Increasing acceptance of COVID-19 vaccines is imperative for public health. Previous research on educational interventions to overcome vaccine hesitancy have shown mixed effects in increasing vaccination intention, although much of this work has focused on parental attitudes toward childhood vaccination. In this study, we conducted a randomized controlled trial to investigate whether vaccination intention changes after viewing an animated YouTube video explaining how COVID-19 mRNA vaccines work. We exposed participants to one of four interventions–watching the video with a male narrator, watching the same video with a female narrator, reading the text of the transcript of the video, or receiving no information (control group). We found that participants who watched the version of the video with a male narrator expressed statistically significant increased vaccination intention compared to the control group. The video with a female narrator had more variation in results. As a whole, there was a non-significant increased vaccination intention when analyzing all participants who saw the video with a female narrator; however, for politically conservative participants there was decreased vaccination intention for this intervention compared to the control group at a threshold between being currently undecided and expressing probable interest. These results are encouraging for the ability of interventions as simple as YouTube videos to increase vaccination propensity, although the inconsistent response to the video with a female narrator demonstrates the potential for bias to affect how certain groups respond to different messengers. Even before COVID-19 became a pandemic in 2020, the World Health Organization considered vaccine hesitancy a top global health threat . AlthougThis study examines an eight-minute, animated, educational YouTube video on the COVID-19 mRNA vaccines that we made called “COVID mRNA vaccines explained.” The video explains how the mRNA vaccine platforms work, highlights some of the positive features of the COVID-19 mRNA vaccines such as high efficacy and rarity of serious side effects, and emphasizes the altruism of vaccination. While the lack of editorial oversight of health information on YouTube and other social media platforms has contributed to the spread of vaccine misinformation and disinformation –8, YouTuMale-Narr-Video https://youtu.be/Fv5bs4SPiYE), b) watching the same video with a female narrator , c) reading a blog post containing the text of the transcript of the video, or d) receiving no information to serve as a control group. The visuals and scripts for both versions of the videos were identical; only the voice of the narrator differed. The results showed statistically significant higher vaccination intention in the group that watched the Male-Narr-Video compared to the control group, a robust association for a variety of alternative specifications. However, despite participants rating the quality of instruction of both the Male-Narr-Video and Female-Narr-Video equally highly, we found less consistent associations on intention to vaccinate for participants exposed to the Female-Narr-Video intervention. As a whole, the Female-Narr-Video produced a non-significant increase in vaccination intention compared to the control group. However, the impact on vaccination intention of the Female-Narr-Video varied by political identity of the participants. Political conservatives who were exposed to the Female-Narr-Video were less likely to express probable or definite interest in getting vaccinated than conservative respondents exposed to no information in the control group and other respondents exposed to the Female-Narr-Video . Adjusting for this conditional association showed that for respondents who did not identify as politically conservative, both videos associated with increased vaccine intention at much closer rates, no matter the narrator. No such conditioning among political conservatives was observed for participants exposed to the Male-Narr-Video. Although further research is warranted to investigate the variation in efficacy based on the gender of the narrator, overall, this evidence supports the idea that educational YouTube videos, such as the Male-Narr-Video, may serve as an easy to share, simple way to increase vaccination intention.Herein we present the results of a randomized controlled trial conducted with 1,184 Mechanical Turk participants to investigate the effect on vaccination intention of an animated YouTube video explaining how the COVID-19 mRNA vaccines work. We investigated whether the exact same information presented in different formats would alter the efficacy of the communication by exposing treatment groups to either: a) watching the video with a male narrator , and the Male-Narr-Video was created later as an additional experimental condition. In other words, the creation of the Female-Narr-Video was independent of the idea of testing whether narrator gender might associate with its effectiveness; only after receiving positive anecdotal feedback on the original video did we decide to study the efficacy of such variations. Given findings that audiences draw on negative stereotypes about women who communicate scientific findings, and rate women teaching about science lower than men, [The han men, ,23, we wThe video begins with an explanation of the flow of genetic information, then explains how weakened virus vaccines work before explaining what an mRNA vaccine means. The video then emphasizes that the Pfizer-BioNTech (referred to as Pfizer in the video) and Moderna vaccines have been tested for safety and efficacy, and ends with an explanation of how getting vaccinated can protect others in society.i) The video emphasizes the messages that approved vaccines are safe and go through evaluations [ii) The video does not focus on messages that have been reported to impede efforts to diminish vaccine hesitancy such as myth-busting, fear-based, or numerically focused messages [iii) The video creates clear bottom-line (gist) messages through: explanations of concepts in simple language rather than scientific jargon; the use of animated illustrations to visually reinforce the concepts explained verbally; and the use of text on the screen to underscore take-home messages. Research in medical decision making has found that gist messages contribute to decision-making in a meaningful way relative to statistics and verbatim information [Previous research on vaccine hesitancy interventions has identified common features for successful communication. This video incorporates many of these features, including: luations , and thaluations . ii) Themessages . iii) Thormation ,7,10, anormation .At the time of making the video, there was not yet much literature on recommendations for interventions specific to the COVID-19 vaccines. In some respects, the unique characteristics of the COVID-19 vaccine may alleviate some of the attitudes that have contributed to parental vaccine hesitancy for childhood vaccinations. For instance, it has been hypothesized that the benefits of some vaccinations may not seem tangible due to unfamiliarity with the harm of the preventable disease , which mPrevious research has indicated that the messaging matters in addition to the message—that is, it is not just what one says, but how it is said that influences the effectiveness of video communication ,28. ThisFemale-Narr-Video version had a female voice reading the transcript and the Male-Narr-Video version had a male voice. In both cases the timing of the narration was matched to the animations (which led to a 3 second difference in length of the videos). The videos used in the survey were posted on unlisted YouTube sites, and reposted on the following links for others beyond the study participants to see: Male-Narr-Video https://youtu.be/Fv5bs4SPiYEFemale-Narr-Video https://youtu.be/j3hTeDyvgPs.Because the narrator is never depicted in the video, we saw the video as a platform to isolate and test the effects of a single variable related to the messenger: the gender of the narrator’s voice. Therefore, two versions were used in the study, identical but for the voice of the narrator: the These videos have different title pages than the original video posted before the study was conceived.Male-Narr-Video, the Female-Narr-Video, or read the text of the video transcript presented as a blog post. On each of these pages, the time the participants spent on the page was recorded and advancing to the next page was disabled for a few minutes  to increase the likelihood that participants engaged the material. After the information was presented in the video or text format, the participants encountered a section with questions that first asked about their intent to get vaccinated and then asked about their attitudes concerning the COVID-19 vaccines. The participants in the 4th path did not receive any information and went directly to the vaccine intention and attitudes section.Participants completed a survey to measure COVID-19 vaccination intention, attitudes, and understanding. Many of the survey items were similar to validated items from the literature, with some adaptations since many of the previous scales of vaccine hesitancy have been used to measure parental attitudes towards childhood vaccinations . Using tThe vaccination intention item was based on the Imperial College London “Global attitudes towards a COVID-19 vaccine” survey  and asketh and 26th, 2021 when the two approved COVID-19 vaccines in the United States were the Pfizer-BioNTech and Moderna mRNA vaccines. Guided by contemporary findings that around 40% of people would get a vaccine if offered one [The survey was administered to 1,632 participants on Amazon Mechanical Turk on February 25ered one . The onlered one –33. The Male-Narr-Video group, n = 255 for the Female-Narr-Video group, n = 282 for the text group, and n = 393 for the control group.Unless otherwise noted, the exclusion criteria that were applied were: exclusion of participants who had indicated they had already been vaccinated, exclusion of participants who answered the attention check question incorrectly, and exclusion of participants who spent less than 7 min on the video page (for a 7 min 37 sec video) or who spent less than 2 min 5 sec on the blog post page. These criteria resulted in exclusion of 321 (28.6%) of respondents in one of the experimental conditions, consisting of 65 excluded for both reasons, 184 excluded for the attention check alone, and 62 excluded on the basis of time on task alone. This exclusion rate is consistent with estimates of untrustworthy MTurk workers . The resgologit2 program in Stata using the program’s autofit option and robust standard errors [Since vaccination attitudes exist on a continuum with vaccine refusal on one end, active demand on the other, and uncertainty and hesitation in the middle ,36, we cd errors ,39. ThesAlthough participants were randomly assigned to treatment conditions, we included a series of control variables  in our models that may associate with vaccine intention. Mechanical Turk respondents are a diverse, but not nationally representative group  . While trust in science is politicized, studies find differences in how political identities relate to such trust ,45. AlthFemale-Narr-Video and vaccine intent varied based on respondents identifying as conservative (Model 2). We first estimated a model with the treatment variables and control variables (Model 1), and then estimated a model testing whether the association