For people at high risk of lung cancer, low-dose computed tomography (LDCT) is proposed as a method to reduce mortality.Our objective was to estimate the effect of LDCT lung cancer screening on mortality in high-risk populations.A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. RCTs of CXR screening were additionally included in the network meta-analyses. Bibliographic sources including MEDLINE, Embase, Web of Science and the Cochrane Library were searched to January 2017, and then further extended to November 2021. All key review steps were done by two persons. Quality assessment used the Cochrane Risk of Bias tool. Meta-analyses were performed.Nine RCTs, with up to 12.3 years of follow-up from randomisation, were included in the direct meta-analysis, which showed that LDCT screening was associated with a statistically significant decrease in lung cancer mortality (pooled relative risk (RR) 0.86, 95% confidence interval [CI] 0.77 to 0.96). There was a statistically non-significant decrease in all-cause mortality . The statistical heterogeneity for both outcomes was minimal. Network meta-analysis including the nine RCTs in the direct meta-analysis plus two further RCTs comparing CXR with usual care confirmed the size of the effect of LDCT on lung cancer mortality and that this was very similar irrespective of whether the comparator was usual care or CXR screening.LDCT screening is effective in reducing lung cancer mortality in high-risk populations. The uncertainty of its effect on lung cancer mortality observed in 2018 has been much reduced with new trial results and updates to existing trials, emphasising the importance of updating systematic reviews. Although there are still a number of RCTs unreported or in progress, we predict that further evolution of summary mortality estimates is unlikely. The focus for debate now moves to resolving uncertainty about the cost-effectiveness of LDCT screening taking into account the balance between benefits and harms which occur in all screening programmes.The online version contains supplementary material available at 10.1186/s41512-023-00162-0. The worldwide burden of lung cancer is huge. Of approximately 20 million cancer cases and 10 million cancer deaths estimated in 2020, lung cancer accounted for 11.4% of cases (2.2 million) and 18% of deaths (1.8 million). The burden is large irrespective of gender or a country’s development status . OutcomeDifferential outcome by stage suggests that screening might be an approach to reducing mortality. Low-dose computed tomography (LDCT) has emerged as the strongest candidate for a screening test to achieve earlier detection of asymptomatic lung cancer and stage shift . A numbeIn 2018, our research group reported a systematic review and network meta-analysis of RCTs of LDCT screening for lung cancer with particular focus on the effect on disease-specific and all-cause mortality, searching up to 2017 , 13. We Here we report an update to our systematic review and meta-analyses. Like the original systematic review, the update was commissioned to support decision making by the UK National Screening Committee.Our objective was to evaluate the clinical effectiveness of screening programmes for lung cancers with LDCT in high-risk populations using a systematic review, meta-analysis, and network meta-analysis of RCTs. The wider project also considered cost-effectiveness. The original systematic review and its update was registered (PROSPERO CRD42016048530). All aspects of the update were undertaken in accordance with the original pre-specified protocol with some minor recorded exceptions . These iWe extended our original search of MEDLINE, MEDLINE In-Process, Embase, PsycINFO , Web of Science (Thomson Reuters), CDSR and CENTRAL (via The Cochrane Library), and CINAHL (EBSCO) from October 2016 to November 2021 . RCTs evaluating the effectiveness of CXR but not LDCT were also included in the network meta-analysis. The outcomes of interest were lung cancer mortality and all-cause mortality, with only lung cancer mortality considered for the network meta-analysis because of insufficient data to construct a network for all-cause mortality.Two researchers independently screened the titles and abstracts of all reports identified by the search strategy. Full-text papers were subsequently obtained and screened in the same way. Data extraction and quality assessment were undertaken by one researcher and checked by a second. The risk of bias of included studies was assessed using the Cochrane Risk of Bias tool . We also2 and the I2 statistic. Based on the advice in the Cochrane handbook, 30 to 50% was categorised as moderate heterogeneity and 50% upwards as substantial heterogeneity [All data were tabulated and primarily considered in a narrative review. DerSimonian and Laird random effect model meta-analyses were used to pool the estimates of effect . We restogeneity . We consNetwork meta-analysis was performed to assess the relative effectiveness of three screening strategies . The original review used mvmeta in Stata . For theIn total, 10,428 records were screened. From these, 178 full texts were assessed for eligibility, from which 80 articles were included. These comprised seven articles referring to four new RCTs not identified in the previous review, and not providing outcome data to allow inclusion in the meta-analyses –29; nineIn combination with the included studies in the original systematic review, there were 15 RCTs included in the qualitative systematic review , 35–52  with follow-up ranging from 5.2 to 12.3 years from randomisation when compared with controls . Sources of heterogeneity were not investigated, but removing the poorest-quality trial (MILD) [p = 0.018). With little heterogeneity, results for the fixed (common) effects model were not substantially different than those from the random effects model   in a senp = 0.19) . The sensitivity analysis removing the low-quality MILD study made no difference to the summary estimate .There was a statistically non-significant reduction in all-cause mortality compared with controls  Fig. . The folNetwork meta-analysis assessed the relative effectiveness of LDCT, CXR screening, and usual care with respect to lung cancer mortality, data for all-cause mortality not being available for all parts of the network. The main network consisted of six RCTs comparing LDCT with usual care , 54, 55;For the main network meta-analysis, LDCT was ranked first with 97% probability, with usual care second (55%) or third (44%) and CXR second (43%) or third (56%) Web Fig. .Direct and indirect results for the primary analysis are presented separately in Fig. The main findings of the direct meta-analysis of RCTs comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) demonstrated a statistically significant decrease in lung cancer mortality , with very little statistical heterogeneity for both outcomes. The risk of bias assessments did not modify these findings as studies were generally moderate to high quality. The single poorer-quality study made little or no difference to the pooled RR when removed from the meta-analysis in sensitivity analyses. The network meta-analysis is consistent with the direct meta-analysis concerning the size of the effect of LDCT on lung cancer mortality. It also indicates that this effect on lung cancer mortality is very similar irrespective of whether LDCT is compared with usual care  or with CXR .These results represent a considerable change from the results of our original systematic review which found that LDCT screening with up to 9.80 years of follow-up was associated with a statistically non-significant reduction in lung cancer mortality compared with controls. This update provides much stronger evidence of a reduction in lung cancer mortality with additional trials and up to 12.3 years of follow-up. There is also much less statistical heterogeneity in this update despite considerable clinical heterogeneity. The results of the network meta-analysis suggest that effect of LDCT on lung cancer mortality is very similar irrespective of whether the comparator is usual care or CXR screening.The contributors to the changes in results are firstly the increased numbers of included studies, with three additional RCTs of LDCT vs usual care  and one additional RCT of LDCT vs CXR screening (LSS). However, more important in terms of numbers of added events are the updates to the results for MILD and NLST, particularly the latter. Updating the results for NLST from a median follow-up of 6.5 to 12.3 years generated 1584 events for lung cancer mortality and 6742 events for all-cause mortality. Combining the additional events from all other sources generated 748 events for lung cancer mortality and 2993 events for all-cause mortality  for lung cancer mortality and 0.95 (95% CI 0.90 to 1.00) for all-cause mortality . HoffmanThere is considerable clinical heterogeneity between trials, including different frequency and number of screens and the use of a baseline screen in some of the control arms. There is some evidence of inconsistency between the direct and indirect evidence which is likely explained by these differences. This article only considers mortality, consistent with the original article. Now that there is confidence that the effect on mortality is beneficial, the wider balance between benefits and harms becomes important too, but is beyond the scope of this article. In addition, cost-effectiveness, which is currently highly uncertain , needs tOn balance, the evidence on mortality does now support implementation of LDCT in high-risk populations. The marked changes from our original review emphasise the importance of updating systematic reviews. There a number of RCTs unreported or in progress, but they are small relative to the total number of included participants in this review. There are unresolved issues, particularly the balance between benefits and harms overall and cost-effectiveness. Nonetheless, greater clarity on the presence and size of the effect on mortality should provide reassurance to the many countries who are currently still considering whether to introduce LDCT screening.Additional file 1:Web Table 1. Example search strategy for MEDLINE. Web Table 2. Included studies in qualitative systematic review. Web Table 3. Notes on the justification of risk of bias assessments. Web Table 4. Illustrating balance/imbalance in baseline characteristics between MILD and three other low dose CT RCTs included in direct meta-analysis. Web Table 5. Event data for included studies. Web Figure 1. Network meta-analysis rankogram – Main analysis.


