How have knowledge of HIV/AIDS and associated socioeconomic disparities changed between 2003 and 2018 among young women aged 15 to 24 years living in low- and middle- income countries (LMICs)?In this cross-sectional study of 282 757 young women living in 51 LMICs, less than one-third reported having correct knowledge of HIV/AIDS; this disparity in knowledge was associated with rural residence, poverty, and low levels of education. Among young women living in the 40 LMICs with multiple surveys available during the study period, there was a significant increase in knowledge in 24 countries and a significant decrease in 10 countries.These findings suggest that future HIV-prevention campaigns in LMICs should pay special attention to young women with disadvantaged socioeconomic status. This cross-sectional study provides an up-to-date assessment of the levels of and changes in knowledge of HIV/AIDs and its association with socioeconomic disparity among young women in low- and middle-income countries. Knowledge of HIV/AIDS among the younger population is crucial for long-term control. Little research has been done on which groups of young women (aged 15-24 years) in low- and middle-income countries (LMICs) have been left behind with respect to obtaining this knowledge.To provide an up-to-date assessment of the levels of and changes in knowledge of HIV/AIDS and its associations with socioeconomic disparity among young women in LMICs.This cross-sectional study used nationally representative Demographic and Health Surveys with available data on HIV/AIDS knowledge in 51 LMICs between 2003 and 2018. The final data set contained 282 757 young women. For 40 LMICs with multiple surveys available, we examined changes in knowledge and socioeconomic disparities. Analyses of the survey data were conducted between December 1, 2019, and July 31, 2020.The percentage of young women who were able to (1) correctly identify the 2 major ways of preventing the sexual transmission of HIV, (2) reject the 2 most common local misconceptions about HIV transmission and (3) know that a healthy-looking person can transmit HIV. The level of and changes in young women’s knowledge of HIV/AIDS as well as knowledge disparities by residential area, wealth status, and level of education on the aggregate and country levels were assessed.Of a total of 282 757 young women from 51 LMICs, 29.3%  reported having knowledge of HIV/AIDS in the latest years, ranging from 1.0%  in Afghanistan in 2015 to 64.9%  in Rwanda in 2014 to 2015. Those living in rural areas, living in households in the lowest income quintile, or with low levels of education reported less knowledge about HIV/AIDS than their counterparts . Among the 40 countries that had undertaken at least 2 surveys during the period, the surveys indicated that there was a significant increase in knowledge of HIV/AIDS among young women in 24 countries (60.0%), but a significant decrease in 10 countries (25.0%). Less than half of countries experienced significant reductions in disparities associated with residential area (8 countries [20.0%]), wealth (5 countries [12.5%]), or education (17 countries [42.5%]).This cross-sectional study of women in 51 LMICs found low levels and large gaps in knowledge of HIV/AIDS between groups, suggesting that future HIV-prevention campaigns should emphasize providing easily accessible information to socioeconomically disadvantaged groups. Indicators on HIV knowledge among young people are among the global indicators for measuring progress in the 2020 Fast-Track Commitments and Expanded Targets to End AIDS.13 The 2015 Millennium Development Goals report indicated that, at the regional level, fewer than 40% of young people aged 15 to 24 years old in sub-Saharan Africa had comprehensive correct knowledge of HIV/AIDS using the most recent data (up to 2014).3 Young women were particularly likely to have insufficient knowledge of HIV/AIDS and engage in risky sexual behavior: condom use among young women was 19 percentage points lower than among young men.3 Evidence about socioeconomic disparities among young women could help policy makers and other stakeholders develop effective interventions for closing the related knowledge gaps. Previous studies have only assessed changes in socioeconomic disparities in knowledge of HIV/AIDS among women of reproductive age (aged 15 to 49 years) in a few LMICS . Those studies found that disadvantaged populations were less likely to report knowledge of HIV/AIDS than their more advantaged counterparts. Little research has been done on country-level progress in reducing socioeconomic disparities among young women between 15 and 24 years. Using Demographic and Health Surveys (DHSs) from 51 LMICs, this study undertook a comprehensive, up-to-date assessment of the levels of and changes in reported knowledge of HIV/AIDS and associated socioeconomic disparities among young women between 2003 and 2018.Educating young people about HIV/AIDS has been an effective preventive measure, even in countries with limited health care provision.17 DHS did not provide information relating to HIV/AIDS knowledge before January 1, 2003. Ethical approval for the DHS program was granted by the US Department of Health and Human Services. The DHS protocols and the process for obtaining oral informed consent for this study from all participants were approved by the ICF International institutional review board.15 No additional institutional review board approval was sought for this study, which followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.This study used nationally representative DHS data from 51 LMICs with available data on knowledge of HIV/AIDS between 2003 and 2018.18 To ensure standardization and comparability across different sites and time, DHS adopted extensive interviewer training, an identical core questionnaire, and standardized measurement instruments and technologies. The response rate was greater than 90%.17The DHSs are used to collect information on sociodemographic characteristics, child and maternal health, and awareness and behaviors associated with HIV/AIDS. Women aged 15 to 49 years were randomly selected through a multistage stratified design with equal-probabilistic sampling for each primary sampling unit  among the population aged 15 to 24 years old, DHS constructed a survey module based on the definition of and knowledge about HIV prevention: identifying the 2 major ways of preventing the sexual transmission of HIV , rejecting the 2 most common local misconceptions about HIV transmission, and knowing that a healthy-looking person can transmit HIV.15 In the DHS, if a respondent answered yes to the question, “Have you ever heard of an illness called AIDS?” she would then be asked to make selections  for the following 5 statements:15 (1) “people can reduce the risk of contracting HIV by using condoms consistently,” (2) “people can reduce the risk of contracting HIV by only having sex with 1 faithful uninfected partner,” (3) “HIV cannot be transmitted by sharing food with people who have HIV,” (4) “a person cannot contract HIV from mosquito bites,” and (5) “healthy-looking people can have HIV.” To measure the percentage of young women who reported having knowledge of HIV/AIDS, those who provided positive answers to all 5 questions were included in the numerator, and all young women (15-24 years old) were included in the denominator.To measure a country’s level of knowledge of HIV/AIDS  the highest vs the lowest wealth quintiles, (2) those with higher education vs those with primary education or lower, and (3) those living in urban areas vs those living in rural areas. A greater than 0 difference indicated that individuals with lower socioeconomic status (SES) reported having a lower level of knowledge of HIV/AIDS, whereas a less than 0 difference indicated that the level of knowledge of HIV/AIDS was lower among populations with higher SES.21The disparities in this study were measured by the absolute differences in the percentage of young women with knowledge of HIV/AIDS in the following 3 socioeconomic domains: residential area, wealth, and education. The DHS has a variable indicating a household’s wealth quintile based on its asset ownership. The methods for constructing wealth quintiles have been validated.We assessed the level of socioeconomic disparities for 51 countries with data for the most recent year since 2010 (ranging from 2010 to 2018). We also examined the changes in disparities over time for 40 countries with available data in multiple survey rounds. We performed the assessment on both the country and aggregate levels.16 For the 40 countries with at least 2 surveys between 2003 and 2018  22 with a dichotomous dependent variable indicating a young woman reporting correct knowledge of HIV/AIDS and a dichotomous independent variable indicating survey rounds. To measure the disparity change and its 95% CIs between the 2 survey rounds, we used the GLM  with dichotomous knowledge indicator as the dependent variable and 3 independent variables . We then used linear combination to generate the change in disparities between the 2 survey rounds.22When generating country-level estimates of knowledge of HIV/AIDS among young women and associated socioeconomic disparities in the most recent years, we followed the DHS guidelines and adjusted for sampling weight, clustering, and stratification variables.21 This approach does not assume a common homogeneous estimate across the countries with the DerSimonian and Laird inverse-variance method. The DerSimonian-Laird random-effects model combines the survey-specific estimates and weights from random-effects meta-analysis.21To generate aggregate-level estimates, we followed previous research and used random-effects meta-analysis by pooling levels and changes of disparity estimates across countries.P < .05, and all tests were 2-tailed. Statistical analyses were performed using Stata version 13 (StataCorp).Statistical significance was set at Using the most recent surveys from 51 LMICs after 2010, we included 282 757 young women  in the analysis. For the 40 