between Male-Narr-Video and vaccination intent, consistent across all levels of intent. Compared to the control group given no information, respondents who watched the Male-Narr-Video were more likely to express vaccination intention as measured by their response to the question how likely they would be to receive a COVID-19 vaccine if it were available to them this week . Male-Narr-Video would have a predicted probability of 53.5% of replying “definitely yes” for their intention to be vaccinated, compared to a predicted probability of 42.6% for the control group. Those exposed to the text intervention had a much smaller, statistically insignificant increase in vaccination intention compared to the control group . The pattern for respondents exposed to the Female-Narr-Video intervention, however, had a more nuanced pattern, as there were asymmetric associations across the different levels of vaccine intent. Although outside of the standard cut-off for statistical significance, those exposed to the Female-Narr-Video had a greater likelihood of answering “definitely yes” to getting the vaccine compared to the control group , albeit to a lesser degree than those exposed the Male-Narr-Video. Again, although not statistically significant, the range of coefficients at different levels of vaccine intent suggests that there may have been heterogeneous effects of being exposed to the female video, which we tested in Model 2.Model 1 shows a positive association between having been exposed to the Female-Narr-Video. The interaction term tests whether exposure to the video with the female narrator had different effects for people who identify as conservative than for those who do not identify as conservative. The addition of the politically conservative x Female-Narr-Video interaction variable showed that the main effect of the Female-Narr-Video for non-conservative respondents was a positive association consistent across levels of intent on the margin of statistical significance . The magnitude of the coefficient is closer to the Male-Narr-Video  than it was in Model 1 for any of the levels of intent, although the larger standard error for the Female-Narr-Video does suggest more heterogeneity remaining in the effect of the Female-Narr-Video. The interaction term shows a notable significant negative association for conservatives exposed to the Female-Narr-Video being less likely to express a vaccination intention greater than the “uncertain” response  when compared to either conservatives in the control condition or to others exposed to the Female-Narr-Video. In other words, among political conservatives, exposure to the video with a female narrator seemed to decrease the propensity of getting to a yes response (whether “probably yes” or “definitely yes”) for the vaccine when compared to political conservatives in the control group.In Model 2, we added a variable testing for a conditional association between respondents who are politically conservative and viewed the Male-Narr-Video of having either a “definitely yes” or “probably yes” response (83.0% and 81.4% respectively). The same comparison for the Female-Narr-Video shows a substantially wider gap . Notably, the predicted probability for a conservative exposed to the Female-Narr-Video to reply to the vaccination intention question with “definitely yes” or “probably yes” (60.6%) is also substantially lower than for a conservative in the control group that was not exposed to any information (73.7%). Tests for similar conditional effects for Male-Narr-Video on political conservatives showed no such conditional association (see Supplementary Information). For example, adding an additional interaction term for conservative x Male-Narr-Video to the variables in Model 2 produced a coefficient with a near zero association , while not changing any substantive patterns reported in These patterns are illustrated in Female-Narr-Video and Male-Narr-Video associate with vaccination intent reflect a difference in how respondents perceived the quality of the two videos; however, we found that participants as a whole rated the quality of instruction in the two versions of the video equally highly. This similarity in rating runs contrary to expectations based on previous research that has found that when quality of instruction is measured on a 10-point scale, gender gaps in favor of men are wider, particularly in male-dominated fields [Female-Narr-Video rated the quality of instruction 0.08 points higher, on average, on a 10-point scale than those who saw the Male-Narr-Video  regression between the analytic sample reported in the main text and the full sample (with no cases excluded). OLS models allow more direct comparison of effect sizes across models than generalized ordered logit models. Male-Narr Video treatment condition is robust across both the limited and full sample. Although there is a small change , the effect still remains statistically significant. Furthermore, both the Female-Narr Video and text treatment coefficients are statistically insignificant in both the limited and full samples and neither coefficient shows a similar change as the coefficient for Male-Narr Video when moving from the limited to full samples. This approach to eliminating the possibility of post-treatment bias based on exclusion comes with two trade-offs. First, it alters the nature of the explanatory variable from treatment to an intent to treat with the condition, which is not a direct test of the main hypothesis that the video treatment can alter vaccination intent [Male-Narr Video from the analytic and full sample approximate these two estimates. Finally, because our models include control variables that could correlate both with the likelihood of exclusion and change in vaccination intent, some of the risk of post-treatment bias may be controlled for in the models. We see the balance of evidence reviewed here favoring the analytic sample. That is, the available evidence is less consistent with post-treatment bias than with the full sample containing nontreatment associated noncompliance that could affect estimates. Nonetheless, we cannot rule out the possibility that some unmeasured characteristic introduced some degree of post-treatment bias. Yet, even if there were some post-treatment bias, our main finding about the robust effect of the Male-Narr Video still receives support in the full sample analysis.These analyses show that the effect associated with the n intent . Second,n intent . We noteFemale-Narr Video among politically conservative respondents does not appear to be as robust to the inclusion in the full sample when examining the OLS models. While this outcome suggests that some caution is warranted in interpreting the specific finding, it does reinforce the general conclusion that the Female-Narr Video condition has greater heterogeneity in association with vaccination intent. That is, if the finding in the models based on the analytic sample is the result of post-treatment bias, it would be a post-treatment bias unique to just the Female-Narr Video treatment. Future research could address concerns about both post-treatment bias and data quality by instituting some of the recommendations for ensuring MTurk, such as using IP addresses as a screening tool [The conditioning of the ing tool .In addition, our analysis is limited in identifying the precise mechanisms that might account for variation and possible mediators of the interventions that we tested. Although we provided both video and text interventions and altered one characteristic of the video (the narrator’s gender), we have little information about the precise qualities of the video that may have been effective and how those qualities might relate to gendered expectations, suggesting many avenues for future research. For example, the use of an animated video does not provide visual cues about the narrator, which could accentuate, attenuate, or interact with vocal characteristics. Similarly, other vocal qualities, such as pitch, accent, or volume could affect how viewers receive messages. These vocal qualities could vary across or within genders, and their association with message effects might vary. For instance, the differences between lower and higher pitches could vary for male and female narrators. Since our study used just one male and one female narrator voice, follow up work can interrogate the role of these other factors on perceived scientific authority and legitimacy.Finally, our study has focused on communication of scientific information in relation to vaccine intent. While it is suggestive of ways that members of the public may react to scientific authority, there may be contextual influences that shape responses to the video in ways that limit generalizability to vaccination intent specifically and scientific authority more generally. The widespread reach of COVID-related hospitalization, death, and economic and social disruption may shape peoples’ openness to scientific information, particularly when vaccines were first introduced and could be seen as the most likely way to end the pandemic. More generally, it could be that people react to scientific authority differently based on the salience of issues and the extent to which they are politicized. Future research on such communication could examine both more and less political and more and less personally experienced scientific topics. Such research could give more insight about whether gender, political ideology, and scientific authority interrelate across topics. Increasing the visibility of women’s roles in scientific advances may contribute to longer-term change in gendered reactions to scientific information, although as others have argued, addressing questions of inclusion more broadly may also be necessary .Widespread uptake of the COVID-19 vaccines worldwide is crucial for ending the COVID-19 pandemic. Previous work on vaccine hesitancy interventions have recommended that health organizations use social media channels such as YouTube to spread pro-vaccination messages, but caution that vaccine communications should first be tested ,19–21. HS1 Appendix(PDF)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