Does a 3-year weight-loss lifestyle intervention affect age-dependent changes in body composition?In this interim analysis of a randomized clinical trial including 1521 individuals, a 3-year intervention based on an energy-reduced Mediterranean diet and physical activity promotion, compared with advice to follow an ad libitum Mediterranean diet, reduced the total and visceral fat and attenuated the loss of lean mass in older adults with overweight or obesity and metabolic syndrome. These changes were likely of public health and even clinical relevance.The findings of this study suggest that a combination of an energy-reduced Mediterranean diet and physical activity mitigates the potential negative effects of age-dependent changes in body composition; continued follow-up is warranted to confirm health consequences in the long term. Strategies targeting body composition may help prevent chronic diseases in persons with excess weight, but randomized clinical trials evaluating lifestyle interventions have rarely reported effects on directly quantified body composition.To evaluate the effects of a lifestyle weight-loss intervention on changes in overall and regional body composition.The ongoing Prevención con Dieta Mediterránea-Plus (PREDIMED-Plus) randomized clinical trial is designed to test the effect of the intervention on cardiovascular disease prevention after 8 years of follow-up. The trial is being conducted in 23 Spanish research centers and includes men and women (age 55-75 years) with body mass index between 27 and 40 and metabolic syndrome. The trial reported herein is an interim subgroup analysis of the intermediate outcome body composition after 3-year follow-up, and data analysis was conducted from February 1 to November 30, 2022. Of 6874 total PREDIMED-Plus participants, a subsample of 1521 individuals, coming from centers with access to a dual energy x-ray absorptiometry device, underwent body composition measurements at 3 time points.Participants were randomly allocated to a multifactorial intervention based on an energy-reduced Mediterranean diet (MedDiet) and increased physical activity (PA) or to a control group based on usual care, with advice to follow an ad libitum MedDiet, but no physical activity promotion.The outcomes (continuous) were 3-year changes in total fat and lean mass (expressed as percentages of body mass) and visceral fat (in grams), tested using multivariable linear mixed-effects models. Clinical relevance of changes in body components (dichotomous) was assessed based on 5% or more improvements in baseline values, using logistic regression. Main analyses were performed in the evaluable population (completers only) and in sensitivity analyses, multiple imputation was performed to include data of participants lost to follow-up .A total of 1521 individuals were included . In comparison with the control group (n=761), participants in the intervention arm (n=760) showed greater reductions in the percentage of total fat . The intervention group was more likely to show improvements of 5% or more in baseline body components . The number of participants needed to treat was between 12 and 17 to attain at least 1 individual with possibly clinically meaningful improvements in body composition.The findings of this trial suggest a weight-loss lifestyle intervention based on an energy-reduced MedDiet and physical activity significantly reduced total and visceral fat and attenuated age-related losses of lean mass in older adults with overweight or obesity and metabolic syndrome. Continued follow-up is warranted to confirm the long-term consequences of these changes on cardiovascular clinical end points.ISRCTN89898870isrctn.org Identifier:  This randomized clinical trial examines changes in body composition components with use of a Mediterranean diet plus physical activity compared with ad libitum use of the Mediterranean diet in adults with overweight and obesity after 3 years. In particular, excess visceral fat and loss of muscle mass, which occurs with increasing age, have been associated with a higher risk for a broad spectrum of health outcomes including cardiovascular disease and type 2 diabetes (T2D).3 Results of the previous Prevención con Dieta Mediterránea (PREDIMED) trial that did not introduce any caloric reduction in the MedDiet after 5 years4 are also supportive that energy-reduced MedDiet might be an optimal approach for weight loss and cardiovascular disease prevention. In addition, a review of 18 intervention trials revealed that a MedDiet intervention, which either does or does not involve an energy-reduced focus, can significantly reduce measures of central obesity, as determined by waist circumference, waist-hip ratio, or visceral fat mass.5 On one hand, trials in this field are hampered by indirect measurement methods, small sample size, or short duration. On the other hand, there is an established positive effect of physical exercise on visceral fat in adults with overweight,6 and on muscle mass and function in healthy older adults.7 However, to our knowledge, the effects of a lifestyle intervention combining an energy-restricted MedDiet and physical activity (PA) on body composition in older individuals have not been examined.The Mediterranean diet (MedDiet), and particularly an energy-reduced MedDiet, is emerging as an effective strategy for weight loss and its long-term maintenance.The PREDIMED-Plus randomized clinical trial (RCT) provides a unique opportunity to assess the effects on body composition of multifactorial intervention with an energy-reduced MedDiet, PA promotion, and behavioral support for weight-loss goals in middle-aged and older adults with metabolic syndrome initially with overweight or obesity. In this study we aimed to determine the long-term effects of the lifestyle intervention on changes in age-related overall and regional body composition after the first 3 years of the PREDIMED-Plus trial.10and the study protocol is available in 9 Participants were randomly allocated in a 1:1 ratio to 1 of the 2 study arms, using a computer-based system with stratification  in blocks of 6 participants. Couples sharing the same household were randomized together using the couple as a unit of randomization . The PREDIMED-Plus study protocol was reviewed and approved by the institutional review boards from all 23 participating centers. All participants provided written informed consent. No financial compensation is provided. The study reported herein was conducted from February 1 to November 30, 2022. This work followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.11This study is a predefined interim analysis after 3 years of follow-up in a subset of participants in the ongoing PREDIMED-Plus RCT. The details on methods and procedures of the trial have been published elsewhere,12Participants were recruited between October 23, 2013, and December 23, 2016, in 23 Spanish centers. Eligible participants were middle-aged and older men (age 55-75 years) and women (age 60-75 years) without previous cardiovascular events. The inclusion criteria included the presence of overweight or obesity  and metabolic syndrome.Of the total cohort (N = 6874), the subsample of participants (n = 1556) who underwent dual energy x-ray absorptiometry (DXA) measurements in 7 of the 23 recruiting centers having access to DXA scanners (DXA substudy) was used for the present study. In each of these 7 centers, either all or a subsample of participants were invited for DXA scans . The percentages of participants with the baseline DXA scans completing the follow-up visits were 79.9% for 1 year and 74.5% for 3 years . In addition to 30% energy reduction, they were encouraged to limit consumption of some foods  to better capture the caloric restriction applied to a MedDiet pattern14 for the purpose of weight loss. They were also encouraged to progressively increase aerobic PA, with the final goal of walking 45 minutes per day or more or the equivalent during 6 days per week, and doing exercises to improve strength, flexibility, and balance. Participants from the intervention group were contacted by trained dietitians 3 times a month  during the first year. They also received behavioral and motivational support strategies including self-monitoring, goal setting, and problem solving. Participants from the control group were given general advice to follow ad libitum the traditional MedDiet,16 without PA promotions, during group sessions twice a year.Participants in the intervention group received a tailored face-to-face nutritional and behavioral program  were measured with a third-generation DXA scanner  connected with enCore software by trained operators