LMICS with at least 2 surveys, we included 398 661 young women  in the analysis   in round 1 to 30.2%  in round 2 . On the On the aggregate level, using the data for the most recent years, the level of reported knowledge of HIV/AIDS was 36.3%  and 23.4%  for young women in urban and rural areas, respectively, and the gap between the two groups was 12.8  percentage points  . On the On the aggregate level, the level of knowledge of HIV/AIDS in the 51 countries with the most recent surveys was 40.5%  and 18.6%  among young women in the highest and lowest wealth quintiles. The gap between the 2 groups was 21.8  percentage points  . On the On the aggregate level, reported knowledge of HIV/AIDS was 37.8%  and 18.4%  between young women with education higher than primary and those with primary education or less, respectively. The gap between the 2 groups was 19.4  percentage points  percentage points in round 1 to 18.5  percentage points in round 2 . On the To our knowledge, this is the first study to systematically assess the level of and changes in socioeconomic disparities in reported knowledge of HIV/AIDS among young women aged 15 to 24 years in 51 LMICs using the most up-to-date data. We found that although reported knowledge of HIV/AIDS has increased over time on the aggregate level, it was still low; less than one-third of young women reported correct knowledge of HIV/AIDS. The study also revealed that in most of the countries studied, residential area–associated, education-associated, and wealth-associated disparities in knowledge remained large. In some countries, the disparities even increased significantly, as the knowledge of the population with higher SES improved more than its lower-SES counterpart.9 Moreover, the finding that socioeconomic disparities existed in almost all countries studied is consistent with previous findings about disparities in health information transmission: people with higher SES have better access to health information regarding HIV/AIDS and better access to health consultation than people with lower SES.24 It is worth noting that in many LMICs, disparities did not decline as the level of knowledge of HIV/AIDS improved. The presence of large socioeconomic disparities raises serious concerns about the effectiveness of combating HIV/AIDS when young women with low SES are left behind. Meanwhile, in some countries, the disparities in knowledge narrowed because of a decrease in the percentage of young women who reported correct knowledge in the group with high SES. These findings highlight the need to provide education on HIV/AIDS to all young women, with additional support for those with low SES, especially in countries with low overall levels of knowledge.Our results regarding the low level of knowledge of HIV/AIDS are consistent with previous studies.7 Inadequate knowledge is associated with lower use of HIV-prevention services , more behaviors that put one’s health at risk ,27 and a higher risk of HIV infection and/or transmission.28 The findings of this study clearly indicate that more efforts are needed to improve the knowledge of HIV/AIDS among young women with low SES. Studies have discovered effective methods for raising awareness of and delivering correct knowledge about HIV/AIDS among young people. School-based HIV/AIDS education is a well-proven intervention strategy to enhance young people’s knowledge of HIV/AIDS10 that has been implemented in many LMICs.29 We need to continue this intervention strategy to increase knowledge of HIV among young populations. Meanwhile, in many LMICs, more and more young people preferred to access HIV/AIDS information through mass media  or social media  than through medical professionals or family members.28 The use of social media has been proven to be complementary to school-based education and to extend the dissemination of knowledge about HIV/AIDS among young people.30 In some countries, mass and social media are the primary sources of HIV/AIDS information among young people.30 Social or mass media could improve the reach of HIV/AIDS information to young people with low SES and provide an important avenue for generating, sharing, and receiving information about HIV.30Knowledge of HIV/AIDS is an important determinant for successful HIV prevention and control of transmission.16 We need to be cautious when making cross-country comparisons because DHS data from different countries may have been gathered in different years, and there may have been intervals of different lengths between the surveys.20 Third, although this is, to our knowledge, the most comprehensive report to date, we were only able to include 51 LMICs in the analysis for the most recent surveys and 40 LMICS in the change analysis. Therefore, our results are not representative on global or regional levels.This study has several limitations. First, the measures of knowledge of HIV/AIDS used may be biased because they were entirely self-reported, but given that all surveys have a similar design, any potential bias should be consistent across countries and survey years. Second, because of unavailable longitudinal data, we had to use repeated cross-sectional data sets from the most recent and earliest DHS surveys to estimate changes.The ongoing inadequacy of knowledge and high socioeconomic disparities among young women in the 51 LMICs studied here is of greatest concern for the prevention and management of HIV/AIDS. Future HIV-prevention campaigns or programs should continue to emphasize the needs of young people with socioeconomic disadvantage and to provide more support for effective interventions, such as public campaigns through mass or social media. Meanwhile, the findings that the gap in knowledge of HIV has largely been narrowed in some countries, such as Burundi, calls for more in-depth studies of how those countries have been able to effectively deliver knowledge of HIV/AIDS to young people with socioeconomic disadvantage. Future research linking our findings to health education policies on HIV/AIDS in these specific countries would be particularly valuable.


Background: Automated ASPECTS has the potential of reducing interobserver variability in the determination of early ischemic changes. We aimed to assess the performance of an automated ASPECTS vs. ASPECTS interpreted for sent CT images on WhatsApp and to correlate these results with the outcome.Materials and Methods: Patients with anterior circulation stroke who had baseline NCCT and underwent successful IV-thrombolysis were included. NCCT-ASPECTS was assessed by two neuroradiologists, and discrepancies were resolved by agreement. Two groups of patients were included; group 1, where treatment was decided after an automated ASPECTS interpretation that was provided by RAPID software, and group 2, where patients received IV-tPA after an assessment of CT images sent on WhatsApp.Results: A total of 122 patients were included: 36 in group 1 and 86 in group 2. In group 2, the interobserver agreement for NCCT ASPECTS was moderate (κ = 0.36), as was the dichotomized data (κ = 0.44). IOA, however, improved (to κ = 0.57 and κ = 0.64) when the same CT images were interpreted on a workstation. In group 1, Automated ASPECTS showed excellent agreement (κ = 0.80) with agreement reads for workstation images. There were significantly (P < 0.001) increased odds of functional independence and fewer hemorrhagic complications with thrombolyzed patients in group 1.Conclusions: Automated ASPECTS provided by the RAPID@IschemaView ASPECTS performs at a level equal to the agreement read of expert neuroradiologists, and this performance was severely degraded when WhatsApp captured CT images used for ASPECTS assessment. In our study, we found that automated ASPECTS might predict outcomes after IV thrombolysis. ASPECTS was introduced in the year 2000 to assess the early ischemic changes in CT scans. It is a 10-point scoring system, with one point deducted for signs of early ischemic change in each defined region of the MCA territory  and reproducibility. Early ischemic changes are often difficult to detect on NCCT, with low interobserver agreement for presence and extent –7.Transmitting CT scans as instant messages captured and sent using smartphones has been shown to be highly reliable in neurosurgical emergencies .Although scientific studies on the use of WhatsApp Messenger remain scarce in medical literature, increasing numbers of health professionals have adopted it as a communication interface and for the exchange of multimedia , 10. A dIn acute ischemic stroke settings, both time and detail are imperative to confounding the incorporated role of ASPECTS in treatment decision-making process.www.ischemaview.com)—and to show the possible impact on the outcome after thrombolysis.To our knowledge, this is the first study to evaluate the reliability of interpreting ASPECTS from three settings—source images, captured images on WhatsApp, and automated ASPECTS obtained from a software-based analysis (RAPID ASPECTS®) by iSchemaView . Between January 2018 and December 2019, 176 AIS patients who met the following inclusion criteria received IV-tPA: (1) time from symptom onset <4.5 h; (2) anterior circulation ischemic stroke; (3) baseline NCCT; (4) no contraindication for IV-tPA; and (5) ASPECT score ≥ 6 (ischemic changes ≤ 1/3 of MCA territory). There were several exclusion criteria: (1) intracranial hemorrhage; (2) pre-existing cerebral defects within the probable current ischemic area that could not reliably be distinguished from acute ischemic changes; and (3) severe motion or other artifacts impeding CT interpretation. To expedite stroke workflow, the thrombolysis decision is remotely taken by a stroke consultant through a closed WhatsApp group where clinical and laboratory data of the patients as well as NCCT images are uploaded by a stroke residency where interpretation of NCCT is carried out on the WhatsApp group by the neuroradiologist on duty. Other stroke neurologists, neurosurgeons, and ICU physicians all are within the same chat group and are notified by the decision. As of 2019, RAPID software (a computer-based automated scoring to assess early signs of brain ischemia) has been deployed in our institution to help develop a faster and more accurate stroke workflow as a part of developing the stroke service to include all reperfusion therapies for AIS. During our study period, we could identify two groups of patients: group 1 consisted of 36 AIS patients receiving the IV-tPA based on the automated ASPECTS processed by the RAPID system, while group 2 consisted of 86 AIS patients receiving treatment based on the decision made using the NCCT images sent via the WhatsApp group.This study was approved by the local institutional review board . We retrospectively reviewed consecutive patients with AIS who presented to the primary stroke unit, which is one our institution-affiliated facilities for stroke care in the Alexandria stroke network . Helical NCCT  was performed using a 5-mm section thickness from the foramen magnum through the vertex.Clear regulations and standardization of medical data sharing are lacking, and the use of Whatsapp(TM) remains a “gray area.” We tried to reduce variation in the image quality transmitted via WhatsApp, where all transferred NECT images were captured by one universal smartphone—the “resident's phone” . The transmitted images were either made up of a full range of series with customized slice thickness (1mm) generated by CT workstation software for printing or a video clip spanning the entire CT study. However, other factors, such as the “camera view angle” and “image light intensity,” that could affect image quality could not be avoided in this study, and this might downgrade the efficiency of the WhatsApp method for transmitting CT images when deciding on AIS treatment compared to a decision based on transferred automated dicom files through dedicated software.On the other hand, in WhatsApp-transmitted images, trying to reduce concerns regarding the identification of patients from non-anonymized shared data was considered in the current study where all data were transmitted to a closed group on WhatsApp that included only physicians who are involved in the treatment workflow of the patient. However, other privacy concerns could not be avoided, such as the fact that images sent through the app will be immediately downloaded into the recipient's smartphone photo library unless that setting is manually switched off. All messages are stored on a server in the US, which means they are not compliant with UK data protection legislation and the General Data Protection Regulation (GDPR). We did not anonymize the process of transmitting the images for the sake of the time factor, which is crucial in AIS treatment.Two neuroradiologists years with more than 10 years' experience independently reviewed all baseline NCCTs and assigned an ASPECTS using a 10-point scale . Axial isotropic sequences from the NCCT for each patient were uploaded to the software, and the automated ASPECTS was calculated without human interaction.For both group of patients, the neuroradiologists and automated ASPECTS were then exported to an IBM SPSS software V23 spreadsheet  for analysis.Finally, we used a cost-effectiveness analysis to compare the use of the automated ASPECTS interpretation (RAPID ischemaView) and the traditional ASPECTS interpretation of the sent NCCT images on the WhatsApp group.A CEA decision tree model was created by TreeAge Pro 2019  to evaluate the cost-utility analysis for both traditional and automated interpretation of ASPECTS CT., where we assumed that 90 days of follow-up could be one of the three possibilities, using mRS to reflect clinical outcome after IV-tPA: either 1-functional independence; 0–2 mRS; 2- functional dependence; 3–5 mRS; or 6 mRS - death. For cost utility, we refer you to Clinical and demographic data were presented as mean (SD) or median (interquartile range) as appropriate. ASPECTS values were presented as median (interquartile range). Comparison of ASPECTS was performed using both the raw/original scores and dichotomized ASPECTS using ≥6 and <6 as a cutoff. The interobserver agreement between two neuroradiologists was performed using a weighted κ test with a calculation of the 95% CI. Agreement and correlation among neuroradiologist agreement reads and automated ASPECTS were performed using the intraclass correlation coefficient with 95% CI.t-tests and χ2 tests as appropriate.Clinical and imaging variables and functional outcome (using a 90-day mRS >2 as a cutoff) were compared between both groups using a combination of A total of 122 patients were included . The mean of the door to needle time was 47.8 ± 16.5 min. The median and interquartile range (IQR) of the NIHSS were 11 and 8–14. Stroke etiology was cardioembolic in 27.9% of cases. A total of 58/122 patients (47.5%) achieved mRS <3 at 90-days follow-up. The median and (IQR) of the final agreement ASPECTS (inferred from source Dicom images) were 8 and 6–9.P = 0.036). By dichotomizing the 90-day outcome by using mRS < 3 as a cutoff value, indicating functional independence, a higher incidence of getting functional independence was observed in thrombolysis based on automated ASPECTS CT interpretation . Additionally, a 14-min reduction in the DTN time was observed in the group of AIS patients with automated ASPECTS interpretation .n = 86), an NCCT file that was uploaded to the WhatsApp group was read by two neuroradiologists to interpret the ASPECTS. Similarly, both were involved blindly  to rate the ASPECTS of the NCCT dicom source images on the workstation for each patient.In group 2, where the NCCT was delivered via WhatsApp  for reader 1 and 7  for reader 2. The interobserver agreement was fair with κ = 0.36 . For the dichotomized ASPECTS (ASPECTS ≥6 or <6), the interobserver agreement was improved to κ = 0.44 .When readers were involved in interpreting ASPECTS from the source of the images on the workstation for the same patients, the median for ASPECTS was 7  for reader 1 and 7  for reader 2, and the IOA was improved to moderate with κ = 0.57 . Similarly, for the dichotomized ASPECTS (ASPECTS ≥6 or <6), IOA was improved with κ = 0.69 . In the dichotomized agreement read, a total of 75 patients had ASPECTS ≥6 and 11 patients had ASPECTS <6.@ IschemaView software, the median was 7  for automated ASPECTS. The source Dicom images were blindly evaluated by both readers in an agreement session in which, for the final agreement read, the median for ASPECTS was 7 .In group 2, where 36 patients received IV-tPA based on automated ASPECTS generated by RAPIDBy dichotomizing Automated ASPECTS, a total of 35 patients had eASPECTS ≥6, while 1 had eASPECTS <6.Comparing the ASPECTS values, which were interpreted automatically by RAPID@ IschemaView software and humanly from source workstation images for the same patients (human agreement reads), we saw excellent agreement  for the dichotomized scores. In only one patient, the software underestimated the extent of early ischemic changes by providing an automated ASPECTS >6, while the score was <6 by agreement read.The rate-adjusted total costs of the treatment decision based on automated interpretation and WhatsApp are summarized and extrapolated from our hospital cost  in the The use of WhatsApp to assess the ASPECTS had a total mean per patient cost of LE 16,126.48, and 0.37 QALYs, while automated ASPECTS had a total mean per patient cost of LE 12,646.48, and 0.73 QALYs. The incremental cost of WhatsApp supported ASPECTS interpretation over automated ASPECTS interpretation was LE 3,480.00. The estimated ICER for RAPID assessment vs. WhatsApp assessment of treatment decision was LE 9,738.35.post-hoc analysis of the European Cooperative Acute Stroke Study (ECASS) suggested that the extent of hypoattenuation on head CT was a predictor of response to thrombolysis and the risk of hemorrhagic transformation  territory is only moderate (κ.4) .This draws attention to the effect of a quantitative approach in judging the extent of ischemia, and this includes the use of ASPECTS and the possibility for it to be integrated into the decision-making process for reperfusion therapy in patients with AIS, similarly to its use in deciding MT in LVO stroke guidelines . The cur@IschemaView neuroimaging platform for the use of selecting stroke patients most likely to benefit from endovascular thrombectomy  service] users were reported worldwide. It has become the primary means of instant messaging in clinical and non-clinical settings in many countries and specialties. Its frequent use in stroke workflow could be due to its live-chat feature, i.e., instantaneous communication with all stroke team with transmitting and sharing a patient's CT images and clinical data with a real-time notification service. Remote viewing images on smartphones and tablets with specialized applications have been shown to be effective for rapidly visualizing radiologic images and for urgent decision making with regards to patient care in different domains of medicine , 29. Thembectomy . Howevermbectomy , 32, we mbectomy , 33. TheWe showed that interpretation of automated ASPECTS by the RAPID@IschemaView ASPECTS software package performs equally well with the agreement read of expert neuroradiologists, and this performance was severely degraded when WhatsApp captured CT images used for ASPECTS assessment. In our study, we showed that automated ASPECTS might predict outcomes following IV thrombolysis.yassinossama@yahoo.com.The datasets analyzed in this article are not publicly available. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by the Alexandria University Ethical Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors contributed equally to drafting the work and revising it critically for important intellectual content. OM has substantial contributions to the conception and design of the work and the acquisition, analysis, and interpretation of data for the work, and contributed to drafting the work, revising it critically for important intellectual content. Final approval of the version to be published.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.