Chronic rhinosinusitis with nasal polyps (CRSwNP) in asthmatic patients has a high recurrence rate even after surgery. For this reason, oral steroids are frequently used, but their long-term use may cause side effects. The purpose of this study is to investigate the long-term effects of budesonide nasal irrigation (BNI) in CRSwNP and asthma. An analysis of 33 patients with CRSwNP and well-controlled asthma, who performed BNI for more than 12 months, was performed. We compared oral steroid and antibiotic dosages as well as nasal endoscopy scores before, and every six months after, BNI. The six-month dosages of oral steroids and antibiotics prescribed were significantly decreased at all time points after BNI compared to before BNI. When the dosages were compared at the time point immediately preceding six months, oral steroid intake decreased significantly until 12 months, and antibiotic intake decreased until 6 months. Furthermore, the endoscopic score decreased significantly until 12 months. The nasal symptom questionnaire score also significantly improved after BNI. Therefore, BNI is considered an effective treatment method that can improve subjective symptoms and objective intranasal findings while reducing oral steroid and antibiotic doses after long-term use in patients with CRSwNP accompanied by asthma. Chronic rhinosinusitis (CRS) is a chronic inflammatory disease, and the clinical course is influenced not only by a bacterial infection but also by various immune cells and their mediators ,2. CRS iMany cases of chronic rhinosinusitis with nasal polyps (CRSwNP) accompanied by asthma show a clinical course of recalcitrant rhinosinusitis, such as a low response to conservative treatment, a high recurrence rate even after surgery, and frequent exacerbation . TherefoRecently, the efficacy of budesonide nasal irrigation (BNI) has been widely reported in patients with CRS ,7. ThrouIn 2017, a prospective study was performed at our center, and we revealed the short-term effectiveness of BNI in patients with CRSwNP and asthma . TherefoThis study was conducted through a retrospective chart analysis of 33 patients with CRSwNP accompanied by well-controlled asthma who performed BNI for at least 12 months between 2014 and 2020. Among the 33 patients, 21 patients performed BNI after endoscopic sinus surgery (ESS), and 12 patients performed BNI without surgery. ESS was performed when the polyp was severe enough to completely block the middle meatus or spheno-ethmoidal recess (SER) so that at least the irrigation solution could enter the ostiomeatal unit and SER. ESS was not performed if there was enough space for the irrigation solution to enter the middle meatus and SER with small polyps. Therefore, the disease burden of patients who underwent ESS and those without ESS were similar, with a Lund-Kennedy (LK) endoscopy polyp score of less than 1.To exclude the effect of the acute phase of surgery, BNI was started more than three weeks after the surgery, when the nasal mucosa was healed. Patients who did not undergo BNI continuously, or who needed to take oral steroids and immunosuppressants for other underlying diseases, were excluded. Patients attended regular follow-ups every three months in both otolaryngology for CRSwNP and the pulmonary medicine department for asthma. Patients with uncontrolled asthma who were not treated for asthma at our hospital pulmonary department, and one patient who needed oral systemic steroids for asthma control, were also excluded.Oral steroids and antibiotics were prescribed according to the state of the patient’s disease at their outpatient visit. An oral steroid was prescribed when symptoms such as anosmia worsened or when the nasal polyp was severely exacerbated on the endoscopic examination. Oral antibiotics were prescribed for severe purulent rhinorrhea on the endoscopic examination.This study was approved by the IRB (IRB No. 2021-06-014) and was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration.®, Kuhnil Inc., Seoul, Korea) was mixed with 250 mL of normal saline. Half of the solution was used for each nasal cavity so that both nasal cavities could be irrigated evenly. After irrigation, oral gargle was performed with clean water to remove any solution remaining on the oral mucosa. BNI was performed once or twice a day depending upon the severity of nasal symptoms and status of endoscopic examination.BNI was performed using a nasal washing bottle . An individually packaged 0.5 mg/2 mL budesonide suspension  scans and total immunoglobulin E (IgE) tests were performed before starting BNI. PNS CT scans were analyzed according to the Lund–Mackay CT score, which scores the degree of disease identified in each sinus.To analyze the oral steroids dosage, the average of 6 months of total steroid dose (mg) taken before BNI, and the six-month total dosage of steroid taken every six months after BNI were recorded. Every six months, we assessed whether the steroid intake was decreased after BNI compared to the dose before BNI. In addition, the six-month dosage of oral steroids was compared to that of the immediately preceding six months to confirm the treatment time point that showed a progressive therapeutic effect, which was represented by a significant decrease in steroid dosage; this period was defined as the “cutoff point”.The oral antibiotic intake was also compared using the same method of analyzing oral steroids. Since various types of oral antibiotics were prescribed, there was a limit to analyzing the antibiotic intake based on dose like steroids, so the antibiotic intake was analyzed by the number of days the antibiotic was taken.To confirm the effect of BNI on the nasal mucosa and polyps, the nasal cavity was checked using endoscopy at outpatient visits every six months, and its state was scored according to the LK endoscopy score. The LK endoscopy score was also investigated and analyzed in the same way as mentioned above, before and every six months after BNI.Finally, in order to identify the effect of BNI on patients’ subjective symptoms and quality of life, a 22-item Sinonasal Outcomes Test (SNOT-22) was performed, and the resulting score was compared between two time points: before irrigation and 12 months after irrigation.t-test. Repeated-measures analysis of variance (ANOVA) was performed to confirm whether there was a continuous and significant decrease in all groups considering the characteristics of different follow-up periods. In addition, to identify the cutoff point for determining the effective therapeutic period of BNI, a paired t-test was performed. In all statistical analyses, a p-value of less than 0.05 was defined as statistically significant, using SAS version 9.4 .All statistical variables were expressed as mean ± standard deviation values. The period of statistical analysis was six months, and values of oral steroid usage, antibiotic usage, and endoscopic findings for each six-month period were analyzed using a paired A total of 33 patients who underwent BNI for at least 12 months were enrolled, including 13 men and 20 women with an average age of 52.48 ± 14.41 years. BNI was performed for an average of 27.64 ± 7.07 months, using 18.48 ± 9.30 boxes (30 respules per box) of budesonide.The patients’ total IgE values were 569.13 ± 620.21 IU/mL, and 27 patients showed a level higher than the normal level. Among the Lund–Mackay CT scores, the anterior ethmoid sinus had the highest score of 1.54 ± 0.65 points, which was significantly higher than that of other sinuses in the ANOVA test. A high total IgE level and a PNS CT finding of anterior ethmoid sinus predominance is consistent with the characteristics of CRSwNP with asthma.The total amount of oral steroid intake (mg) was checked every six months . The sixIn order to confirm the cutoff point showing a significant therapeutic effect, we compared the total six-month dosage of steroids and that of the immediately preceding six months. A significant decrease in the steroid dose was confirmed up to 12 months after irrigation; after 12 months, there was a decreasing trend, albeit without statistical significance .The total number of days of antibiotics taken over six months was investigated in the same manner as the oral steroids . The numThe LK endoscopy score was analyzed before, and every six months after, irrigation . The scop < 0.001).The patients’ subjective nasal symptoms were also improved. A significant improvement in the SNOT-22 score was obtained, from an average score of 40.03 ± 14.5 points before irrigation to an average score of 17.27 ± 10.68 points after irrigation  axis or intraocular pressure could be affected by the topical steroid absorption. The safety of use of long-term BNI related to the HPA axis and intraocular pressure has already been confirmed in many studies ,25. HoweAdditionally, if long-term use is possible, another essential issue is how long BNI should be carried out. Our study was conducted to check for the “cutoff point” by comparing oral steroid doses, antibiotic doses, and endoscopic findings every six months with the previous six months to confirm this issue. Both oral steroid doses and endoscopic findings showed a cutoff point of 12 months, proving that performing BNI for about 12 months had a significant therapeutic effect compared to during the period before. Based on the results, performing BNI for about 12 months is recommended, during which time the nasal sinus mucosa is stabilized through remodeling by budesonide irrigation. It is thought that this should be elucidated in detail by further studies with histological and immunological examinations of the mucosa. Furthermore, if the mucosa stabilizes after irrigation for about one year and no symptoms manifest, then BNI could possibly be stopped. However, even if there is no significant improvement after irrigation for 12 months, the use of BNI can be extended while monitoring the symptoms of HPA-axis inhibition and intraocular pressure. In this study, most of the patients showed significant improvement after 12 months of continuous BNI. However, in 10 patients (30.3%), the course of the disease was so poor that they required more than 36 months of treatment. These patients can be regarded as cases of more severe recalcitrant CRS, which is not well responsive to BNI. For these patients, biologics, which have recently been developed and have expanding indications, may be available. Biologics have already begun to be used in refractory asthma and atopic dermatitis. Recently, they have been proven to be effective in CRSwNP, especially in the refractory cases associated with a Th2 immune response, like the subjects of our study ,27. HoweThe significant decrease in antibiotic dosage up to six months after BNI suggests that the role of the nasal mucosa in a Th2 immune response is greater than the role of the bacterial infection in CRSwNP with asthma. When the nasal mucosa stabilizes and the nasal polyps decrease with 12 months of budesonide nasal irrigation, the ostiomeatal unit could remain open such that bacterial infection secretions do not easily occur, which results in a reduced role of antibiotics as a treatment option.Although this study is a long-term report of a relatively large number of patients (33) with follow-up data collected to 36 months, it has several limitations. One of the limitations is that it is not a randomized controlled study. Another limitation is that the patient population was not uniform. If additional research is to be conducted, it is necessary to separate the operated and non-operated patients and to analyze them further according to the asthma control status. Finally, since BNI was stopped when the condition improved after 12 months, the number of enrolled patients decreased over the treatment period. As the number of subjects was reduced, it may appear that there was no statistical significance. In patients with CRSwNP accompanied by asthma with repeated exacerbations and recurrences, BNI can help reduce the need for oral systemic steroids and antibiotics by objectively improving the nasal condition and the patients’ subjective symptoms. When BNI was used for more than 12 months, many patients improved, and even after using it for up to 36 months, it was safely used without side effects. For those patients who do not improve after long-term budesonide nasal irrigation, the use of biologics can be considered.In patients with CRSwNP accompanied by asthma with repeated exacerbations and recurrences, BNI can help reduce the need for oral systemic steroids and antibiotics by objectively improving the nasal condition and the patients’ subjective symptoms. When BNI was used for more than 12 months, many patients improved, and even after using it for up to 36 months, it was safely used without side effects. For those patients who do not improve after long-term budesonide nasal irrigation, the use of biologics can be considered.