at baseline, 1-year, and 3-year follow-up. Operational definition of regions of interest for body composition measured with DXA is available in the eMethods in 17 The primary end points were lean and fat mass expressed as the percentage of DXA-derived total body mass , to better capture changes in body composition proportions during weight loss, and visceral fat mass expressed in grams, given that it is the most usual measure for this body fat compartment. To deepen our understanding of body composition changes, other secondary outcomes were also examined: overall lean and fat mass expressed in absolute amounts (grams), and visceral fat expressed as the percentage of total fat mass. Furthermore, the ratio of android to gynoid fat was calculated to account for age-related adiposity redistribution from central to peripheral regions, as well as the ratio of lean mass to fat mass as a marker of sarcopenic obesity.For visceral fat measurements in an android region, DXA scans were reanalyzed using CoreScan software application  validated using computed tomographic scans as a reference tool.A general questionnaire was administered to participants at baseline to collect data on sociodemographic characteristics and medical conditions. Smoking status was categorized as current, never, or former smoker, and educational level as higher education or technician, secondary education, and primary education or less. The prevalence of T2D was used as a dichotomous variable  footnote18Height (centimeters) was measured without shoes in duplicate using a wall-mounted stadiometer. Population questionnaires validated in Spanish were used to collect data on total leisure-time PA , sedentary behavior (hours per day), total energy intake , and alcohol intake (grams per day).9 Required sample size was calculated only for the primary outcomes of the trial (for the combined cardiovascular end point the required sample size was 3000 in each group and for weight loss 337 in each group)9 but not for intermediate outcomes. However, under analogous assumptions than those a priori adopted for weight change, the statistical power will be sufficiently high for assessing changes in body composition with a total sample size of 1521. Main analyses were performed in the evaluable population (completers only) and in sensitivity analyses, multiple imputation was performed to include data of participants lost to follow-up .These analyses were prespecified and performed according to the previously published statistical analysis plan .9 Requirz scores .Linear mixed-effects models were used to assess between-group differences in changes in body components at baseline, 1 year, and 3 years of follow-up. Three-level linear mixed models were fitted with random intercepts at the recruiting center, cluster family, and individual participants, including an interaction term of study arm with time. Multivariable models were adjusted for sex, age, and baseline levels of smoking status, educational level, T2D, height, total leisure-time PA, sedentary behavior, total energy intake, and alcohol intake. To enable a direct comparison between body composition parameters, models were rerun with all outcome variables converted into In sensitivity analyses, the missing follow-up data on primary and secondary outcomes were handled using multivariate imputation with chained equations (Stata mi command), creating 100 imputations for each missing measurement. The imputation models included as factors age, sex, study arm, weight , height, smoking habit, educational level, leisure-time PA, sedentary behavior, total energy intake, alcohol intake, T2D, recruiting center, and the baseline value of the imputed variable as factors.19 the threshold of 5% was chosen as it is a cutoff point customarily used for weight-loss strategies targeting beneficial cardiometabolic changes.21 We used logistic regression analysis with a robust variance estimator after adjusting for the same set of covariates as in the main analyses. Logistic regression models for marginal effects estimating absolute risk differences23 and the numbers needed to treat25 were applied to estimate the intervention effect magnitude.We also evaluated the potential effect of the PREDIMED-Plus intervention on dichotomous variables indicating at least 5% improvement in baseline body composition as an indicator of clinically relevant changes over follow-up. Given that the targets for clinically relevant changes in body composition are still unclear,P value at .002 (0.05/24) after applying a Bonferroni correction to account for multiple testing in this subgroup analysis.Post hoc stratified analyses were conducted for primary outcomes by baseline categories of sex (men and women), age (<65 and ≥65 years), T2D prevalence (yes and no), and smoking habits  using linear mixed-effects multivariable models. An interaction term between time, randomization arm of the trial, and each potential effect modifier was included in the models. We set the Statistical analyses were performed using Stata, version 17.0 (StataCorp LLC). All statistical tests were 2-sided, and the threshold of significance was set at .05, unless stated otherwise.Participants with DXA scans  assigned to the intervention and control groups showed similar characteristics at baseline . The subOverall, significant between-group differences were observed across follow-up for all primary outcomes . ParticiWhen looking at body mass components in absolute amounts  . For eveIn the post hoc analyses, no interactions with sex and smoking habits were found for any of the outcomes studied over follow-up time, but significant interactions with age were observed  than those in the control group over the entire follow-up time.z scores body components  and the total lean mass to total fat mass ratio. This finding is noteworthy as it represents a more favorable body composition profile sustained during a 3-year period, suggesting that participants in the intervention group achieved weight loss preferentially at the expense of total fat rather than lean mass. Lifestyle interventions for weight loss should include strategies preserving lean body mass to delay age-dependent loss of muscle mass or sarcopenia (loss of muscle mass and strength),10 and other RCTs29 have evidence that total or visceral fat reductions (independent of the type of intervention) were paralleled by beneficial changes in most classic cardiometabolic risk factors. Undoubtedly, continued follow-up is warranted to confirm whether these moderate improvements may be effective in preventing cardiovascular events or mortality.Despite the fact that the magnitude of body composition changes was rather mild, although statistically significant, we found that these changes were likely of clinical relevance . In particular, we found that for every 12 or 17 persons receiving an intervention with energy-reduced MedDiet and PA, as opposed to advice to follow ad libitum MedDiet, 1 additional individual would improve visceral fat mass (n = 12) or percentage of fat and lean mass (n = 17). In the same direction, previous findings from the pilot study of the PREDIMED-Plus trialIn addition to the multicenter clinical trial design, the relatively large sample size and follow-up period, the strengths of our study include use of repeatedly measured data and determination of body composition with precise imaging techniques with standardized measurements. The trial also has limitations. First, our findings are based on interim analysis of the intermediate outcomes of an ongoing RCT. Second, the generalizability of these results to other populations  may be limited. Furthermore, measures of body composition were not available in the total cohort, due to limited access to DXA scanners in most of the recruiting centers. Lastly, there were losses to follow-up in DXA participation leading to missing data in body composition variables; however, the results were similar when multiple imputation was conducted.In this interim subgroup analysis of body composition in the PREDIMED-Plus RCT, we found evidence that a 3-year weight-loss intervention with energy-reduced MedDiet and PA may mitigate age-dependent changes in body composition by reducing total and visceral fat and delaying loss of lean mass in middle-aged and older adults with overweight or obesity and metabolic syndrome. These changes are likely of public health and clinical relevance. Given the metabolic relevance of specific body components, especially visceral fat and lean mass, the benefits of this lifestyle intervention could be very promising. However, continued follow-up is warranted to confirm the long-term consequences of these changes on health.


