient’s postoperative pain was reevaluated using the FPRS; nurses administered a bolus dose based on an FPRS score of >4 points if it did not match the NRS score. We treated PONV of >4 points on the NRS with an intravenous injection of metoclopramide (10 mg). Our research staff decided whether to stop the PCA device based on the severity of signs and symptoms, and we excluded such cases from the final statistical analysis. The primary outcome of this study was the NRS at the eighth postoperative hour. We recorded pain intensity using the NRS, VAS, and FPRS, as well as the need for additional rescue analgesics and antiemetics 30 min after admission to the RR, followed by 8 and 24 h postoperatively. We downloaded data from the PCA device  using its built-in Wi-Fi system in 2-h intervals until 24 h postoperatively. We recorded data on demographics  and perioperative adverse effects.http://powerandsamplesize.com/Calculators/Compare-2-Means/2-Sample-Non-Inferiority-or-Superiority, accessed on 17 May 2019). Assuming that a difference of less than 1 point in the NRS was of no clinical importance, we selected the non-inferiority margin (δ) 1.0. Based on a previous study, the mean NRS scores were 4.20 and 4.07 12 h postoperatively in groups using nefopam monotherapy and nefopam-fentanyl polytherapy (standard deviation: 1.45), respectively ). We analyzed continuous variables using the Student t-test and nominal variables with the χ2 or Fisher’s exact test. For analysis of time-interval data that passed Mauchly’s sphericity test, we used repeated measures analysis of variance; for data that did not pass Mauchly’s sphericity test, we used Wilk’s lambda multivariate analysis of variance. To compare two groups in a given time interval, the Student t-test was used. p values < 0.05 were considered statistically significant.The non-inferiority of nefopam to fentanyl was analyzed using 95% confidence intervals (CI) for the difference in VAS. Non-inferiority was confirmed when the upper 95% CI was less than the non-inferiority margin (δ = 1.0). IBM SPSS Statistics for Windows, ver. 26.0 , was used for all statistical analyses. All data were analyzed as if their probability distributions were normal based on the central limit theorem, and are presented as means , means ± standard deviation (SD), numbers of patients , and they decreased with time in both groups , and they decreased with time in both groups , and they decreased with time in both groups , nefopam, diclofenac, and pethidine. The proportion of patients requiring rescue analgesics and antiemetics were not significantly different between the groups throughout the recovery period  was not inferior to opioid-based PCA  at 12 h postoperatively ; this produced a mean VAS of 3.3 and a lower incidence of nausea in patients undergoing laparoscopic gynecologic surgeries ,17,18. ITwo-day PCA using fentanyl alone 16 μg/kg) has been shown to be effective in controlling postoperative pain as much as 3.1 in VAS scores at 6 h postoperatively in patients undergoing laparoscopic cholecystectomy, but a high incidence of PONV  was a major concern . To mini μg/kg haIn this study, we set equal doses of fentanyl equivalents in each group using the following guidance: fentanyl 100 μg = morphine 10 mg = nefopam 20 mg . We usedNefopam is associated with adverse effects such as nausea, drowsiness, light-headache, dizziness, dry mouth, and sweating, which are mostly non-significant and favorable at an appropriate dose ,20,21,22Even though the analgesic mechanisms of nefopam are not clearly understood, the postoperative analgesic effect is known to result from its role as a serotonin–norepinephrine–dopamine reuptake inhibitor and is not related to direct action on opioid receptors or the induction of an anti-inflammatory effect as observed with NSAIDs ,24. SomePCA using a combination of nefopam (4 mg of bolus dosing) and fentanyl (10 μg of bolus dosing) showed an overall fentanyl-sparing effect of 54.5% in patients who underwent laparoscopic hysterectomy . NefopamThe present study has some limitations. First, we used a fixed dose of nefopam and fentanyl for each patient, regardless of their weight. Second, the efficacy of PAC using nefopam alone is not guaranteed in surgeries with varying levels of postoperative pain intensity, because this study was conducted in laparoscopic surgery. Third, we did not assess the risk factors for PONV  with the Apfel score, even though laparoscopic surgery is a risk factor for PONV . In addiIntravenous PCA using nefopam alone has a non-inferior and effective analgesic efficacy and produces a lower incidence of opioid- and nefopam-related adverse effects compared to a combination of fentanyl and nefopam after laparoscopic cholecystectomy.