What is stolons . Criticasumption ).4-grasses) and browsers  species) have different ratios of 13C isotopes in their bone collagen: pure C4-grazer values exceed −9‰, whereas obligate C3-woody feeders measure below −21.5‰. Hansford & Turvey , that supports processes to facilitate ancient ecological patterns, and avoids practices that do not . Studiesca 1200–1050 BP, at the time when agro-pastoralism led to intensive conversion of forest to grassland [Aepyornis hildebrandti) obtained up to 48% of its diet from C4-grasses, interpreting this as evidence for a grazing guild among Madagascar's Holocene megaherbivores. Here, we offer an alternative interpretation.For specialist grazers, prime candidates have been thought to be the various species of hippopotamus that once inhabited Madagascar . These srassland  analyses4-grass representing under half of dietary intake , Aepyornis hildebrandti groups with African mixed-feeding browser guilds  that favour proximity to woodland/scrubland/thicket [4-grazing specialists tolerant of treeless grasslands, that exert the type of top-down control that forms obligate grazing-lawns, like Connochaetes taurinus [With C/thicket , and notRhea americana). Rhea prefer legumes and other dicots, but also eat seeds, fruits, small vertebrates, invertebrates and tall grasses [Aepyornis hildebrandti had similar feeding habits, we would expect bill-feeding in minimally grazed swards that bear no functional similarity to cropped obligate grazing-lawn grasses . This, despite the presence of prime candidates, Malagasy hippopotamus species, which Hansford & Turvey [Importantly, endemic Malagasy grasses are sensitive to ungulate trampling and grazing, and probably ‘evolved under conditions of light grazing or no grazing' . ng-lawns , and evian today ,12 avert


There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone , DEC alone , AZA-VEN  and DEC-VEN . VEN improved CCR rates to HMAs overall  and to AZA , but not to DEC ; it did not improve OS, and only improved EFS for AZA . CCR rates were lower with AZA than with DEC , but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN , but OS and EFS were longer for AZA-VEN . Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC. Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by diverse cytogenetic and molecular abnormalities, including aberrant DNA methylation . The medThe hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DEC) are used to treat AML patients unlikely to tolerate or respond to cytotoxic chemotherapy, recently in combination with the B-cell lymphoma-2 (Bcl-2) inhibitor venetoclax (VEN) . AZA andThere is a deficiency of data on real-world outcomes of adding VEN to HMAs. Moreover, there are no studies comparing AZA-VEN with DEC-VEN. This propensity score-adjusted cohort study aims to evaluate CCR, OS and event-free survival (EFS) in newly diagnosed AML patients treated with HMAs with or without VEN.2 body surface area subcutaneously or intravenously on days 1-7 of 28-day cycles. DEC was administered at a dose of 20 or 10 mg/m2 body surface area intravenously on days 1-5 or 1-10 of 28-day cycles  with newly diagnosed AML treated with an HMA (AZA or DEC) with or without VEN from 2013 through 2020. Comparison groups included HMA vs. HMA-VEN, AZA vs. AZA-VEN, DEC vs. DEC-VEN, AZA-VEN vs. DEC-VEN and DEC vs. AZA. AZA was administered at a dose of 75 mg/my cycles . PatientBone marrow aspirate and biopsy were obtained to assess response at the end of cycle one (~ Day 28). Treatment response was defined according to the 2017 European LeukemiaNet (ELN) criteria . Cycle tData were collected from medical records of all patients diagnosed with AML at the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC) between 2013 and 2020.de novo, myelodysplasia-related, myeloproliferative-related, therapy-related), cytogenetics, myeloid mutations including FLT3, IDH1, IDH2, NPM1, TP53, ASXL1 and RUNX1, and treatments received, including transplant. Cytogenetic risk groups were defined using ELN 2017 criteria  performance status, baseline comorbidities, AML categories  . We inclalancing . We usedNPM1 mutational status modifies the effect of VEN combined with HMA on OS and EFS, we fitted a weighted Cox proportional hazards model with an interaction term between NPM1 mutational status and treatment received. Regression diagnostics were used to evaluate model assumptions. Cluster-robust standard errors were used to account for subclass membership in the matching process. All statistical tests were two-sided, and P-values <0.05 were considered statistically significant. The R statistical packages’MatchIt’ and ‘WeightIt’ were used for propensity score modeling . Baseline characteristics were compared using Pearson chi-square or Fisher’s exact test for categorical variables or t-test or ANOVA for continuous variables. OS, EFS and time to achieve CCR were compared using log-rank and Gehan Breslow-Wilcoxon rank tests. Both 30-day and 60-day mortality was compared between groups using Pearson chi-square or Fisher’s exact test. Multivariable and univariable Cox proportional hazards models were used to assess relative mortality. In addition, weighted regression models were obtained to estimate outcomes , 18. Mulmodeling , 20. R-sWe identified a total of 468 AML patients treated at UMGCCC during the study period (2013-2020) and included 170 patients who were treated with HMA or HMA with VEN as first-line therapy in this study. Median age was 71.5 years (IQR 63.4-78.6) and 99 (58%) were male. Patients included 35 treated with AZA alone (20.5%), 84 with DEC alone (49%), 24 with AZA-VEN (14.1%), and 27 with DEC-VEN (15.9%). Median follow-up for all patients in the study was 53 months (IQR 24.23-78.7). TP53 and ECOG stage III-IV were associated with increased 60-day mortality. In contrast, age was not predictive. An increase of age by one year was associated with an absolute increase of 2.5% odds ratio of 60-day mortality, adjusted for other variables; however, this was not statistically significant. We also estimated whether median age (71 years) would predict 60-day mortality; this was not statistically significant.Unadjusted CCR rates were 58.3% for patients treated with AZA-VEN, 14.3% for AZA, 44.4% for DEC-VEN, and 33.3% for DEC (P=0.93). We further tested the median time to achieve CCR; it was 2.97 months (CI: 1.3-NA) for AZA-VEN, 6.5 months (CI: 4.3-NA) for AZA, 2.57 months (CI: 1.33-NA) for DEC-VEN, and 4.97 months (3.07-16.6) for DEC (P=0.003). Unadjusted and propensity score-adjusted baseline characteristics of patients treated with HMA-VEN vs. HMA are shown in The adjusted CCR rate for patients treated with HMA-VEN and HMA was 52% compared to 27% (P=0.004). In contrast, adjusted m-OS was 7.43 (CI:4.33-16.8) compared to 8.8 (CI: 6.77-11.4) months (log-rank P= 0.94), and the unadjusted m-OS was 7.43 months (CI: 4.33-15.8) compared to 8.3 months (CI: 6.77-10.6) (log-rank P=0.8). Adjusted OS at months 12 and 24 for patients treated with HMA with and without VEN was not statistically different Figure 3NPM1 mutational status modifies the effect of combining VEN with HMA, an interaction term was modeled in a weighted Cox proportional hazards regression. The impact of VEN on OS or EFS did not differ in NPM1 mutated AML compared to wild-type , .To determine if The adjusted median age for AZA-VEN vs. AZA was 69.2 (IQR:56.5-78.13) vs. 71.2 (IQR: 60.85-77.6) years (P=0.81). Median follow-up was 20.53 (CI: 18.20-26.47) vs. 53.03 (CI: 21.40-NC) months. Covariate balance before and after propensity score weighting is shown in The adjusted CCR rate for patients treated with AZA-VEN and AZA was 54% compared to 10% (P=0.0007), and the adjusted m-EFS was 10.5 (CI: 5.83-NC) compared to 3.8 (CI: 3.43-5.93) months (P=0.023) eTable 5In contrast, the adjusted m-OS for patients treated with AZA-VEN compared to AZA and was 17.9 (CI: 11.3-NC) vs. 8 (CI: 7.3-24.1) months (P= 0.263), and the unadjusted m-OS was 12.3 (CI: 9.2-NC) vs. 8 (CI: 4.73-22.9) months (P=0.4). Adjusted OS difference at 12 and 24 months for patients treated with AZA-VEN vs. AZA was not statistically differenteTable 6To explore if VEN addition to AZA increases toxicity, we estimated the unadjusted and adjusted TRM. Unadjusted and adjusted 30-day TRM in AZA-VEN vs. AZA was 4.2% vs. 14.4% (P=0.41) and 2% vs. 13.6% (P=0.07), respectively. Unadjusted and adjusted 60-day TRM in AZA-VEN compared to AZA was 12.5% vs. 28.6% (P=0.25) and 11.8% vs. 22.4% (P=0.35), respectively.2 for 10 days (65%), 21 received 10 mg/m2 for 10 days (25%), 7 received 20 mg/m2 for 5 days (8%) and one received 10 mg/m2 for 5 days. On the DEC-VEN arm, 24 patients received 20 mg/m2 for 10 days (89%) and 3 received 20 mg/m2 for 5 days (11%) (The adjusted median age for DEC-VEN vs. DEC was 72.6 (IQR: 64.36-77.89) compared to 71.9 (IQR: 64.4-79.05) years (P=0.75). Median follow-up for patients treated with DEC-VEN and DEC was 21.13 (CI: 21.13-NC) compared to 78.70 (CI: 53.03-NC) months. Covariate balance before and after propensity score weighting is shown in ys (11%) eTable 7The adjusted CCR rate for patients treated with DEC-VEN and DEC was 43% compared to 32% (P=0.35). The adjusted m-OS for patients was 5.33 (CI: 1.53-11.3) compared to 8.3 (CI: 5.83-10.4) (P=0.076) months, and unadjusted m-OS 2.23 (CI: 1.53-11.3) and 8.57 (CI: 5.83-10.6) months (P=0.08). Adjusted OS difference at 12 months was not statistically different eTable 8TRM was 25.9% vs. 17.9% (P=0.52) and 24.2% vs. 18.6% (P=0.53) in DEC-VEN vs. DEC arms, respectively. Unadjusted and adjusted 60-day TRM in DEC-VEN compared to DEC was 40.7% vs. 22.6% (P=0.11) and 37.1% vs. 23.5% (P=0.17), respectively.2 for 10 days combined with VEN to 55 patients who received DEC 20 mg/m2 for 10 days alone. The adjusted CCR rate was 54% compared to 34% (P=0.15), and the adjusted m-OS was 2.17 months (CI: 1.47-16.8) compared to 8.8 months (CI: 6.2-10.4) (P=0.38) and adjusted m-EFS 1.47 (CI: 1.17-16.43) compared to 5.37 (CI: 2.07-7.43) months (P=0.73).In this subgroup analysis, we compared 24 patients who received DEC 20 mg/mThe adjusted median age for AZA vs. DEC was 71.5 (IQR: 61-86) compared to 71.95 (IQR: 65.3-77.9) years (P=0.74). Median follow-up for patients treated with AZA and DEC was 53.03 (CI: 21.40-NC) compared to 78.70 (CI: 66.10-NC) months. Covariate balance before and after propensity score weighting is shown in The adjusted CCR rate for patients treated with AZA vs. DEC was 13% compared to 33% (P=0.04), but the adjusted m-OS for patients treated with AZA vs. DEC was 9.07 months (CI: 7.3-25.3) compared to 9.03 months (CI: 6.2-10.6) (P= 0.63). The unadjusted m-OS for patients treated with AZA and DEC was 8.0 (CI: 4.73-22.9) and 8.57 (CI: 5.83-10.6) months (P=0.6). Adjusted OS difference at years 1-4 for patients with AZA vs. DEC was not significantly different (The unadjusted