Greater trochanteric pain syndrome (GTPS) possesses a harmful influence on quality of life. Numerous conservative management modalities with varying success have been proposed for patients with GTPS. However, it is not clear which treatment is more effective for reducing pain. The purpose of this Bayesian analysis was to assess the current evidence for the effectiveness of conservative treatments on improving Visual Analog Scale (VAS) pain scoring of GTPS and to determine the most effective treatment protocol.A comprehensive study search was performed from inception until July 18, 2022, via the electronic databases PubMed, the Cochrane Library, and Web of Science for potential research. The risk of bias assessment for the included studies was independently performed based on the Cochrane Collaboration Risk of Bias Tool. Bayesian analysis was conducted by using ADDIS software (v1.16.5). The DerSimonian-Laird random effects model was used to perform the traditional pairwise meta-analysis.Eight full-text articles with a total of 596 patients with GTPS were included in the analysis. In comparing ultrasound-guided platelet-rich plasma application (PRP-U) to ultrasound-guided corticosteroid injection (CSI-U), patients who received PRP therapy experienced reduced pain as the VAS decreased significantly . VAS score in group of extracorporeal shockwave treatment (ESWT) was significant improved than that in exercise (EX) group . There were no statistically significantly different VAS scores between the CSI-U group and the CSI under landmark (CSI-B) group. The treatment efficacy rankings of the different treatments on improving VAS scores showed that the most likely efficacious treatment was PRP-U (99%) followed by ESWT (81%), CIS-U (58%), usual care (48%), CIS-B (54%), and EX (84%).Bayesian analysis revealed that PRP injection and ESWT are relatively safe and effective in the treatment of GTPS. More multicenter high-quality randomized clinical trials with large sample sizes are still needed in the future to provide further evidence.The online version contains supplementary material available at 10.1186/s12891-023-06443-5. Greater trochanteric pain syndrome (GTPS), a recalcitrant lateral painful condition of the articulatory coxae, has a significant negative impact on physical function and sleep quality and affects 1.8 per 1000 patients annually . NeverthAccurate diagnosis of the specific etiology of GTPS and the degree of gluteal tendon injury are critical to guiding appropriate treatment. Traditional conservative treatments including physical therapy, anti-inflammatory drug treatment and corticosteroid injections (CSIs), are usually used to treat GTPS at the initial stage . In receAmong the many scales used to assess acute pain, Visual Analog Scale (VAS) pain scoring is one of the most commonly used one-dimensional measurement and evaluation tools of pain intensity in clinical and scientific research of GTPS , 18. Thehttps://doi.org/10.37766/inplasy2022.8.0068.This study was conducted using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines in accordance with the Cochrane review methodology , intervention (I), comparison (C), and outcome (O) framework was used to formulate the research question of our Bayesian analysis as follows:◽ How does conservative management affect the VAS pain score in patients with GTPS?◽ What were the rankings on the effect of conservative management, and which one is more suitable for patients with GTPS?A comprehensive, literature search was conducted to identify studies meeting the inclusion criteria within the electronic databases PubMed, the Cochrane Library, and Web of Science from inception until July 18, 2022. Eligible studies were identified with text words or Medical Subject Headings (MeSH): “greater trochanteric pain syndrome,” “GTPS”, “trochanteric bursitis,” or “gluteal tendinopathy”. The search method and details of the query are added in Additional file The initial eligibility screen of all study types, titles, and abstracts was conducted by two independent authors (YL and YH). Studies that specifically referred to conservative management in patients with GTPS were collected for further assessment. Then, full-text assessments were performed independently, and research achieving the following criteria were candidates for inclusion: 1) randomized controlled trials (RCTs), quasi-RCTs, or clinical controlled trials; 2) patients with GTPS; and 3) VAS pain scoring was included in the outcome measures of the full-text articles. The exclusion criteria were as follows: 1) duplicate studies and 2) animal experimental studies, letters, case reports, review articles, meta-analyses and so on.Two independent authors (JH and XH) carried out data collection and extraction included first author, year of publication, countries, study type, sample size, age of patients, follow-up time, and the main outcomes from the included full text. For both test and control groups, the values of VAS score which presented as mean ± SD was extracted in to the final Bayesian analysis. Any disagreement concerning study selection and data extraction between the two evaluating authors was resolved through the assessment of discussion or a third author (CS). If we encountered significant skew in the outcome data in the published research, the corresponding author will be contacted to solicit the missing information.A risk of bias assessment for the included randomized studies was independently conducted by two authors (CL and XL) using the Cochrane Collaboration Risk of Bias Tool . Each au2 statistic was used to measure the statistical heterogeneity, and moderate-to-high heterogeneity was shown when the value was greater than 50% [P ≤ 0.05.The data were extracted and assessed by using ADDIS software (v1.16.5) and STATA . Estimated effects were reported as the mean differences (MDs) with 95% CIs for the continuous outcomes for each study. The DerSimonian-Laird random effects model was used to perform the traditional pairwise meta-analysis . The I2 than 50% . To obtathan 50% . OutcomeWe assessed the confidence in the evidence based on the GRADE  approach, which classified evidence as very low, low, moderate, or high certainty for each outcome .Figure The characteristics of the 8 enrolled studies are presented in Table The risk of bias in the included RCTs is presented in Fig. 2=58.3%). In the study in which ESWT was compared with EX, the ESWT group revealed a significant improvement in VAS scores . There were no statistically significantly different VAS scores between the CSI-U- and CSI-B-treated patients . Another study compared ESWT with CSI-U; although shock wave therapy shows a better tendency to reduce pain, there was no significant difference between the two treatments in improving VAS scores as the confidence interval included zero . The remaining study [The network map concerning the VAS of the included studies is shown in Fig. ng study  that comThe results of the Network Meta-Analysis (NMA) indicated that ESWT interventions markedly elevated the reduction in pain when compared with EX interventions Table  showed tIn accordance with the GRADE approach, the overall quality of evidence ranged from very low to moderate as shown in Table For the management of pain in patients with GTPS, at present, there is no evidence-based approach. Conservative management, the gold standard for the treatment of GTPS, has become more prevalent in recent years , 34. PhyLocal injection of glucocorticoids is a common method to treat the disease, but its effectiveness, safety, and rationality are controversial. A systematic review of CSI in GTPS has revealed that CSI has a short-term benefit . A previRegenerative injection treatment is another potential therapy option for GTPS. Platelet-rich plasma, an autologous blood product with various anabolic functions for tissue regeneration, is recommended for use in patients with GTPS , 26. Theet al., ESWT was efficient in reducing the pain  of GTPS at mid-term and short follow-up [et al. retrospectively reviewed the pain and functional outcomes of patients with gluteal tendinopathy and confirmed the