The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty  participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% . The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 . In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity. Pseudomonas aeruginosa is commonly implicated in secondary bacterial lung infections and colonisation. Aminoglycoside antibiotics, usually combined with a beta-lactam, are frequently used to treat respiratory exacerbations in CF1, as they are effective against P. aeruginosa. Whilst this approach generally leads to improved patient outcomes, aminoglycoside use is also associated with an increased risk of nephrotoxicity.In Cystic fibrosis (CF) the resistant pathogen 4, with rates of 20% reported using daily monitoring of serum creatinine5. The risk of AKI is higher with longer duration of aminoglycoside use and with recent previous aminoglycoside exposure6. In one cohort of adults with CF, between 31% and 42% had evidence of chronic renal impairment which was significantly associated with cumulative aminoglycoside exposure7. However, this has not been replicated in other cohorts9. Strategies such as therapeutic drug monitoring and extended-interval dosing10 are only partially effective in preventing aminoglycoside-induced nephrotoxicity. It is therefore important to develop further, more effective, strategies.The incidence of acute kidney injury (AKI) in children with CF is increased with current or recent exposure to aminoglycosides11. This pathway is activated by intermediates derived from mevalonate, which is formed from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) via the enzyme HMG-CoA reductase12. We hypothesised that inhibiting HMG-CoA reductase with a statin would lead to a reduction in toxicity. Statins are inhibitors of megalin-mediated endocytosis in vitro14, and are therefore likely to reduce uptake of aminoglycosides in the proximal tubule. Indeed, in vivo studies of aminoglycoside-induced nephrotoxicity in rats have consistently demonstrated a protective effect of statins20.Aminoglycosides cause targeted toxicity to renal proximal tubule epithelial cells. Megalin, a multi-ligand receptor, facilitates the endocytosis and accumulation of aminoglycosides in these cells21 . In addition, it is highly potent, and licensed for use in children. This trial was designed to test the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with CF.In this paper, we describe the first clinical trial to evaluate the repurposing of a statin for the prevention of aminoglycoside-induced kidney toxicity. Rosuvastatin was chosen as it is hydrophilic, has minimal hepatic metabolism, and has some renal elimination of the parent drugA total of 258 patients were assessed for eligibility across 13 CF centres in the UK (May 2015-January 2017); 208 were not randomised as they failed to meet the inclusion/exclusion criteria or did not provide consent. The planned sample size was met with twenty-three participants randomised to the intervention and 27 to the control  and four 15%) participants randomised to the intervention and control groups, respectively, discontinued tobramycin treatment early. Median duration of treatment was 14 days in both the intervention and control groups  was 1.85 and 2.00 in the control and intervention groups respectively Table . There wThe estimated geometric mean fold-change of normalised Neutrophil Gelatinase-Associated Lipocalin (NGAL) was 8.90 and 4.99 in the control and intervention groups respectively. The estimated mean treatment difference was 0.56   AKI criteriaTwo participants randomised to the intervention group withdrew consent prior to receiving the intervention and were therefore not included in the safety analysis. Twelve adverse reactions were reported by 5 (25%) of the 21 participants in the intervention group Table . All eveRecurrence of pulmonary exacerbation during follow-up, requiring hospitalisation, was the only serious adverse event in the control group, reported for one (4%) participant. Abnormal blood results requiring prolonged hospitalisation were reported as a serious adverse event for one (5%) participant in the intervention group but this was not considered to be related to the intervention.23. The trial was powered to detect a difference in fold-change between the groups of 2. The PROteKT and URBAN CF populations were similar, although PROteKT contained a greater proportion of female participants, and had higher mean age, height and weight (due to differences in the inclusion criteria for age). There were no differences in aminoglycoside prescribing practices between the two studies. We do not believe that the differences between the populations used in PROteKT and URBAN CF account for lower than expected levels of nephrotoxicity observed in our randomised controlled trial. Therefore, it is unclear whether this reflects lower than usual levels of toxicity in the PROteKT cohort, or higher than usual levels of toxicity in the cohort upon which the sample size calculation was based. This makes it difficult to definitively exclude the possibility of a protective effect of rosuvastatin. Indeed, some of our secondary outcome measures suggest a trend towards a protective effect. Importantly, the use of rosuvastatin was generally well tolerated.This is the first randomised controlled trial in man to assess whether rosuvastatin has a protective effect against tobramycin-induced nephrotoxicity. It was designed as an early phase trial using KIM-1 as a surrogate outcome measure. We found little evidence of a protective effect of rosuvastatin in this trial as determined by both primary and secondary outcomes, but this should be interpreted with caution as the control group only demonstrated a mean fold-change of KIM-1 of 1.85. The sample size calculation for this study was, however, based upon an expected mean fold-change in KIM-1 of 3.03 during exposure to tobramycin derived from an early analysis of samples in the URBAN CF study24. It was chosen as the primary outcome measure as it has previously shown potential for the identification of aminoglycoside-induced nephrotoxicity in preterm neonates25, and in children with CF26, as well as outperforming other biomarkers of aminoglycoside-induced nephrotoxicity in pre-clinical models27. In clinical practice, changes in serum creatinine meeting agreed criteria for AKI22 are more widely accepted for defining nephrotoxicity. However, changes in serum creatinine are a relatively late event in the process of nephrotoxicity, and for the purposes of a phase IIa trial, it was felt that KIM-1 was a good surrogate measure. Indeed, we identified no significant treatment effect upon serum creatinine in this study, consistent with our previous experience in the URBAN CF study23. The use of a change in serum creatinine as an outcome measure may be relevant to use in future trials, but given that this is estimated to occur in 14–20%6, a much larger sample size will be required.Urine KIM-1 is a cell membrane glycoprotein upregulated by proximal tubule epithelial cells in response to toxicity28. It is a sensitive predictor for AKI29, and has previously been shown to be elevated during aminoglycoside exposure in neonates25, and in children with CF23. Patients in the intervention group had a smaller estimated geometric mean fold-change of normalised NGAL (p = 0.11), and a significantly lower AUC of normalised NGAL. The difference in AUC between the groups must be interpreted in the light of a higher baseline urinary NGAL in the control compared to the intervention group (61.08 ng/mgCr and 22.46 ng/mgCr respectively). This may, in part, be explained by the higher proportion of females in the control versus intervention groups as females have been consistently shown to have higher baseline NGAL concentrations than males30. Whilst our results may be interpreted to suggest a protective effect of rosuvastatin, we feel that these should be interpreted cautiously.Urine NGAL is a 25 kDa protein expressed by kidney epithelial cells 19, simvastatin16 and rosuvastatin20. We felt that rosuvastatin was the most promising candidate based upon its pharmacology. It is a hydrophilic statin, and has greater renal excretion than the more lipophilic atorvastatin and simvastatin. It causes more proteinuria than other statins, probably because it is secreted in the proximal tubules31 and inhibits megalin-mediated endocytosis. We considered whether we should have given the statin for a few days in advance of commencing the tobramycin in order to achieve steady-state concentrations. However, published pre-clinical studies demonstrated a protective effect of statins without the need for this20.Published studies in rat models of aminoglycoside-induced nephrotoxicity have consistently demonstrated a protective effect with a range of statins, including atorvastatinThe recruitment of children with CF from thirteen different sites in the UK to participate in this trial ensures that differences in practice between centres should be accounted for in the randomisation. The trial was designed to cause the least disruption possible to standard daily care, and for the intervention to be minimally burdensome to patients . This was reflected in the good adherence to the randomised intervention, and by a low number of reported adverse reactions.20, we feel further studies in humans are warranted. These would need to be powered for a clinically acceptable primary outcome measure such as AKI (rise in creatinine). There are of course other interventions which have been attempted to reduce the risk of aminoglycoside nephrotoxicity, including extended-interval dosing and drug trough level monitoring10, and morning (versus evening) administration of the aminoglycoside32. All these interventions are not mutually exclusive, and it may be that combinations of interventions may be more successful in preventing renal injury when compared with individual interventions, and such a possibility should be investigated in an appropriately designed clinical trial in the future.In conclusion, given the lower than expected level of nephrotoxicity seen in this study we feel that we can neither confirm nor refute the hypothesis that statins protect against aminoglycoside nephrotoxicity. Given the large amount of pre-clinical data which shows that statins can be protectiveThis multi-centre, randomised, open-labelled, parallel group, phase IIa trial was registered in duplicate on both the EU Clinical Trials Register  and the ISRCTN Registry . It received ethical approval from the National Research Ethics Service Committee North West – Greater Manchester Central, and was conducted in accordance with the Declaration of Helsinki. Participants were recruited at 13 paediatric CF treatment centres in the UK. Each parent or guardian gave written informed consent, and each child gave assent where appropriate.33), previous adverse reaction to a statin, and existing treatment with a statin. Participants with renal disease, elevation of either transaminases and/or creatine kinase were also excluded. The full inclusion and exclusion criteria are described in the trial protocol , course of treatment with IV tobramycin were eligible for randomisation. Key exclusion criteria included participants of Asian ancestry  and local protocols. The first dose of rosuvastatin was given