and adjusted 30-day TRM in AZA compared to DEC was 14.3% vs. 17.9% (P=0.84) and 12.5% vs. 15.1% (P=0.66), respectively. The unadjusted and adjusted 60-day TRM in AZA compared to DEC was 28.6% vs. 22.6% (P=0.65) and 20.5% vs. 19.3% (P=0.87), respectively.The adjusted median age for AZA-VEN vs. DEC-VEN was 69.9 (IQR: 67.01-80.04) compared to 73.02 (IQR: 64.37-79.8) years (P=0.60). Median follow-up did not differ, at 20.53 (CI: 18.20-26.47) compared to 21.13 (CI: 21.13-NC) months. Covariate balance before and after propensity score weighting is shown in The adjusted CCR rate for patients treated with AZA-VEN vs. DEC-VEN did not differ, at 58% compared to 52% (P=0.66), but adjusted m-OS was 12.3 (CI: 9.2-NC) compared to 2.8 (CI: 2-16.8) months (P= 0.0056), and unadjusted m-OS was 12.27 (CI: 9.2-NC) compared to 2.23 (CI: 1.53-11.3) months (P=0.009). Adjusted OS at 12 months was not different (Unadjusted and adjusted 30-day TRM in DEC-VEN compared to AZA-VEN was 25.9% vs. 4.2% (P=0.08) and 21.4% vs 2.4% (P=0.03), respectively. Unadjusted and adjusted 60-day TRM in DEC-VEN compared to AZA-VEN was 40.7% vs. 12.5% (P=0.052) and 37.2% vs. 11.6% (P=0.04), respectively.2 DEC for 10 days with VEN to patients who received 20 mg/m2 DEC for 10 days; the outcomes were qualitatively similar to the combined 5- and 10-day DEC -VEN vs. DEC comparison.There is a paucity of studies reporting real-world treatment outcomes of AZA-VEN compared to AZA alone and AZA-VEN compared to DEC-VEN in patients with newly diagnosed AML. Moreover, we used causal-inferential methods to compare outcomes of the treatment groups. de novo AML, intermediate-risk cytogenetics, and wild-type TP53  and a nonsignificant difference in PFS (5.5 vs. 3.8 months) compared to AZA, but OS was similar (9 vs. 9 months). This indicates improved leukemia control but greater toxicity with DEC, with a resultant similar OS. These outcomes were similar to those in previous reports , 25.ASXL1 or RUNX1 mutation status  under the Cigarette Restitution Fund Program.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The Multi-Agency Autism Team (MAAT) diagnose Autism Spectrum Disorder (ASD) in children and young people using a multi-stage assessment process. In March 2020, the UK went into lockdown due to the COVID-19 pandemic, affecting the MAAT’s ability to continue their typical diagnostic pathway.This qualitative study aimed to assess the effectiveness and feasibility of a virtual ASD diagnostic pathway.From March – September; one hundred detailed developmental history assessments were conducted over the telephone, fifteen socially-distanced BOSA (Brief Observation of Symptoms of Autism) assessments were piloted, twenty-five multi-disciplinary formulation meeting were held over a video platform, and sixty diagnosis feedback consultations were conducted via telephone or video call. Structured interviews were conducted with clinicians and service-users.revealed that telephone developmental history assessments were generally preferable over face-to-face appointments, and video-based formulation meetings were effective, productive and resulted in higher clinician attendance. The qualitative data on feedback appointments was mixed. Clinicians felt that telephone appointments were less personable and ethical; whereas, video-based feedback appointments allowed for more empathy. However, the majority of service-users opted for tele-calls over video-calls for these appointments. Socially-distanced BOSAs obtained positive clinician feedback in general. Service-user feedback was mixed; some found the experience uncomfortable and unfamiliar, whilst others enjoyed the experience. Overall, service-users were content with the knowledge that it may support a diagnostic outcome for their child.We concluded that the overall experience of the virtual ASD diagnostic pathway was a positive and informative process, identifying opportunities for permanent change to the service.


US and Northern European studies have found a higher prevalence of alcohol-related problems among men who have sex with men (MSM) than among the general population of men (GPM). However, most of them relied on traditional sampling methods, not profiting from MSM dating apps and websites for recruitment. Besides, analogous comparisons in Southern Europe are lacking.This study aimed to compare several indicators of excessive drinking between MSM and GPM in Spain.Overall, 5862 MSM were recruited through dating apps or websites for the Méthysos Project, and 10,349 GPM were recruited using probability sampling via the Household Survey on Alcohol and Drugs in Spain from 2018 to 2020. The outcomes were the prevalence of hazardous or harmful drinking (Alcohol Use Disorders Identification Test [AUDIT] ≥8), hazardous drinking (AUDIT-Consumption ≥4), harmful drinking (AUDIT-Problem ≥4), regular hazardous drinking (>14 standard drinks per week), and monthly binge drinking. The prevalence of excessive drinking indicators was calculated for MSM and GPM and compared using the adjusted prevalence ratio (aPR). Two different aPRs and their 95% CIs were estimated using Poisson regression models with robust variance. The first was adjusted for sociodemographic characteristics, and the second was adjusted for the aforementioned covariates plus other drug use.The prevalence of hazardous or harmful drinking was 15.6% (913/5862) among MSM versus 7.7%  among GPM. After adjusting for sociodemographic covariates, the risk was higher in MSM than in GPM for harmful or hazardous drinking , harmful drinking , and binge drinking ; the same in both populations for hazardous drinking ; and higher in GPM than in MSM for regular hazardous drinking . The relative excess risk of harmful drinking and binge drinking among MSM tended to increase with increasing education level and size of the place of residence, and the opposite was true for the deficit risk in regular hazardous drinking. Additional adjustment for other drug use greatly buffered the relative excess risk in harmful drinking and binge drinking in MSM, while it deepened its deficit risk in regular hazardous drinking.The use of web-based resources allowed recruiting a large sample of MSM. The risk of hazardous or harmful drinking was 80% greater in MSM than in GPM, which was mainly because of the higher risk of harmful drinking and binge drinking among MSM. Nearly 1 in 6 MSM would benefit from early brief alcohol intervention procedures. The subgroup with harmful or binge drinking combined with other drug use is an important contributor to excess MSM risk in hazardous or harmful drinking and must be a priority target for harm reduction interventions. In recent years, concerns have been raised about health disparities due to sexual orientation -5. SurveTo our knowledge, the only studies in Europe that compared alcohol use between MSM and GPM have been conducted in Northern or Central European countries ,17-21. OKnowledge of alcohol use among MSM living in southern European countries is important given that historical cultural norms regarding alcohol use differ between these countries and those where research has been conducted . The MedIn contrast, most of the former studies comparing MSM and GPM are based on representative population samples ,9,12,16.A common problem when comparing drinking indicators between MSM and GPM is the existence of important differences between both groups in sociodemographic characteristics  that can distort the comparison -28. To aThe Alcohol Use Disorders Identification Test (AUDIT) is a 10-item scale that screens for alcohol use disorders to identify and assist individuals at high risk . It inclTo the best of our knowledge, only 2 published studies have compared AUDIT scores between MSM and GPM ,41. The In this study, we took advantage of dating apps and websites commonly used by MSM to recruit a large sample of MSM and compare various indicators of excessive drinking, including hazardous and harmful drinking, between MSM and GPM in Spain. We used the AUDIT to assess MSM who would potentially benefit from early alcohol interventions. In addition, we aimed to discern the differences between the 2 dimensions of hazardous drinking (distinguishing regular hazardous drinking from binge drinking) and harmful drinking.We conducted a cross-sectional comparison of several measures of excessive drinking between MSM and GPM in Spain. Data were obtained from the results of the AUDIT questionnaire on 2 different samples for MSM and GPM.Participants, MSM Sample) between May and July 2020. The GPM sample was recruited between February and April 2018 within the framework of the Household Survey on Alcohol and Drugs in Spain  [The MSM sample included participants from the Méthysos Project, which aimed to investigate their health status. Participants were recruited through different web-based resources (see edition) .MSM were invited to participate through 3 types of web-based resources:A total of 7 MSM dating apps using promotional banners , personal messages (GROWLr), or both  contributed 70.5% (4655/6602) of the participants.Furthermore, 3 influencers largely followed by the MSM community (Gabriel José Martin–with a video on YouTube available throughout the recruitment period–and @frewaskachannel and @tigrilloig–with 24-hours available stories launched twice (@frewaskachannel) or once (@tigrilloig) during the recruitment period), which contributed 26.3% (1741/6602) of the participants.Finally, a message encouraging the diffusion of the study among friends and acquaintances, placed at the end of the questionnaire, and distribution lists from 3 organizations , which contributed with 3.1% (206/6602) of the participants.Individuals who decided to participate were addressed to an initial screen where they were informed about the aim and content of the survey. Before starting, they were obliged to check on the “I am of legal age for sexual intercourse and want to participate in the study.” All participants were required to meet the inclusion criteria of being male, at least 16 years old, and having ever had anal intercourse with a male. We provided unique links to each recruitment site to identify the recruitment site for each participant. To avoid multiple participation, the initial screen also included a request to complete the questionnaire only once if the invitation was received in various ways. In addition, to further limit the possibility of multiple responses from one individual, we used the option provided by the software that only allowed the completion of one questionnaire per electronic device. No incentive was offered for participation, limiting the chances of multiple participation. The questionnaire was self-administered, computer- or app-based, and treated for sexual behavior and drug and alcohol use (including AUDIT). The full questionnaire is available