positive effect of electrohydraulic ESWT for GTPS as the short-term success rate was 83.3% [In recent years, an accumulating body of research has indicated that ESWT appears to provide beneficial effects in the management of GTPS. According to the study of Carlisi, ollow-up . Seo, etas 83.3% . In termas 83.3% . On the It is important to note that this study has several limitations. First, the most obvious limitation is the small number of included studies and their small sample sizes, which may have insufficient strength to assess the differences and limited the interpretation of our pooled result. Second, some studies were evaluated using different pain scales, and we were unable to combine all the results. Third, for studies in which this information was shown, there were no differences among studies in the diagnostic process and severity of the disease.This Bayesian analysis has supported the efficacy of conservative management in reducing pain in patients with GTPS, and PRP injection therapy has demonstrated superior outcomes for the VAS and has the highest ranking probability as the best treatment for GTPS. ESWT was effective in reducing pain compared with physiotherapy alone. Considering the long-term injury of tendon structure and few GPTS-patients having clinical manifestation of bursitis, we appeal that corticosteroid or anti-inflammatory drug treatment by high-dose or long-term should be avoid. When the initial conservative management including home training, physiotherapy, corticosteroid or anti-inflammatory drug treatment has failed in patients with refractory GTPS, PRP injection and ESWT can serve as viable alternative therapies with safety and efficacy, avoiding unnecessary use of healthcare resources and allowing for cost reduction. We believe that conservative treatments are still the main management of choice for the majority of patients with GTPS in the future, and further research with a high degree of scientific evidence is essential to draw definitive conclusions on optimal conservative management.Additional file 1. Additional file 2. Additional file 3. Additional file 4.


To examine neonates in Scotland aged 0–27 days with SARS-CoV-2 infection confirmed by viral testing; the risk of confirmed neonatal infection by maternal and infant characteristics; and hospital admissions associated with confirmed neonatal infections.Population-based cohort study.All live births in Scotland, 1 March 2020–31 January 2022.There were 141 neonates with confirmed SARS-CoV-2 infection over the study period, giving an overall infection rate of 153 per 100 000 live births . Among infants born to women with confirmed infection around the time of birth, the confirmed neonatal infection rate was 1812 per 100 000 live births . Two-thirds  of neonates with confirmed infection had an associated admission to neonatal or (more commonly) paediatric care. Six of these babies  were admitted to neonatal and/or paediatric intensive care; however, none of these six had COVID-19 recorded as their main diagnosis. There were no neonatal deaths among babies with confirmed infection.Confirmed neonatal SARS-CoV-2 infection was uncommon over the first 23 months of the pandemic in Scotland. Secular trends in the neonatal confirmed infection rate broadly followed those seen in the general population, although at a lower level. Maternal confirmed infection at birth was associated with an increased risk of neonatal confirmed infection. Two-thirds of neonates with confirmed infection had an associated admission to hospital, with resulting implications for the baby, family and services, although their outcomes were generally good. Ascertainment of confirmed infection depends on the extent of testing, and this is likely to have varied over time and between groups: the extent of unconfirmed infection is inevitably unknown. SARS-CoV-2 infection in neonates appears uncommon, but some studies have suggested that neonates are at higher risk than older children of severe infection.Population-based data on neonates with confirmed infection are lacking: most studies to date have only included babies of infected mothers or those admitted to the hospital.Confirmed SARS-CoV-2 infection in all neonates in Scotland from 1 March 2020 to 31 January 2022 was uncommon, occurring in 0.15% (141/92 009) of live births.Confirmed maternal SARS-CoV-2 infection around the time of birth was associated with an increased risk of confirmed neonatal infection at 1.8% (15/828) of live births.65.2% (92/141) of neonates with confirmed infection had an associated hospital admission with 6.5% (6/92) involving neonatal/paediatric intensive care: there were no neonatal deaths.Ascertainment of confirmed infection depends on the extent of testing, and this is likely to have varied over time and between groups.Continued data collection and vigilance will be important to assess the ongoing impact of SARS-CoV-2 in the neonatal population as the pandemic evolves.Confirmed neonatal infection with SARS-CoV-2, defined as a positive viral test in the first 27 days after birth, is uncommon.To date, most neonatal SARS-CoV-2 studies have focused on the risk and consequences of transmission to the neonate from an infected mother.Detailed methods are provided as 10.1136/fetalneonatal-2022-324713.supp1Supplementary dataCOPS includes information on all positive SARS-CoV-2 viral tests undertaken on women and babies within the cohort.For all babies with confirmed neonatal infection, data were obtained from the COPS database regarding the age of the baby in days at date of onset of infection; maternal age, socioeconomic level, ethnicity, and infection status at the time of birth: and the baby’s sex and gestation at birth. Maternal socioeconomic level was based on the Scottish Index of Multiple Deprivation quintile.A hospital admission associated with confirmed neonatal SARS-CoV-2 infection was defined as an admission of a baby with confirmed neonatal infection to neonatal or paediatric care (1) where the date of onset of infection was in the 7 days prior to, or during, the admission (hence date of admission at up to 27+7=34 days old inclusive), or (2) where the admission occurred at any point in the neonatal period (hence date of admission at up to 27 days old inclusive) if COVID-19 was recorded as the main diagnosis . An ‘admission’ was defined as an entire hospital stay from admission to discharge. The main diagnosis was taken from the first episode of care during an admission.Admissions to neonatal units were identified through the Scottish Birth Recordhttps://github.com/Public-Health-Scotland/COPS-public.git).All data reported here are descriptive only with no formal statistical comparisons. Rates were calculated using the number of babies with confirmed neonatal infection and the total number of live births during the study time period. The CIs were calculated using Wilson score estimates. The analysis and generation of figures were carried out using R V.3.6.1 and RStudio V.1.1.463, and codes are available online  had a total of 101 admissions to neonatal and/or paediatric care that were temporally associated with their positive SARS-CoV-2 test . There were no additional associated admissions in the neonatal period with COVID-19 coded as the main diagnosis that did not meet the temporal association criteria.None of the six SARS-CoV-2-associated admissions to a neonatal unit had COVID-19 coded as the main diagnosis, and three involved probable nosocomial infection. By contrast, 66% (64/97) of the SARS-CoV-2-associated admissions to paediatric care had COVID-19 coded as the main diagnosis, and only one involved probable nosocomial infection. Six of the babies with an associated admission  had a total of six admissions involving an episode of care in neonatal and/or paediatric intensive care . None of these admissions had COVID-19 coded as the main diagnosis . Over thThere were no neonatal deaths among the 141 babies with confirmed neonatal infection. The background neonatal mortality rate in March 2020–January 2022 was 2.2/1000 live births  among uninfected babies.These results show that confirmed neonatal