on the same calendar day and prior to the first dose of IV tobramycin. Subsequent daily doses of rosuvastatin were given prior to that day’s dose of tobramycin. Treatment with oral rosuvastatin continued for the duration of the course of IV tobramycin. If the tobramycin course was shorter than 14 days, rosuvastatin was discontinued after the final tobramycin dose. If the tobramycin course was longer than 14 days, rosuvastatin was continued until the final day of the tobramycin course. Participants randomised to the no intervention arm received usual care during their IV tobramycin treatment course. No placebo was provided.Each participant randomised to the intervention arm received a daily oral dose of 10 mg rosuvastatin  for the duration of a treatment course of IV tobramycin . Tobramycin was the first choice aminoglycoside in CF for all centres, and dosing and monitoring of drug concentrations followed the British National FormularyBaseline assessment before tobramycin therapy (T0) included collection of urine and blood samples for confirmation of eligibility criteria, and spirometry. During treatment with IV tobramycin urine samples were collected daily from each child. Participants had assessments on days T + 1, T + 8 and T + 13. These included adverse event assessment, a symptom-directed physical examination if required, and collection of blood and urine samples. Spirometry was performed at the T + 8 and T + 13 visits. A final follow-up visit, with collection of blood/urine samples and spirometry, was conducted 3–5 weeks following completion of tobramycin treatment.38.Urine samples were normally collected by clean catch into a sterile container. If the participant was an inpatient, the daily samples were sent directly to the local laboratory. If the participant received IV tobramycin at home, samples were stored in the home refrigerator in a sealed container until the next scheduled study visit. All samples were stored at fridge temperature (4 °C) for a total of one week (including time spent at the patient’s home) and then aliquoted and stored at −80 °C (or −20 °C for a maximum of 6 months) in the local laboratory. Stability of KIM-1 has previously been reported in urine stored at 4 °C for periods of one weekWherever possible, study bloods were collected by venepuncture at the same time as any clinically indicated bloods in order to minimise the burden to the patient. A minimum of two 1.2 ml samples in Lithium/Heparin tubes, and one 1.2 ml sample in a serum tube were collected at each time point. Plasma and serum were extracted locally at each site, aliquoted and stored at −80 °C.Batched samples were couriered on dry ice to the Good Clinical Practice Laboratory (GCPLab) facility in Liverpool for subsequent storage and analysis (here samples were stored at −80 °C). All laboratory analyses were undertaken in a standardised manner, being blinded to allocation, time of sampling and clinical outcomes of patients.The primary outcome was the difference in mean fold-change in urinary KIM-1 from baseline to ‘highest value’ concentration during exposure to tobramycin between the intervention and control arms.39, and was measured locally during study visits. We also compared change in C-Reactive Protein (CRP), as a marker of inflammation/infection, between the two groups. Rosuvastatin concentrations were measured in the intervention arm participants to describe the pharmacokinetic profile of rosuvastatin, to assess compliance, and to relate rosuvastatin concentrations to change in urinary KIM-1.The secondary outcome measures were the difference in serum creatinine, estimated glomerular filtration rate (eGFR) and urinary NGAL between the intervention and control arms during exposure to tobramycin. We assessed for pharmacokinetic interaction between rosuvastatin and tobramycin by comparing tobramycin concentrations between the rosuvastatin treated arm and the control arm. We assessed for pharmacodynamic interaction between rosuvastatin and tobramycin, by comparing change in percent of predicted Forced Expiratory Volume in 1 second (FEV1), between the rosuvastatin treated and control arms. This is a widely used indirect measure of aminoglycoside treatment outcome in children with CFAll the participants who received at least one dose of rosuvastatin were included in the safety analysis. Adverse reactions and serious adverse events were recorded from the point of informed consent and throughout the trial treatment period up until the final assessment .30. Biomarker values were normalised to urinary creatinine which was determined spectrophotometically as previously described40. Serum creatinine, tobramycin concentrations and CRP were measured in the laboratory serving the local hospital site.Urinary KIM-1 and NGAL were measured using validated electrochemiluminescent assays , US) as previously describedRosuvastatin concentrations were measured centrally at the University of Liverpool. A high performance liquid chromatography mass spectrometric method for the estimation of rosuvastatin in plasma, was developed and validated using rosuvastatin-D6 as internal standard. Sample preparation was accomplished by protein precipitation. The samples were chromatographed on a C-18 Halo column using mobile phases consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The method was validated over a concentration range of 0.5–100 ng/mL for rosuvastatin.23 from 10 participants receiving a single course of treatment with tobramycin. The same data was also inspected to assess that the assumption of normality is reasonable. Using these assumptions and utilizing a 2-sample t-test, a sample size of 20 in each arm would be sufficient. We planned to include 50 patients in order to compensate for 10% loss to follow up.The statistical analysis plan Appendix  was writThe principle of intention-to-treat was the main strategy of the analysis adopted for the primary outcome and all the secondary outcomes. These analyses were conducted on all randomised participants, in the group to which they were allocated, and for whom the outcome(s) of interest have been observed/measured.The primary outcome was analysed using the method of analysis of covariance (ANCOVA). The outcome measure was the mean log-transformed fold-change of normalised KIM-1 (ng/mgCr) calculated by dividing the peak value, corresponding to the ‘highest value’ of normalised KIM-1 during exposure to tobramycin, by the baseline normalised KIM-1 value for each participant. The explanatory variables were treatment group and baseline normalised KIM-1 value. 95% confidence intervals will be reported and a p-value of <0.05 considered statistically significant. The secondary outcomes were analysed longitudinally using random intercept models with unstructured covariance matrices, including an interaction between treatment group and visit.In an additional analysis of normalised NGAL (ng/mgCr), an ANCOVA model was used, as for KIM-1 above, comparing log-transformed mean fold-change from baseline to peak NGAL between the treatment groups, controlling for the baseline normalised NGAL. The model estimates were exponentiated to be interpretable on the normal scale.22.In an additional descriptive analysis of serum creatinine data, change from baseline serum creatinine during tobramycin exposure was defined according to the KDIGO AKI criteria Pre-specified sensitivity analyses tested impact of missing data; the statistical analysis plan includes full details of sensitivity analyses and analyses of secondary outcomes. Analyses were performed using SAS® version 9.4 .PROteKT Supplementary Material.


Conducting a thorough check to ensure that all equipment and personnel are positioned correctly at the start of any operation is essential for both the safety of the surgical team and the patient outcome. Orthopaedic surgery in particular carries a high risk of occupational injury and this group could benefit greatly from ergonomic improvements. This review highlights multiple factors that can influence safety of surgeons, surgical efficiency and patient outcomes.“TULIPS” is a mnemonic that lists six key steps in optimising the surgical procedure through effective positioning of equipment and personnel pre-operatively. This was trialled by distribution amongst orthopaedic registrars regionally and it received excellent feedback, with the majority changing their current practice. Here we report that using this simple and memorable checklist can assist orthopaedic surgeons in setting up the operating theatre, facilitating ergonomic improvements that can reduce the risk of musculoskeletal injury and radiation exposure. Set-up for surgical procedures is essential for the safety of the patient, the surgeon and patient outcomes. It has been suggested orthopaedic surgeons would benefit most from ergonomic improvements, as they are particularly at risk of occupational injury . Data byThe checklist method has been a proven approach across both medical and non-medical disciplines including aviation, from where many of our current protocols in healthcare were developed from . ImplemeA survey was sent to all the Trauma and Orthopaedic (T&O) registrars working in the Oxfordshire deanery before the introduction of the TULIPS mnemonic. The aim of the survey was to assess whether surgical teams had a methodological approach to setting up the operating theatre, and whether individuals had experienced problems in setting up in theatre.Participants were then asked to trial the TULIPS mnemonic in their daily practice as a checklist for setting up the operating theatre prior to their surgical procedures over a period of two weeks. After this period, participants were contacted with a second survey for feedback on its impact in practice.TULIPS mnemonicT - Table and Tourniquet positionU - You and Your positionL - Lighting positionI - Imaging and Image Intensifier positionP - Patient and Personnel positionS - Screen Image positionA total of 14 responses were received in our pre-intervention survey, and 14 responses  in our post intervention survey.Pre-intervention survey results8/14 (57%) registrars reported they had a method of setting up the operating theatre, however only 2/14 (14%) reported using a checklist approach to help them set-up. 12/14 (86%) reported having experienced difficulties in surgery directly linked to poor theatre set-up, with 8/14 (57%) all mentioning that image intensifier position had been problematic. Other frequent comments related to all other areas of the TULIPS mnemonic, including table position, their position, staff positioning and lighting. Of the 12 who had difficulties due to their surgical set-up, 9/12 (75%), did not have a formal checklist approach. Of the eight surgeons who had a method for setting-up, only 3/8 (38%) used a formal checklist approach, and 6/8 (75%) still had difficulties with their surgical set-up.Post-intervention survey resultsAfter a trial phase of two weeks, 13/14 (93%) reported finding TULIPS useful. This included all 12/14 (86%) from the pre-intervention survey who had previously reported experiencing difficulties in surgery. 