in the In studies using this type of methodology, it is impossible to calculate or estimate the response rate. The apps identify the number of displayed banners and sometimes the number of clicks on the banner, but not the number of different people who see or click on them to obtain some information. Something similar happens with influencers. They may know the number of views on a promotion, but not the number of people, or whether those people meet the criteria to participate. Of the 6602 MSM who began the questionnaire, 740 abandoned it before completing the AUDIT questions; thus, the final sample comprised 5862 MSM.The GPM sample was obtained from the anonymous database of EDADES, 2017 edition provided by the National Plan on Drugs. The EDADES is a biennial national survey of a representative sample of the population aged 15-64 years living in Spain. It uses a 3-stage random sampling design . Census tracts and subjects within households were selected using random probabilistic methods. The sample was stratified by age (15-34/35-64) and living region (19 categories). In this edition, people aged 15 to 34 years and living in small regions were oversampled, so analyses were weighted to account for strata imbalance compared with the universe. The global response rate was 50.6%, and the main causes of nonresponse were not opening the door, preventing interviews, and the absence of all household members or the selected person. Before classifying a household or person as absent and selecting another household, the fieldworker should visit the household that was initially selected at least three times on different days and times.We selected all men aged 16-64 years who participated in the survey (women and men aged 15 years were excluded). EDADES does not have any variables to identify sexual identity or behavior; thus, we could not estimate the proportion of MSM among the group of men participating in the survey, nor excluding them in our analysis. Therefore, we refer to this group as GPM. However, we can infer that this sample is principally composed of heterosexual men, relying on the most recent estimation of the Spanish population on sexual orientation, in which 93.9% (2791/2972) of people declare themselves heterosexual . The EDAOnly the participants who had consumed alcohol in the past 12 months answered the AUDIT questionnaire. For the remaining participants, the AUDIT score was imputed as 0. Questionnaire skips were automatically included in the resources used by the MSM sample but had to be manually included in the GPM sample. This study uses labels and concepts from the recently published 11th revision of the International Classification of Diseases  to referRegarding consumption levels, we differentiated a variable of regular hazardous drinking  from binge drinking to identify differences in drinking patterns. Although weekly alcohol consumption above a certain threshold entails health-related consequences , these aQ1. How often do you have a drink containing alcohol?0. Never (skip to Qs 9-10)1. Monthly or less2. 2-4 times a month3. 2-3 times a week4. 4 or more times a weekQ2. How many drinks containing alcohol do you have on a typical day when you are drinking?0. 1 or 21. 3 or 42. 5 or 63. 7, 8, or 94. 10 or moreQ3. How often do you have six or more drinks on one occasion?0. Never1. Less than monthly2. Monthly3. Weekly4. Daily or almost dailySkip to questions 9 and 10 if total score for questions 2 and 3=0Q4. How often during the last year have you found that you were not able to stop drinking once you had started?0. Never1. Less than monthly2. Monthly3. Weekly4. Daily or almost dailyQ5. How often during the last year have you failed to do what was normally expected from you because of drinking?0. Never1. Less than monthly2. Monthly3. Weekly4. Daily or almost dailyQ6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session?0. Never1. Less than monthly2. Monthly3. Weekly4. Daily or almost dailyQ7. How often during the last year have you had a feeling of guilt or remorse after drinking?0. Never1. Less than monthly2. Monthly3. Weekly4. Daily or almost dailyQ8. How often during the last year have you been unable to remember what happened the night before because you had been drinking?0. Never1. Less than monthly2. Monthly3. Weekly4. Daily or almost dailyQ9. Have you or someone else been injured because of your drinking?0. No2. Yes, but not in the last year4. Yes, during the last year.Q10. Has a relative or friend or a doctor or another health worker been concerned about your drinking or suggested you cut down?0. No2. Yes, but not in the last year4. Yes, during the last year.Scores for the full-scale AUDIT (hazardous or harmful drinking), AUDIT-C (hazardous drinking), and AUDIT-P  instruments were calculated by adding the scores in Q1-10, Q1-Q3, and Q4-Q10, respectively. The weekly average number of standard drinks was used as an indicator of the intensity of regular alcohol consumption. It was estimated by multiplying the answers for questions on drinking frequency (Q1) and quantity (Q2). To this end, the median values of each response category of Q1 and Q2 were used, except for the extreme categories “monthly or less” in Q1, where 0.25 drinking days per week was assigned, and “ten or more were assigned to Q2, where 10 standard drinks per day were assigned. A similar method was used previously . The occ2χ test. The main outcomes were the prevalence of harmful or hazardous drinking (AUDIT score≥8), hazardous drinking (AUDIT-C score≥4), harmful drinking or alcohol-related problems (AUDIT-P score≥4), regular hazardous drinking , and monthly binge drinking (occurrence of binge drinking at least monthly in a year). The AUDIT cutoff was originally established by the World Health Organization [For the GPM sample, to account for strata imbalance compared with the universe, data were weighted by region (19 categories), size of place of residence (7 categories), age (7 categories), and sex (2 categories), resulting in 619 different values for the ponderation factor (from 0.04 to 3.06). For the MSM sample, as the global universe of MSM residing in Spain was unknown, all participants were assigned a ponderation factor of 1. An initial descriptive analysis of the general characteristics of the MSM and GPM samples was performed, and the statistical significance of the differences was assessed using the Pearson nization , and thenization ,42. As tnization  considernization ,29. We snization -55.P-values were <.05. The analysis was not preregistered, and the results should be considered exploratory. Statistical analyses were performed using Stata version 15 (StataCorp).The prevalence of the different drinking indicators was calculated in both MSM and GPM and compared between the groups using the adjusted prevalence ratio (aPR). aPR is a measure of relative inequality without units, which indicates the number of times the risk is higher or lower in MSM compared with GPM. Two different aPRs and their corresponding 95% CI were estimated using Poisson regression models with robust variance . The firThis study was approved by the Research Ethics Committee of the Instituto de Salud Carlos III . Concerning the MSM sample, individuals approved their conformity to participate by clicking on “On my age, I am legally authorized to have sexual relations and I want to participate in the study.” This message appeared before starting the questionnaire, as can be observed in the . PrivacyParticipants were more frequently aged 25-34 years (MSM) and 35-44 years (GPM). Compared with the GPM, they had a higher education level, lived more frequently in urban settings, and declared a better economic status. The prevalence of alcohol use in the past 12 months was similar between MSM and GPM, but that of other drugs was much higher among MSM .The prevalence of hazardous or harmful drinking among MSM was 15.6% (913/5862) compared with 7.7%  in the GPM group, leading to an aPR of 1.8 (95% CI 1.6-2.0). Significant MSM-GPM disparities in prevalence in the same direction were observed in all subgroups, except for those who did not consume other drugs in the past 12 months . The preThe prevalence of regular hazardous drinking (>14 drinks per week) was lower among MSM  than among GPM , with an aPR of 0.7 (95% CI 0.6-0.9). A statistically significant MSM-GPM disparity in such prevalence was not observed among individuals aged between 16 and 34 years, with university education level, or living in places with >500,000 inhabitants .The prevalence of monthly binge drinking was higher among MSM  than among GPM , with an aPR of 1.7 (95% CI 1.5-1.9). Significant MSM-GPM disparities in prevalence in the same direction were observed in all subgroups, except for other drug users .Finally, the prevalence of harmful drinking was higher among MSM  than among GPM , with an aPR of 2.3 (95% CI 2.0-2.7) Significant MSM-GPM disparities in such prevalence in the same direction were observed in all subgroups .The aPRs of Model II after further adjustment for the use of other drugs in the past 12 months are shown in Tables S1 and S2 in Compared with GPM, we found a relative excess risk of hazardous or harmful drinking  among MSM living in Spain. Nearly 1 in 6 MSM had hazardous or harmful drinking and would benefit from early brief alcohol intervention procedures  . The MSMThe relative excess risk in the GPM of hazardous drinking and regular hazardous drinking tended to increase among older, less educated, and rural-dwelling individuals. In contrast, the relative excess risk of harmful and binge drinking in MSM tended to be larger among individuals aged 16-24 years (only in the case of harmful drinking) or with university education level and living in big cities (in both cases).Additional adjustment for other drug use greatly buffered the considerable relative excess risk in MSM compared to that in GPM for harmful drinking and binge drinking while deepening the risk deficit in MSM for regular hazardous drinking. This suggests that drinking behaviors and other drug use were strongly associated in the studied populations. Therefore, the considerable excess of risk in MSM compared with GPM for binge drinking and harmful drinking is mainly because of the subgroup having both these drinking patterns and the use of other drugs. This subgroup represents a much higher proportion of the total in MSM than in GPM, and must clearly be a priority target for harm reduction interventions.This is the first study to directly compare excessive drinking indicators (hazardous and harmful drinking) between MSM and GPM in a southern European country. Moreover, this is the first study ever published that differentiates between these 2 dimensions using a validated instrument (AUDIT). Moreover, because of the use of new technologies in the recruitment process, namely apps and