SARS-CoV-2 infection was uncommon in Scotland over the first 23 months of the pandemic, with only 141 neonates having confirmed infection between 1 March 2020 and 31 January 2022. The secular trend in the confirmed neonatal infection rate followed that seen in older age groups, although at much lower levels. Factors associated with higher infection rates among pregnant women, such as young maternal age and living in a more deprived area, were associated with higher neonatal infection rates. The rate of confirmed neonatal infection was significantly higher in babies born to women with (compared with without) confirmed infection at the time of birth. Two-thirds of neonates with confirmed SARS-CoV-2 infection had an associated hospital admission, primarily to paediatric care. However, only 6.5% of admitted babies required intensive care, and none of these babies had COVID-19 coded as their main diagnosis. There were no neonatal deaths among babies with confirmed infection.These data align with previous studies on admission rates for neonatal SARS-CoV-2This was an observational study, with cases of confirmed infection identified through the results of ‘real-world’ testing carried out in the community and hospitals across Scotland. Not all babies will have been tested, and some infections may therefore have been missed. The extent of unconfirmed infection is inevitably unknown. The proportion of all infections that are confirmed will be influenced by the extent of testing, and this is likely to have varied over time and between groups.During the study period, infants may have been tested due to having clinical signs of infection, having contact with a case, or as part of routine hospital admission testing.It is likely that over the study period, babies showing more severe clinical signs, those born to mothers with confirmed infection and those admitted to neonatal or paediatric care (for whatever reason) are more likely to have undergone testing, and hence ascertainment of confirmed infection is likely to have been more complete in these groups. However, this is unlikely to account for the greater than 10-fold increased risk of confirmed neonatal infection seen in babies born to mothers with confirmed infection at the time of birth.Reassuringly, we demonstrate that the clinical outcomes of neonates with confirmed SARS-CoV-2 infection are good, with no deaths and no intensive care admissions for which COVID-19 was the main diagnosis. Other studies have recorded higher rates of critical care admissions; Swann reported that up to 33% of UK neonates with confirmed infection early in the pandemic required critical care,Despite these positive outcomes, around two-thirds  of neonates with confirmed SARS-CoV-2 infection had a temporally associated hospital admission. This is perhaps not surprising, as fever is a common sign of SARS-CoV-2 infection in neonates,In summary, confirmed SARS-CoV-2 infection in neonates was uncommon over the first 23 months of the pandemic in Scotland. Two-thirds of neonates with confirmed infection had an associated hospital admission. There were no neonatal deaths among babies with confirmed infection. Continued vigilance will be important to assess the ongoing impact of SARS-CoV-2 in the neonatal population as testing, isolation requirements and vaccination programmes continue to evolve, and new viral variants emerge.


Monomorphic ventricular tachycardia (VT) is a life-threatening condition often observed in patients with structural heart disease. Ventricular tachycardia ablation through radiation therapy (VT-ART) for sustained monomorphic ventricular tachycardia seems promising, effective, and safe. VT-ART delivers focused, high-dose radiation, usually in a single fraction of 25 Gy, allowing ablation of VT by inducing myocardial scars. The procedure is fully non-invasive; therefore, it can be easily performed in patients with contraindications to invasive ablation procedures. Definitive data are lacking, and no direct comparison with standard procedures is available.The aim of this multicenter observational study is to evaluate the efficacy and safety of VT-ART, comparing the clinical outcome of patients undergone to VT-ART to patients not having received such a procedure. The two groups will not be collected by direct, prospective accrual to avoid randomization among the innovative and traditional arm: A retrospective selection through matched pair analysis will collect patients presenting features similar to the ones undergone VT-ART within the consortium (in each center independently). Our trial will enroll patients with optimized medical therapy in whom endocardial and/or epicardial radiofrequency ablation (RFA), the gold standard for VT ablation, is either unfeasible or fails to control VT recurrence. Our primary outcome is investigating the difference in overall cardiovascular survival among the group undergoing VT-ART and the one not exposed to the innovative procedure. The secondary outcome is evaluating the difference in ventricular event-free survival after the last procedure  between the two groups. An additional secondary aim is to evaluate the reduction in the number of VT episodes comparing the 3 months before the procedure to the ones recorded at 6 months (from the 4th to 6th month) following VT-ART and RFA, respectively. Other secondary objectives include identifying the benefits of VT-ART on cardiac function, as evaluated through an electrocardiogram, echocardiographic, biochemical variables, and on patient quality of life. We calculated the sample size (in a 2:1 ratio) upon enrolling 149 patients: 100 in the non-exposed control group and 49 in the VT-ART group. Progressively, on a multicentric basis supervised by the promoting center in the VT-ART consortium, for each VT-ART patient enrollment, a matched pair patient profile according to the predefined features will be shared with the consortium to enroll a patient that has not undergone VT-ART.via an observational, multicentric study of two groups of patients with or without VT-ART in the multicentric consortium (with subgroup stratification into dynamic cohorts).Our trial will provide insight into the efficacy and safety of VT-ART through a matched pair analysis,  Monomorphic ventricular tachycardia (VT) is a life-threatening condition often observed in patients with structural heart disease. Recurrence poses a serious threat to both patient survival and quality of life (QoL). The most common cause of recurrent monomorphic VT is the presence of an ischemic scar that induces arrhythmias through re-entry mechanisms. Endocardial and/or epicardial radiofrequency ablation (RFA) represents the gold standard for VT ablation, along with medical therapy.Stereotactic arrhythmia radioablation (STAR) uses stereotactic body radiation therapy (SBRT) for the ablation of cardiac arrhythmias, which is technically related to any arrhythmia. The present study focuses on ventricular tachycardia ablation through radiation therapy (VT-ART), applying STAR particularly focused on sustained monomorphic ventricular tachycardia.Stereotactic body radiation therapy using VT-ART delivers focused high-dose radiation in a single fraction of 25 Gy, allowing the ablation of VT by inducing myocardial scars. The procedure is fully non-invasive; therefore, it can be easily performed in patients with contraindications to invasive ablation procedures.Owing to the highly experimental profile of an innovative procedure such as VT-ART, too little is known to draw definitive conclusions about its efficacy, safety, and long-term results.Our trial aims to assess the benefits of VT-ART for the ablation of VT in patients with optimized medical therapy in whom traditional techniques, namely, RFA, have either failed to control VT recurrence or cannot be performed.The importance of our trial relies on the identification of new management options for patients who have not responded to traditional ablation techniques or have contraindications to invasive procedures. The efficacy of VT-ART will be indirectly compared through matched pair analysis with a population of patients not treated with