13/14 (93%) reported that it had made them reconsider their surgical set-up. 8/14 (57%) stated TULIPS had changed their practice for setting-up in theatre and they now incorporated this checklist approach into their standard practice.6/14 (43%) did not change their practice as a result of TULIPS, however the pre-intervention survey showed 5/6 (83%) of those that did not change their practice already had a method of surgical set-up prior to the two week trial of TULIPS.Out of the 8/14 (57%) who reported having a current method for setting up in theatre, all 8/8 (100%) reported TULIPS to be a useful method of approaching set-up, of which 7/8 (88%) also reported that TULIPS made them reconsider their own set-up, with 3/8 (38%) still choosing to change their practice permanently as a result.Most importantly, of the 6/14 (43%) who reported in the pre-intervention survey that they did not have a method of surgical set-up, 5/6 (83%) changed their practice permanently because of TULIPS.TULIPS is a simple, memorable mnemonic that can be adopted in operating theatres and is easily understood and implemented by surgeons. Our results show that the TULIPS method of approaching surgical set-up was effective in changing practice and serves as a useful checklist for orthopaedic surgeons. The introduction of TULIPS regionally has been adopted into standard practice prior to operations for those who do not already have a similar method in place. Table and tourniquet positionCorrect positioning of the operating table has been shown to benefit the surgeon by providing proper ergonomic support and reducing the risk of occupational musculoskeletal injuries common across all surgical disciplines . AdjustiTourniquets are commonly used in limb trauma surgery to exsanguinate blood flow to a distal extremity. The decision to use tourniquets, along with its location and timing also has important effects on patient outcome . A systeYou and your positionCorrect positioning of the surgeon facilitates better economy of movement, visualisation of anatomical structures and comfort. In one study, surgeons were found to be rotating more than 50% from their midline or stretching to 50% of their limit, for a third of the duration of the operation . IdeallyLighting positionAll lighting systems in the operating room must be positioned to adequately illuminate the surgical area, prevent glare and provide true colour rendering . These aReducing the handling of light handles is also suggested as they can carry a significant level of bacterial contamination. It is important the surgeon considers the lighting position preoperatively and pre-empts any movements needed, which could be performed by a colleague to reduce chance of contaminationImaging and image intensifier positionFluoroscopy is a valuable imaging tool used frequently in orthopaedic surgery. This is composed of an X-ray tube, an image intensifier, a collimator and a display. Given the associated risks from radiation exposure, it is important to encourage surgical teams during set-up to adhere to protocols that limit this as much as possible . Many faOrthopaedic surgeons have been shown to have an increased risk of cancer that has partly been attributed to occupational radiation exposure from theatre c-arm fluoroscopy . ReducinIn surgery involving regular c-arm repositioning, its placement should facilitate the adjustment for imaging the required structures, and its movement should be as unobstructed as possible. For example, insertion of dynamic hip screws in the proximal femur requires regular anteroposterior (AP) and lateral views. The c-arm is positioned obliquely between the legs of the patient to enable an axial view and must then be tilted by 10-15 degrees to compensate for the anteversion of the femoral neck . SimilarLastly, pre-operative imaging must also be considered at this stage on the checklist. This ensures nothing blocks the field of view, and therefore fracture patterns and angles can be clearly seen on previous x-rays to help plan the surgical approach.Patient and personnel positionPositioning of the patient correctly on the surgical table directly impacts patient outcomes. In one study, surgical positioning led to serious but preventable injuries. Of the 172 patients, 12.2% experienced injuries resulting from their surgical positioning on the table including peripheral nerve injuries, pain around pressure points, and erythema . A pressIn a survey across nine laparoscopic surgical procedures, 85 items were recorded in the log of encountered problems, of which 57 related directly to the positioning of equipment and personnel. Both surgeons and nurses experience substantial musculoskeletal strain resulting from fixed postures for prolonged periods of time . Whilst Secondly, effective communication between members of the team and efficient division of labour is owed to a good awareness of everyone’s positioning in the room. Additionally, all individuals present in the theatre must have a good awareness of wires and other trip hazards, as well as an appreciation for the demarcation between sterile and non-sterile areas. Correctly positioning everyone prior to the operation is important in enabling good teamwork which will reduce the risk of preventable adverse outcomes.Screen image positionThe optimal positioning for any video display terminal was shown to be between 10-25 degrees below the line of sight . Neck stIn conclusion, this review has highlighted multiple theatre set-up factors that can influence patient outcome, surgical efficiency, and safety of surgeons. These include table, personnel, and equipment positioning. Better theatre set-up has been shown to improve patient outcomes and surgical efficiency and reduces risk of occupational injury and physical fatigue of the surgeon.We recommend the use of this mnemonic as a checklist during pre-operative set-up to promote surgical best practice. Incorporating a method of remembering six key tasks into routine practice may provide a simple but effective tool to avoid preventable outcomes and Never Events caused by incorrect set-up prior to the operation.


Introduction: High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes. Methods: Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article . Results: The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers. Conclusions: A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet. Advanced glycation end-products (AGEs) are a class of chemical compound that are created by the non-enzymatic reaction between reducing sugars and free amino groups. This reaction occurs endogenously in the body during the course of normal cellular metabolism ,2. AGEs In addition to the endogenous creation of AGEs, exogenous sources such as pre-formed AGEs from food contribute significantly to the body’s pool of AGEs. AGEs exist in most foods, but they are particularly abundant in animal-derived foods. Exposure to high temperatures  and long cooking times can greatly increase the amount of AGEs in food ,5.AGEs affect cellular functions by binding to the receptor for advanced glycationend-products (RAGE), resulting in the activation of inflammatory and oxidative stress cascades ,6. High T2D has been consistently shown to increase the risk ofAD ; diabetiwww.clinicaltrials.gov (NCT02739971).The study was designed according to the CONSORT criteria extension to pilot trials  and was Minimum inclusion criteria to participate in the study included being age > 65, a diagnosis ofT2Dand subjective memory complaints. T2D was defined by the use of medications for T2D, health records indicating a diagnosis of T2D, or tworecent routine blood tests indicating fasting glucose above 126 mg/dl. Candidates with any existing neurological condition that can affect cognition were excluded . All participants were required to have a family member as an informant. The study was advertised using mass mailing to recruit volunteers from among people who had previously agreed to receive health-related emails and by advertising through websites and social media forums for clinical trials, dementia, and diabetes. Interested candidates were contacted by telephone to ascertain age and T2D status and were invited to a face-to-face screening visit where cognition and nutritional status were assessed. Participants were eligible if they met the following criteria at the screening visit: a clinical dementia rating scale (CDR) <1  , MontreaUpon enrollment, participants were assigned by a computerized random sequence generator to follow one of two diets for 6 months. The standard of care (SOC) arm was instructed to follow dietary guidelines for achieving good glycemic control . The AGEParticipants were asked to follow the instructions of the study for 6 months and to avoid any new diet or life-style program during this period. Those assigned the AGE-lowering arm were provided the same guidance on glycemic control, but in addition were taught how to reduce their dietary AGEs intake by modifying the cooking methods and reducing cooking time and temperature without changing the nutrient composition of their food). They were advised to boil, poach, stew, or steam and to avoid frying, baking, or grilling anyanimal-derived products . All parTo minimize potential bias, the study dietitian categorized participants’ self-reported adherence upon completion of the study but before serum AGEs results were available and before analyzing any outcomes. Each phone call scored 0 for a negative answer and 1 for a positive answer to the following questions:Did the participant report fully maintaining the guidelines for good glycemic control since the previous call ? As carbohydrates intake is a key strategy in achieving glycemic control , the ansDid the participant report using any cooking methods that they wereadvised to avoid for animal derived food items since the previous call? (yes/no for AGE-lowering arm only).Scores (0/1) obtained from each telephone call were summed for two adherence scales: A T2D adherence scale for all participants and a low AGEs adherence scale for the AGE-lowering arm only. The total score for each scale was divided by the average number of calls and was presented in percentage of “positive answers” reflecting adherence to the guidelines. A 1–5 Likert scale with the following categorization was built: A score of 1 represented participants who maintained the dietary instructions above 80% of phones call (“very high adherence”), a score of 2 represented those who complied with the diet between 60–80% of the calls (good adherence), and a score of 3 referred to adherence of between 40–60% . For adherence lower than 40%, participants were asked if they wished to continue participating in the study. A score of 4 represented those compliant below 40% of the calls but with a desire to continue participating in the study(“lack of adherence but desire to continue”), and finally, a score of 5 referred to those who had below 40% adherence and who wished to withdraw from the study (“lack of adherence and desire to withdraw”). If the total number of phone calls with the participant was below the 5th quintiles , another point was added to the final score of the adherence scale, as not answering phone reflect low adherence.Identical assessments were repeated at baseline and post-intervention (after 6 months). A fasting blood sample was drawn to analyze markers related to diabetes , lipid profile , kidney function , the inflammatory marker C reactive protein (CRP), and a complete blood count. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated according to the following equation: insulin (mu/l) Xglucose (mg/dl)/405 . HOMA-IRAGEs were measured in a blinded fashion by liquid chromatography–mass spectrometry (LC-MS) using an Agilent model 6490 Triple Quadrupole MS with a 1290 Rapid Resolution LC system and stable heavy isotope substituted internal standards, as described elsewhere  , which was specifically designed to assess nutrition in older adultsand is commonly used in this population . The queAnthropometrics: Weight, height, and waist circumference (measured in centimeters at the level of the umbilicus) were assessed by the study dietitian. Participants wore their shoes and clothing to avoid discomfort but were asked to leave only basic clothing during measurements. Demographic information: year of birth, years of education, profession, and family status. Lifestyle: physical activity was assessed using the Minnesota Leisure Time Physical Activity Questionnaire  and smokAlthough diet allocation could not be concealed from the participants and study dietitian, care was taken to blind all other research staff to the arm assignments, including the neuropsychologist, the MRI technician, the lab technician where the blood tests were analyzed, and the research assistant who entered the data.The primary analysis of the effect of the intervention used intent-to-treat (ITT) methods and secondary analyses used per-protocol (PP) methods. The ITT analysis included all randomized participants who finished 6 months of follow-up. For the PP analysis, participants were considered to be fully compliant if they were at least 80% adherent to their assigned diet as assessed by weekly phone interviews .2 test for categorical outcomes, t-test for continuous outcomes distributed normally, and by Mann–Whitney tests for non-normal distributions.Baseline demographic and clinical characteristics are presented descriptively as proportions or as means with standard deviations. Comparison between arms was analyzed by χt test or Wilcoxon tests for within-arm changes and by 2 sided t-test or Mann–Whitney for the between-arms analysis. Alpha of 0.05 was used for significance levels. SPSS version 23  was used forall analyses.Changes in serum AGEconcentrations from baseline to 6 months were analyzed with paired In total, 75 eligible participants were randomized to enter the study. Baseline characteristics of arms randomized to the AGE-lowering and SOC diet are shown in p = 0.12) indicating that the extent of patient-dietitian interactions did not differ by arm.During the 6 month follow-up period, only five participants withdrew, 3 from the SOC arm and 2 assigned to the AGE-lowering diet so that 70 (93%) had complete data for analysis at the 6 months follow-up visit. The average number of completed phone calls was 16.5 calls per patient, with no significant difference in call rates between the two arms (p = 0.34). The relative proportion of macronutrients at baseline was similar between the 2 diet arms and remained the same at follow-up, as it was at baseline for each diet, indicating that the decline in energy reflected a decrease in the amount of food consumed rather than a shift in food preferences  declined in both arms by 15.5% on average with no difference between the 2 diet arms (ferences . Estimatp < 0.001) and MG-H1 (p = 0.015). In contrast, in the AGE-lowering arm, circulating AGE concentrations tended to be relatively stable with slight declines that were not statistically significant. Between-arm comparisons of the diet-induced change in AGE serum levels was statistically significant for CEL  and MG-H1 .The effect of the intervention on the five serum AGEs  is shown in Participants assigned to both the SOC diet and the AGE-lowering diet improved in several metabolic parameters . In the p = 0.035), 3DGH , and MG-H1   were classified as “very highly adherent”, 10 (30.9%) had “good adherence”, 4 (12.1%) had “partial adherence”, and none of the participants were classified as having “low adherence”. Since the “partial adherence” category had a small number of participants, we analyzed it together with the “good adherence” category. On average, all serum AGEs declined in the very highly adherent group, while they increased in those classified as having only good or partial adherence. The differences in the very high vs. good and partially adherent groups were statistically significant for CML  .2 (p = 0.012). Estimated AGE, energy, protein, carbohydrate, and fat intake all declined significantly in both groups. However, the decrease in estimated AGE intake was significantly greater in the very highly adherent group compared to the good and partially adherent group .Other metabolic biomarkers tended to show a greater improvement in the very highly adherent vs. the less adherent groups but this was not statistically significant: HOMA-IR  and creatinine clearance . No other metabolic or nutritional differences were observed.Similarly, when metabolic markers were analyzed by adherence, only the very highly adherent group experienced a significant decrease in BMI of 0.77 kg/mOur results show that dietary reduction of AGE intake in older diabetics can have the additional benefit of decreasing circulating AGE levels, beyond that which can be achieved by following the standard of care diet for good glycemic control. As expected, reductions in serum AGEs were more prominent in individuals who were highly adherent to the diet. We designed our intervention based on several earlier randomized controlled trials of dietary AGE reduction, which had demonstrated that limiting dietary AGE intake by modification of cooking methods could reduce circulating AGEs, specifically CML and MG, in healthy individuals , as wellOf interest, participants in the SOC arm showed a tendency for all serum AGEs to increase over time reaching statistical significance for G-H1 (+30%) and MG-H1 (+33%).Other trials with participants with the metabolic syndrome and diabetes have also documented that participants who didnot follow the AGE-lowering diet hada tendency to increase serum AGE levels ,28. Our In contrast to other trials, dietary AGE-lowering did not improve HOMA-IR in our population. This might simply reflect the relatively modest reduction of circulating AGEs in our study and the older age of our population. Of note, our average baseline HbA1c at 6.6% wasrelatively low for older adults with T2D, thus indicating good glycemic possibly that could explainthe lack of effect of the low AGE diet on metabolic markers. Moreover, 24% of our patients did not have assessment of HOMA because they were medicated with insulin and the number of participants might have not been large enough to demonstrate an effect of AGE change. This together with the high education level, low drop-out rate, and high adherence to diet may indicate selection bias towards a relatively well educated, diet-conscious, motivated, and resilient study population. Future clinical trials should include participants with more severe T2D as they may be amenable to a greater reduction in metabolic markers so the possible “floor effect” of good glycemic control found in our sample may be avoided. In addition, as reported in previous trials in participants with T2D ,29, the Our study has several limitations including that by the nature of the design (explicit dietary interventions) neither the investigators nor the patients were blind to the intervention. The dropout rate in this clinical trial was relatively low (6.7%) and the two arms did not differ neither in number nor cause of dropout. Yet, it is possible that the relatively high adherence to the low-AGE diet was related to its novelty. The novelty of a dietary approach may increase adherence, at least in the short-term. We attempted to minimize this by providing tailored  recommendations for T2D  for the The study has several strengths. The number and length of phone calls with the two arms was essentially identical limiting the placebo effect. In addition, the study used MS for the measurements of AGEs, which is more precise than ELISA used in the most RCT in the field. Lastly, our low dropout rates emphasize the feasibility of such programs in older adults with T2D.The current study provides new evidence that dietary AGE restriction is feasible in older adults with T2D and that there are modest decreases in specific serum AGE levels resulting from a low AGE diet unrelated to changes in other metabolic markers. These decreases occur primarily in individuals who are highly adherent to the diet. Larger and longer-term studies are required to ascertain the health benefits of low AGEs diet in older adults with T2D. The ability of participants from a clinical trial setting to maintain such dietary guidelines for long term should also be tested.


In the ‘Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism’ (SELECT-D) trial, rivaroxaban showed relatively low venous thromboembolism (VTE) recurrence but higher bleeding compared with dalteparin in patients with cancer. We aim to calculate the cost-effectiveness and budget impact of rivaroxaban compared with dalteparin in patients with cancer at risk of recurrent VTE.We built a Markov model to calculate the cost-effectiveness from a societal perspective over a 5-year time horizon for the Dutch healthcare setting.A hypothetical cohort of 1000 cancer patients with VTE entered the model with baseline characteristics based on the SELECT-D trial.Six months of treatment with rivaroxaban (15 mg two times per day for first 3 weeks followed by 20 mg once daily) was compared with 6 months of treatment with dalteparin (200 IU/kg daily during month 1 followed by 150 IU/kg daily).The primary outcome of the cost-effectiveness analysis was the incremental cost-effectiveness ratio (ICER). The robustness of the model was evaluated in probabilistic and univariate sensitivity analyses. A budget impact analysis was performed to calculate the total annual financial consequences for a societal perspective in the Netherlands.In the base case and all scenarios, rivaroxaban were cost-saving while also slightly improving the patient’s health, resulting in economically dominant ICERs. In the probabilistic sensitivity analysis, 77.8% and 98.7% of the simulations showed rivaroxaban to be cost-saving and more effective for a 5-year and 6-month time horizon, respectively. Rivaroxaban can save up to €11 326 763 (CI €5 164 254 to €17 363 231) in approximately 8000 cancer patients with VTE per year compared with dalteparin based on a 1-year time horizon.Treatment with rivaroxaban is economically dominant over dalteparin in patients with cancer at risk for recurrent VTE in the Netherlands. The use of rivaroxaban instead of dalteparin can save over €10 million per year, primarily driven by the difference in drug costs. This analysis used sophisticated pharmacoeconomic modelling methods to conduct cost-effectiveness and budget impact analyses, presenting the economic impact on a patient and on a population level.Our model is based on timely, robust data from the important SELECT-D trial.Various additional scenarios were used to analyse the effect of different assumptions and clinical situations.We assumed a 6-month treatment duration for all patients, while in clinical practice the treatment duration may vary between patients.Due to lack of data, the productivity losses were not taken into