websites, it includes a larger sample of MSM than that in most previous studies inside and outside Europe -18,41,58Only one study has compared hazardous or harmful drinking between these 2 populations using full-scale AUDIT , and theThere are 3 studies ,12,17 thOne study  comparedNo other study has analyzed harmful drinking using AUDIT-P; however, our findings of a high aPR MSM or GPM are similar to those previously described in studies using Diagnostic and Statistical Manual of Mental Disorders criteria -8.Considering these findings, we can affirm that there is a slight difference in hazardous drinking between MSM and GPM, but a remarkable increase in harmful drinking among MSM also exists in Mediterranean countries such as Spain. However, the reasons for this discrepancy are not well understood. In the case of Spain, it could be that MSM adopted Northern European drinking patterns more quickly, characterized by a higher frequency of binge drinking, which is more likely to produce harmful consequences . As an iIn contrast, minority stress theory has also been proposed to explain the increase in harmful and hazardous drinking among MSM ,60. AccoOther factors may have influenced the results. It is well known that certain potentially alcohol-linked phenomena, such as sex work , chemsexIn summary, it could be that there are differences in consumption patterns between MSM and GPM that have not been properly analyzed, or, more probably, that MSM are more susceptible to the harmful effects of alcohol use or that they have a greater ability to identify or disclose them. Further research is needed to clarify this last point, which requires the use of large samples for both comparison groups. Studies based on general population surveys, which represent the majority to date, do not permit discerning of these particular issues and often include a small number of MSM.Finally, although not an objective of this study, our findings suggest that AUDIT measures 2 different domains . It alsoThe use of 2 different sampling methods for MSM and GPM is a limitation of this study. However, using dating apps and websites for the recruitment of MSM was a way to overcome 2 handicaps: the small sample of MSM frequently included in studies based on representative samples of the general population and the fact that the national drug survey in Spain does not include questions about sexual orientation. Although this sampling method may have overrepresented hazardous drinkers among MSM, it provided a significantly larger MSM sample than that in most studies with probabilistic sampling methods, in which the inclusion of a large number of MSM was hindered by the low percentage of men who reported having sex with other men. In our study, the MSM questionnaire was self-administered, which is not always guaranteed in general population surveys. This might have reduced the probability of reporting bias for nonnormative behaviors, such as homosexual behavior or alcohol use.Another limitation related to recruitment is the different contexts in which alcohol was more frequently consumed in these 2 groups. Even though dating apps as well as other Internet-based resources were used to recruit MSM, a skew toward “party-goers” may have taken place. As some questions in AUDIT  are related to nightlife drinking, this point may have had an influence. Unfortunately, we did not have a variable to measure the context of consumption. On the contrary, we do not think that recruiting MSM, but not GPM, during the COVID-19 pandemic (between May and July 2020) may have increased the differences favoring MSM. It has been observed that hazardous drinking increased during lockdowns -68, but Another limitation is related to AUDIT thresholds. Cutoffs are needed for screening; however, when different cutoff points are used, epidemiological research is hindered. We offset this limitation by estimating new results by applying different cutoffs used in other studies. In addition, problems related to thresholds were not exclusive to AUDIT; they also appeared when establishing the recommended levels of weekly alcohol consumption. The final limitation relates to the use of only 2 AUDIT questions (quantity and frequency) to estimate alcohol consumption. Although this was not the first study to measure this variable using these 2 questions (or similar questions) , a more This is the first study to compare indicators of hazardous and harmful drinking (problems or consequences) between MSM and GPM living in southern Europe. The use of different Internet-based resources in recruitment (mainly apps and influencers) allowed us to obtain information on alcohol use from a large and diverse sample of MSM. Using a validated brief screening tool (AUDIT), we found an 80% excess risk of hazardous or harmful drinking among MSM, which was mainly owing to the higher risk of harmful drinking and binge drinking among MSM.From the perspective of the implications for clinical practice, it is important to emphasize that the periodic use of brief screening tools such as AUDIT would seem to be highly recommended in health consultations of MSM. This would result in a significant proportion of MSM benefiting from early brief alcohol harm reduction interventions and from referral to specialized services when needed. Harm reduction strategies should focus on binge drinking. Nursing professionals in primary care and sexual transmitted infections or HIV clinics (which take care of a large number of MSM) may provide appropriate services for the implementation of these screening instruments.From the perspective of future research, it is desirable to enrich these findings by conducting studies based on a single population-based survey. To achieve this goal, surveys in Spain (and in other countries) should include a variable on sexual behavior or gender identity, as it has been common in the United States for a decade. Second, we want to highlight that there are currently no clear explanations for the disparity in the findings in the 2 domains of AUDIT. Neither the tendency toward incorporation of non-Mediterranean consumption patterns among MSM nor the minority stress theory satisfactorily explains these results. Therefore, further studies are needed to analyze whether differential consumption patterns exist or whether there are different levels of susceptibility to alcohol use and its harmful consequences.


Use of medical devices represents a unique opportunity to facilitate scale-up of early infant male circumcision (EIMC) across sub-Saharan Africa. The ShangRing, a circumcision device prequalified by WHO, is approved for use in adults and adolescents and requires topical anaesthesia only. We aimed to investigate the safety and efficacy of the ShangRing versus the Mogen clamp for EIMC in infants across eastern sub-Saharan Africa.NCT03338699, and is complete.In this multicentre, non-inferiority, open-label, randomised controlled trial, we enrolled healthy male infants (aged <60 days), with a gestational age of at least 37 weeks and a birthweight of at least 2·5 kg, from 11 community and referral centres in Kenya, Tanzania, and Uganda. Infants were randomly assigned (1:1) by a computer-generated text message service to undergo EIMC by either the ShangRing or the Mogen clamp. The primary endpoint was safety, defined as the number and severity of adverse events (AEs), analysed in the intention-to-treat population  with a non-inferiority margin of 2% for the difference in moderate and severe AEs. This trial is registered with Clinical. Trials.gov, vs 30 [4·4%] in the Mogen clamp group; difference –0·1%; one-sided 95% CI upper limit of 1·7%; p=0·89). No treatment-related deaths were reported.Between Sept 17, 2018, and Dec 20, 2019, a total of 1420 infants were assessed for eligibility, of whom 1378 (97·0%) were enrolled. 689 (50·0%) infants were randomly assigned to undergo EIMC by ShangRing and 689 (50·0%) by Mogen clamp. 43 (6·2%) adverse events were observed in the ShangRing group and 61 (8·9%) in the Mogen clamp group (p=0·078). The most common treatment-related AE was intraoperative pain , with 19 (2·8%) events in the ShangRing and 23 (3·3%) in the Mogel clamp group. Rates of moderate and severe AEs were similar between both groups (29 [4·2%] in the ShangRing group Use of the ShangRing device for EIMC showed safety, achieved high caregiver satisfaction, and did not differ from the Mogen clamp in other key measures. The ShangRing could be used by health systems and international organisations to further scale up EIMC across sub-Saharan Africa.Bill & Melinda Gates Foundation. Observational studies suggested in 1986 that voluntary medical male circumcision (VMMC) was associated with reduced male HIV acquisition.15 countries in east and southern Africa with low rates of VMMC and a high incidence of HIV have scaled up VMMC programmes, which resulted in nearly 27 million male circumcisions by the end of 2020.Evidence before this studyWe searched PubMed on Sept 1, 2018, before the initiation of the trial, for articles published in English only without date restrictions. Previous studies have shown that voluntary medical male circumcision (VMMC) reduces the incidence of HIV and urinary tract infections in men. Although most VMMC procedures are performed in adolescents and adults, the most long-term coverage and potential population-level impact on HIV transmission might ultimately be achieved through early infant male circumcision (EIMC). Medical devices simplify the performance of VMMC and, therefore, have been proposed to facilitate WHO's goal of 90% access to VMMC in sub-Saharan Africa by 2020, which has not been reached to date. The ShangRing device is the only medical circumcision device prequalified by WHO for use in individuals from age 10 years to adulthood; however, its use in EIMC has not been explored previously.Added value of this studyIn this multicentre, non-inferiority, open-label, adaptive randomised controlled trial in eastern sub-Saharan Africa, we compared the safety and efficacy of the ShangRing versus the Mogen clamp, which is currently considered to be the gold standard for EIMC, in a cohort of 1420 male infants. To our knowledge, this is the first randomised controlled trial to assess the use of ShangRing for EIMC in this age group. Our results show that EIMC by ShangRing is safe and offers excellent outcomes.Implications of all the available evidenceUse of the ShangRing in EIMC showed safety and achieved high caregiver satisfaction. This device could be used by health systems and international organisations to further scale up EIMC efforts across sub-Saharan Africa.Medical devices simplify the performance of VMMC and facilitate task shifting from physicians to non-physicians to augment service delivery. The ShangRing is the only male circumcision device prequalified by WHO for