VT-ART, thus avoiding setting a randomized controlled trial that is considerable technically demanding and possibly premature in this research field.With current knowledge, it is difficult to set a randomized trial between a population undergoing VT-ART  and a population not undergone to that. Randomizing a patient’s accrual to VT-ART instead of the conventional option implies that some patients would skip a conventional procedure in favor of a procedure still considerate at least still non-standard, although promising. Multiple, reliable phase I and phase II trials are not available, although case series and at least one phase I/II trial have investigated VT-ART efficacy .Finally, it would be difficult to define two balanced treatment arms that are suitable for a clinical randomized comparison, since patients undergoing VT-ART would have either already received RFA or are unable to receive it, and they have already undergone other standard treatments. On the other hand, setting a single-arm trial would test less efficiently the clinical of VT-ART and could imply the adoption of VT-ART only for worse clinical case presentations.This multicenter observational study will evaluate the efficacy and safety of VT-ART. Our trial will enroll patients with optimized medical therapy, in whom endocardial and/or epicardial RFA is either unfeasible or fails to control VT recurrence. The trial is set as observational since it indirectly comparing VT-ART with a conventional procedure .Each patient recruited for VT-ART will be profiled according to a predefined list of characteristics that will be circulated within the centers participating to the consortium to collect other patients with a similar profile, not having undergone VT-ART, for final analysis.The peculiar setting of our trial will avoid precluding VT-ART to patients possibly taking advantage of such a therapeutic option; moreover, it will compare VT-ART with retrospective series not having receive VT-ART anyway. Furthermore, this approach will retrieve otherwise sporadic data about single or limiter case series of each center joining the consortium. This trial is not strictly investigational but can add notable scientific information to the current scenario.The multicenter setting of this study will allow for faster recruitment of the sample size.Multicenter recruitment will allow for a more precise assessment of the effects of VT-ART, with the aim of demonstrating that implementing such a procedure is both feasible and safe among centers. Moreover, it will increase the chances to recruit patients with profiles matching the ones in the arm undergone VT-ART.A standardized data collection has been defined for data regarding both VT-ART and RFA.The trial will thus both collect prospective and retrospective data about VT-ART (following the predefined standardized data collection). Prospective data collection will be applied within the consortium for the patients referred to VT-ART after the beginning of the trial; retrospective data collection will be allowed for the VT-ART procedure delivered before the formal start of the trial if the data required by the predefined standardized data collection are available for defining the primary and secondary endpoint (see following sections). Similarly, prospective and retrospective data collection will be allowed for data about conventional treatment .Our aim is to enroll patients with structural heart disease, in whom the presence of a myocardial scar induces refractory monomorphic VT or ventricular fibrillation (VF), as documented by either implantable cardioverter defibrillator (ICD) appropriate shocks or anti-tachycardia pacing (ATP) at ICD interrogation. We will enroll patients with recurrent VT/VF episodes despite optimal medical therapy  and at least one previous attempt of RFA or patients in whom ablation is not feasible, because of contraindications to the procedure or of patient intolerance. Previous percutaneous stellate ganglion blockade is neither a requirement for inclusion criteria nor exclusive criteria that will be collected in the standardized data collection for potential subgroup analysis.Eligibility criteria are summarized in Our trial will investigate the effects of administering a single fraction of external beam radiation delivered through SBRT techniques at a dose of 25 Gy on patients with recurrent episodes of VT and in whom optimal medical therapy and previous RFA attempts have failed to provide benefit from VT burden control. We will perform matched pair analysis with dynamic cohorts. We will compare two groups of patients: One that has been treated by all the standard approaches but has not undergone VT-ART and a second group that has also received VT-ART. The entire enrolled group (by multicentric recruitment) will be stratified according to some predefined characteristics and analyzed by matched pair analysis, based on the characteristics of patients treated with VT-ART. Once a patient is enrolled to undergo VT-ART within the multicentric consortium, the search for two patients with similar feature profiles not undergoing VT-ART will be shared.Matching factors taken into account are summarized in Ventricular tachycardia ablation through radiation therapy will be administered through image-guided radiotherapy (IGRT) by a linear accelerator (Linac) , an SBRT-dedicated Linac, including a dedicated Linac with gating delivery  with 6 MV flattening filter-free photons and dose calculation algorithm Acuros , or a MR-guided Linac . Selection of a specific Linac type for each patient will be addressed based on the best personalization achievable, after a multidisciplinary discussion of the patient-specific clinical background, needs, compliance, and technical possibilities. The target area (TA), in terms of the clinical target volume (CTV), set-up margin (SM), and internal target volume (ITV), will be determined for each patient on a 3D computer tomography reconstruction based on CT scan or MRI , 12-lead ECG data, and electroanatomical mapping (EAM).Three-dimensional EAM will be performed by three different systems on the basis of availability of the three workstations . Electrical information from the EAM and information from imaging will be combined to build a volumetric target for VT-ART .Electroanatomical mapping data will be fused with CT-reconstructed 3D models applying the previously described approach for non-invasive EAM, through a series of electrode strips (worn by the patient) containing 256 electrodes , with small radiopaque markers attached at the location of the electrodes, to assist with visualization on cardiac imaging. A gated chest CT scan with 3 mm axial resolution was obtained to provide patient-specific heart-torso geometry and the location of the body surface electrodes relative to the heart –3. SinceA 2–5-mm margin will be provided to the TA to determine the planning target volume (PTV). The prescribed dose will be 25 Gy in a single fraction to 80% isodose. A 4D-CT will be applied to account for respiratory motion and either cone-beam computed tomography (CBCT)-based or MR-guided Linac positioning with the addition of either breath hold (BH) or free-breathing respiratory gating, depending on the patient’s compliance. If BH could be applied, deep inspiration breath hold (DIBH) should be preferred, but mid inspiration breath hold (MIBH), mid expiration breath hold (MEBH), and deep expiration breath hold (DEBH) are allowed if more suitable for planning.Volumetric modulated arc therapy (VMAT) will be applied by multiple partial arcs (PA) depending on the arrhythmogenic scar volume and morphology to cover the TA. If an MR-guided Linac is used, static intensity-modulated radiotherapy (IMRT) will be applied.Dose constraints for organs-at-risks and dose to target will follow the indications from the AAPM report Task Group 101 for single-fraction SBRT .Our trial will combine two IGRT procedures to increase safety: intra-fractional and inter-fractional motion management devices and procedures are mandatory to be used. Volumetric imaging (CBCT- or MR-guided) scans before delivering each PA with regard to