account.Venous thromboembolism (VTE), comprising both pulmonary embolism (PE) and deep vein thrombosis (DVT), is a major challenge in patients with cancer.VTE is treated with anticoagulation therapy, and this is continued as prophylaxis for recurrence over a longer period because of the high risk of recurrence during the first months after the initial VTE.6 7The guidelines recommend against the use of VKAs in patients with cancer because of potential drug interactions, liver dysfunction and malnutrition, all of which lead to fluctuations of the international normalised ratio (INR) and could result in negative patient outcomes.15 16et al.17The SELECT-D is a multicentre, randomised, clinical pilot trial in the UK; it is a head-to-head comparison of rivaroxaban and dalteparin in 406 patients with active cancer who had experienced a symptomatic PE, incidental PE or symptomatic DVT.Based on the results of these studies and the fact that DOACs can be orally administered (unlike the subcutaneously injected LMWHs), a greater utilisation of DOACs for VTE in patients with cancer might be expected. Since the introduction of DOACs, there has been an ongoing discussion about the economic impact of these drugs. To help guide this discussion and inform decision-making in this area, we designed and developed an economic model based on the SELECT-D trial to evaluate the cost-effectiveness and budget impact of rivaroxaban compared with dalteparin in patients with cancer at risk of recurrent VTE in the Netherlands.The economic model comparing rivaroxaban with dalteparin was designed based on the SELECT-D trial,We developed a decision-tree-based Markov model using Microsoft Excel V.2016 to calculate the ICER. Transition probabilities were used to calculate the number of patients in each health state per 1 month cycle. 10.1136/bmjopen-2020-039057.supp1Supplementary datawhere P is the transition probability, r is the event rate and t is the cycle length (1 month).20et al, who described the use of distributions around model input parameters  or even confined between 0 and 1 (probabilities)).18 20Event rates of recurrent VTE, MB and CRNMB in the first 6 months of treatment were based on the SELECT-D trial.All cost parameters are standardised to 2019 euros, and summarised in . Event-rDrug costs were retrieved from the national medication costs database.Based on a previously published report on informal care in the Netherlands, we made a distinction between intensive (26 hours per week) and non-intensive (8 hours per week) informal care.Costs were discounted at an annual rate of 4%.Utility scores, used to calculate the QALYs, were derived from a subanalysis from the CATCH study assessing the EQ-5D scores associated with VTE and recurrent VTE in patients with cancer .28 The C18 20Sensitivity analyses were conducted to check the robustness of the model results to uncertainty and known variations in key input parameters. In the probabilistic sensitivity analysis, all input parameters were varied simultaneously over their 95% CI. If the 95% CI was unavailable and calculating the 95% CI based on the number of events was not possible, the 95% CI was calculated based on a 25% SE. The ICER was calculated with 2000 iterations and plotted in a cost-effectiveness plane. A univariate sensitivity analysis was conducted to show the influence of an individual parameter on the ICER. The 10 most influencing parameters were presented in a tornado diagram.We conducted several scenario analyses to show the effect on the outcomes of different  situations .A budget impact analysis was conducted to estimate the total annual financial consequences of the implementation of rivaroxaban for the treatment and prevention of VTE in patients with cancer within the Dutch healthcare setting. The budget impact was calculated from a societal perspective using the costs calculations from the cost-effectiveness model with a 1-year time horizon. We extracted from the model the costs  per patient with a cut-off point of 1 year for rivaroxaban and dalteparin. The difference in cost per patient was multiplied by the annual number of cancer patients with VTE in the Netherlands. The incidence of VTE in patients with cancer and the total number of Dutch cancer patients were used to calculate the yearly number of cancer patients with VTE. The Netherlands Cancer Registry estimated a total of 579 781 patients with cancer in 2017.It was not appropriate to involve patients or the public in the design, or conduct, or reporting or dissemination plans of our research, because this health economic analysis was based on publicly available data and solely concentrated on the analysis of the economics consequence of treating cancer patients with rivaroxaban instead of the current standard of care.The number of events and the corresponding average costs per patient in the base case analysis and scenario 4  are presented in In the probabilistic sensitivity analysis, we assessed the robustness of the model over a 5-year time horizon (base case) and a 6-month time horizon (scenario 1). The results are presented in cost-effectiveness planes in The influence of the individual input parameters on the base case incremental costs and QALYs is analysed in the univariate sensitivity analysis. The tornado diagrams  present The results of the budget impact analysis are presented in Thrombosis treatment is a challenge in patients with cancer. According to the guidelines, LMWHs and DOACs edoxaban and rivaroxaban are the preferred treatment for the prevention of recurrent VTE in patients with cancer.The cost-savings associated with rivaroxaban were mainly driven by the difference in treatment costs. It should be noted that this is specifically the case for the Netherlands and may differ in other countries. The VTE recurrence and MB risks also showed to have a high influence on the incremental costs and QALYs in the univariate sensitivity analysis. The SELECT-D trial showed a relatively low VTE recurrence but higher bleeding  compared with dalteparin. This cost-effectiveness model allowed to address the question if the reduction in VTE recurrence outweighs the increase in bleeding events.A total of 84 VTE-related events were prevented over 5 years, leading to an average cost-saving of €131 per patient. This is line with findings from a recent study that assessed the VTE-related healthcare costs in patients with cancer, which found that rivaroxaban-treated patients had a significantly lower total VTE-related costs relative to patients treated with LMWH.On the other hand, MB events were more frequent with rivaroxaban compared with dalteparin . MB events are very burdensome and frequently severely disabling, leading to high acute and long-term direct and indirect costs. In line with the findings from the SELECT-D trial, CRNMB events were much more frequent with rivaroxaban compared with dalteparin . Although the difference between rivaroxaban and dalteparin in CRNMB (105 events over 5-year time horizon) is greater than for MB (20 events over 5-year time horizon), the influence on the incremental costs and QALYs was lower because CRNMB is relatively less burdensome.The indirect costs were higher for rivaroxaban than for dalteparin in the base case scenario. This can be explained by the increased number of MB events with rivaroxaban compared with dalteparin. Moreover, there were no data available on leisure activity losses caused by the occurrence of a VTE event in patients who are already burdened with cancer. Therefore, the indirect costs might have been underestimated, possibly leading to lower cost-savings. The indirect costs account for €196–€177 per rivaroxaban and dalteparin patient, respectively, over 5 years—approximately 4%–6% of the total cost—however, they do not have a major influence on the differences between the two drugs . This suggests that, although the indirect costs might have been underestimated, rivaroxaban is still likely to be cost-saving compared with dalteparin.As mentioned, the main driver of the cost-savings is the difference in treatment costs. In the cost-effectiveness analysis, we estimated that more than €1700 per patient over a 5-year period can be saved on treatment costs, compared with dalteparin. Moreover, in the scenario analysis, we varied the price of dalteparin based on weight. Although the lowest dose (12 500 IU daily during month 1 followed by 10 000 IU in months 2–6 based on weight class 57–68 kg) had a lower price, €8.06 vs €9.93, the ICER remained cost-saving. Rivaroxaban users were assumed to require an annual check-up of their renal function. However, patients with cancer  are at higher risk for renal impairment and may be tested much more frequently.In the budget impact analysis, we calculated that rivaroxaban replacing LMWH  leads to cost-savings of €11 326 763 within 1 year over a total of 8000 patients with cancer. This is the absolute maximum, since it is not possible to treat each patient with rivaroxaban from a clinical perspective. In practice, the market share of rivaroxaban will be lower—despite the fact that there are three other DOACs that could be prescribed—because there are some clinical considerations that should be taken into account. First, although DOACs have far fewer drug interactions than VKAs, it should be noted that rivaroxaban is metabolised by CYP3A4 enzymes.Second, the balance between the risk of thrombosis and the risk of bleeding should always be a consideration in the prescription of anticoagulants. For example, DOACs are not advised in patients with gastrointestinal (GI) tumours, due to a higher risk of GI bleeding.A third consideration is the oral administration of rivaroxaban. Although it is less burdensome than the LMWH injections, oral administration can be problematic in patients with anorexia and vomiting, which is often seen as a side effect in cancer therapy.Our analysis is not without limitations. It should also be noted that 58% of the patients included in the SELECT-D trial had metastatic cancer, and thus results and conclusions pertain mostly to severely ill patients. Also, the majority (53%) of the initial VTE events were incidental PE, related to CT imaging for tumour status.et al,We assumed that patients were treated with anticoagulation over 6 months, which is in line with the guidelines.In the univariate sensitivity analysis, we have shown that the risks of MB and VTE for both rivaroxaban and dalteparin have a high influence on the incremental costs and QALYs. In the SELECT-D trial,This study focuses on the secondary prevention of VTE, based on the results of the SELECT-D and, partially, the HOKUSAI VTE Cancer trials. However, recently, apixaban was also assessed in patients with cancer at risk of recurrent VTE and found to be non-inferior compared with dalteparin.Treatment with rivaroxaban is dominant  over dalteparin in patients with cancer at risk for recurrent VTE in the Netherlands. The use of rivaroxaban instead of LMWH  can save more than €11 million per year, which is primarily driven by the difference in treatment costs. Since treatment with rivaroxaban is economically dominant compared with dalteparin and its oral administration is more convenient than daily subcutaneous injection, it is logical that certain patients with cancer can benefit from DOAC treatment and provide savings to the healthcare system.