use in individuals from age 10 years to adulthood.We conducted a multicentre, non-inferiority, open-label, randomised controlled trial in 11 community and referral centres across Kenya (Homa Bay and Kisumu), Tanzania , and Uganda . Eligible participants were healthy male infants (aged <60 days) with a gestational age of at least 37 weeks and a birthweight of at least 2·5 kg, who had been brought to the centres to discuss circumcision. Infants with perinatal illnesses requiring treatment, congenital genitourinary abnormality requiring surgical repair , allergies to known anaesthetic components, or a family history of bleeding disorders were excluded.The trial was reviewed and approved by the institutional review board at Weill Cornell Medicine  and institutional review boards or medical councils from each collaborating organisation  and participating country . Written informed consent was obtained from the parents or legally authorised representatives of infants at enrolment. The trial, data collection, and data management adhered to good clinical practice guidelines for clinical trials.Enrolled infants were randomly assigned (1:1) to undergo EIMC by either the ShangRing or the Mogen clamp. Random allocation was achieved with a text message service . The allocation sequence was generated by computer, uploaded to Sealed Envelope, and entered into a secured electronic database. Parents and legally authorised representatives, investigators, physicians and non-physicians, and providers who evaluated infants for pain and other adverse events (AEs) after the procedure were unmasked to the allocated intervention.All participating infants received a rectal suppository of 40 mg acetaminophen 30 mins before the procedure and a 2·0% sucrose solution as a pacifier during the procedure. A mixture of topical 2·5% lidocaine and 2·5% prilocaine cream was applied to the shaft and the glans of the penis before any intervention. Dwell time was measured from agent application to either the absence of response to a noxious stimulus on the foreskin or to the start of the procedure. Supplemental injectable local anaesthetic was available if inadequate analgesia was noted by the provider. The Neonatal Infant Pain Scale (NIPS) score was used to standardise pain assessment. NIPS is a validated pain scale assigning points on the basis of the provider's observation of the infant's facial expression, cry, breathing pattern, arms, legs, and state of arousal.Before trial initiation, all staff performing the procedure completed a training course on EIMC using both devices. The previously described no-flip techniqueFollow-up was performed by an initial telephone call to parents or legally authorised representatives 24 h after the procedure, followed by scheduled clinic visits every 7 days until complete wound healing. Complete healing was defined as complete re-epithelialisation of the circumcision incision. Infants whose parents or legally authorised representatives could not be reached despite multiple telephone attempts were seen in person at the follow-up visits. Interviews assessing satisfaction among parents and legally authorised representatives were conducted at the last follow-up visit.The primary endpoint was safety, defined as the number and severity of AEs. AEs were prespecified as mild, moderate, or severe on the basis of WHO definitions .22 The sSecondary endpoints included time to complete wound healing; the ease of use associated with both circumcision devices and provider preference, determined by procedure time and problems encountered during the procedure provided by in postoperative interviews; neonatal infant pain scale scores, assessed by NIPS; and satisfaction among parents and legally authorised representatives, evaluated by interviews at the final follow-up visit.Sample size was estimated using WHO's requirements for prequalification of adult and adolescent circumcision devices. We expected that the benefits of the ShangRing would allow a non-inferiority margin of 2·0% for the AE rate. This margin was selected because the anticipated rate of moderate and severe AEs is 2·0% for the Mogen clamp based on the literature.t test and Kaplan-Meier survival analysis using a log-rank test to compare the time to complete wound healing between the two intervention groups. In the event that a participant received an intervention that differed from the one randomly assigned, the discrepancy was documented and an intention-to-treat analysis was performed. Continuous variables were analysed with the Student's t test and categorical variables with the χ2 test . Differences in proportions are reported as a point estimate and a 95% Agresti-Caffo CI. Statistical significance was set at p=0·05 and all tests were two-sided for secondary analyses. The p values were not adjusted for the multiple secondary analyses. Statistical analyses were done with R (version 3.6.1). This trial is registered with Clinical. Trials.gov, NCT03338699.The primary endpoint was analysed in the intention-to-treat population, defined as all infants who underwent an EIMC procedure. We established non-inferiority in the rate of moderate and severe AEs for use of ShangRing versus use of the Mogen clamp using a one-sided 95% Agresti-CaffoThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Between Sept 17, 2018, and Dec 20, 2019, a total of 1420 infants were assessed for eligibility, of whom 1378 (97·0%) were enrolled. 689 (50·0%) infants were randomly assigned to undergo EIMC by ShangRing and 689 (50·0%) by Mogen clamp . The medvs 12·4 mins [9·5] in the Mogen clamp group; mean difference –0·1 mins [95% CI –1·0 to 0·8]). In both groups, the procedures were performed mainly by nurses, followed by clinical officers and doctors  received their assigned procedure while 18 (2·6%) underwent EIMC with the Mogen clamp and one (0·1%) underwent EIMC by dorsal slit alone . Of the  doctors . All proThere were no missing data for the primary endpoint. There were few missing data for other endpoints and the analyses were done on a complete-case basis. A total of 43 (6·2%) AEs were observed in the ShangRing group and 61 (8·9%) in the Mogen clamp group, with no significant difference between both groups (p=0·078). We observed a total of 59 moderate and severe AEs, with no difference between both groups: 29 (4·2%) in the ShangRing group and 30 (4·4%) in the Mogen clamp group  in the ShangRing group and 16·9 days (5·9) in the Mogen clamp group , favouring EIMC by Mogen clamp. By day 35, complete healing was observed in almost all infants . In the A total of 1327  parents and legally authorised representatives completed a satisfaction interview; 665 (96·5%) parents or legally authorised representatives of infants who underwent EIMC by ShangRing and 662 (96·1%) parents or legally authorised representatives of infants who underwent EIMC by Mogen clamp (difference 0·4% [95% CI –1·6% to 2·5%]). When parents and legally authorised representatives were asked what they liked about the procedure, top responses included less pain than expected, improved hygiene, cosmetic appearance, and short procedure time . When asThis is the first multicountry randomised controlled trial comparing the use of ShangRing versus Mogen clamp for EIMC in three eastern sub-Saharan countries. Our results show that the ShangRing was safe and efficacious for EIMC by non-physicians. AEs, postoperative pain, and satisfaction rates were similar between the two techniques. Thus, we believe that ShangRing could be included in the armamentarium of countries implementing EIMC and could help to achieve the goal of increasing the number of circumcisions and decreasing HIV transmission in Africa.Except for pain, no severe or serious AEs related to the ShangRing were observed in this study. Importantly, severe complications, such as complete or partial transection of the glans, wound infection, or necrosis, which have been previously reported with the Mogen clamp and other devices, were not noted.Pain was not only the most frequently reported but also the most challenging AE to assess in infants. We chose to use NIPS to minimise providers’ subjectivity;Both the ShangRing and Mogen clamp techniques showed short and similar procedural times and were easily performed by non-physicians. Notably, all physicians, nurses, and clinical officers safely performed both interventions, similar to rates of successful medical circumcision interventions in older individuals. Several studies have found no association between AEs and provider type, which further facilitates task-shifting initiatives.We also explored the effects of EIMC on parents and legally authorised representatives. The newborn and early infant period is a stressful time for caregivers. Therefore, maximising the satisfaction of parents and legally authorised representatives and understanding their motivations behind opting their infant for EIMC are of paramount importance in all efforts to scale up EIMC. Mavhu and colleaguesThis study has several limitations. First, the use of multiple sites and personnel introduces heterogeneity in terms of interpretation of clinical data, even though it improves the generalisability of our findings. Second, the trial was designed to detect non-inferiority of the ShangRing versus Mogen clamp, a widely used device for EIMC. Our results suggest that the two techniques do not differ in efficacy, usability, or, most importantly, their safety profile. Third, the NIPS was not as effective at sufficiently differentiating between mild, moderate, and severe pain in infants as has been reported in adolescent and adults. Fourth, paternal circumcision status was not obtained when assessing the views of parents and legally authorised representatives on EIMC, despite its previously described influence on perceptions of EIMC.EIMC by the ShangRing is non-inferior to EIMC by the Mogen clamp and represents a safe and efficacious tool with excellent outcomes and a mostly high satisfaction rate among parents and legally authorised representatives. Despite how accurate pain evaluation was challenging in this trial, almost all EIMC procedures by ShangRing were successfully performed with use of local topical anaesthetics only. Thus, this device could be used by health systems and international organisations as an integral part of efforts to scale up future EIMC services across sub-Saharan Africa.Data collected for the study, including individual participant data and a data dictionary defining each field in the set, will be made available to the sponsor and participating researchers. Deidentified patient data, the data dictionary, the study protocol, and the informed consent form will be made available at publication upon request to the corresponding author with investigator approval and a signed data access agreement.We declare no competing interests.