inter-fractional monitoring. Intra-fraction monitoring through the gating system is also mandatory. Continuous intra-fraction monitoring through an optical surface monitor system (OSMS) will be applied if available . Online adaptive procedures will be applied for the MR-guided Linac.The primary outcome is investigating the difference in overall cardiovascular survival among the group undergoing VT-ART and the one not exposed to the innovative procedure.The primary efficacy endpoint is a statistically significant difference in overall cardiovascular survival between the group undergoing VT-ART and the one not exposed to the innovative procedure; this will be defined in months and calculated from the time of the last procedure .The secondary outcome is evaluating the difference in ventricular event-free  survival after the last procedure between the two groups . The respective endpoint is a statistically significant difference in ventricular event-free survival (in months) after the last procedure between the two groups.An additional secondary aim is to evaluate the reduction in the number of VT episodes compared to the pre-treatment period between the two dynamic cohorts that will be investigated.Ventricular tachycardia recurrence will be defined as evidence of monomorphic VT at ICD interrogation (either self-limiting or terminated by appropriate shock therapy or ATP). The number of VT episodes, defined as VT burden, in the 3 months before and after the procedure will then be compared.The respective secondary endpoint will be evaluated facing 3 months before the last procedure  and 3 months after.We did set a blanking period after VT-ART before evaluate the effect on VT burden; in a recent study by Kautzner et al., the authors supported the pre-clinical theorem of myocardial apoptosis (up to 3 months post-stereotactic ablation) followed by a creation of fibrotic lesion (6–9 months post-stereotactic ablation) in the irradiated region . ConsequSince a blanking period of 3 months after the procedure will be applied, the secondary endpoint will evaluate the number of VT episodes interval accounted for the last 3 months before the procedure and of the 3–6 months after it.Other secondary objectives include identifying the benefits of VT-ART on cardiac function, as evaluated through an electrocardiogram, echocardiographic, biochemical variables, and patient’s quality of life.In particular, we will evaluate the reduction or suspension of antiarrhythmic drug use compared to the baseline and the improvement of cardiac parameters .Analyzed biochemical variables will include heart failure biomarkers, such as NT-proB-type natriuretic peptide (NTproBNP), troponin (hs-TnI), and inflammation markers, such as polymerase chain reaction (PCR), tumor necrosis factor-alpha , and interleukin 6 (IL-6).Improvement in the patient’s quality of life will be assessed compared to the pre-treatment period using the SF36 scale.The patient’s QoL will be assessed before and after VT-ART using the SF36 scale  in the experimental arm.A descriptive analysis will summarize the total number and stratification of patients with RFA and VT-ART.We will perform a comparative analysis between RFA and VT-ART in patients with structural heart disease and refractory VT. Each patient who will be treated by VT-ART will be compared with two patients in the control group treated with RFA and best standard care but without VT-ART, on the basis of the following matching factors: Etiology of cardiomiopathy , ventricular arrhythmia presentations , diagnostic tools used for scar definition , arrhythmogenic focus anatomical intracardiac location (on the basis of VE exit by ECG and by activation map of VT), TA volume , heart volume, heart-to-TA volume, rate number of previous RFA attempts, type of previous RFA attempts , time (in days) between the first RFA attempt and VT-ART, time (in days) between the last RFA attempt and VT-ART, previous percutaneous stellate ganglion blockade, time (in days) between the percutaneous stellate ganglion blockade and VT-ART previous use of amiodaron, NYHA group, LVEF, BMI, age, and gender.As mentioned, applied matching factors are summarized in T-test will be performed.Continuous data will be expressed as mean ± standard deviation, as appropriate, for all variables collected from the entire population or specific subgroups. A comparative analysis for subsequent levels of qualitative variables through the chi-square test and quantitative variables  with the Non-parametric tests will be provided where the population distribution does not have a known form .Q-tests for categorical ones.The differences in baseline and follow-ups between the same group will be analyzed with repeated measures approach: using the Friedman test and MANOVA for continuous variables and McNemar or Cochran’s p < 0.05.The significance of the tests is fixed with The calculation of the sample size considered followed assumptions:-A total of 95% confidence level;-The drop-out rate of 10%;-Expected difference between the two treatments for 3-month and 6-month VT burden in terms of overall response rates: 20% higher in arm including VT-ART compared to the control group;-Power of 80%.To improve clinically adequate balancing, we will enroll two matching paired patients in the group not undergoing VT-ART for each patient who undergoes VT-ART in a 2:1 ratio, favoring a larger proportion of patients not undergoing the innovative procedure .Under these hypotheses, to detect a 20% improvement in the VT burden control rate in the VT-ART group vs. the control group, we calculated the sample size (in a 2:1 ratio) upon enrolling 149 patients: 100 in the non-exposed control group and 49 in the VT-ART group. Progressively, on a multicentric basis supervised by the promoting center in the VT-ART consortium, for each VT-ART patient enrollment, a matched pair patient profile according to the predefined features will be shared with the consortium to enroll two similar patients who have not undergone VT-ART. For enrollment into the control group, recruitment of clinical cases from retrospective case series within the multicentric consortium will also be allowed, with the only condition to be not earlier than 5 years from the enrollment of the matched pair patient in the VT-ART group (to avoid the possible influence of a too early approach for standard procedures).® version 25.0 software .All statistical analyses will be performed using SPSSDue to the potential difficulty of enrolling the patients through the complete match of all matching factors, a protocol rule will be applied through patient’s collection.Once the planned number of the innovative procedure will be collected, the trial will put a 6-month observation time. If after that, 60% of the planned conventional arm patients will be collected , a further 3 months will be provided to reach the planned accrual. If that would have not been the case, then the patient’s enrollment will be allowed by mandatory matching factors only (only beyond that point). The detail of “mandatory matching factors” is reported in The final analysis will not be performed at all if less than a 1:1 ratio  of patient’s enrollment will be collected, and the study will be closed.The final analysis will be performed specifying that the planned accrual is not met if at least a 1:1 ratio  enrollment will be accomplished; results will be explored and cautiously evaluated.Radiotherapy-related toxicity will be defined using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. All adverse events, regardless of the toxicity grade and all-cause mortality, will be reported in the final study. Patients will be re-evaluated at 2 years of follow-up for late-onset toxic effects.The secondary safety endpoints for VT-ART include the evaluation of all adverse events, which are classified as follows:•Acute, during the patient’s hospital stay;•Subacute, in the first 90 days from discharge;•Chronic, 6–12 months following discharge.Follow-up will be conducted for 36 months after treatment administration.Patients prospectively enrolled within the consortium and treated by VT-ART will undergo ICD interrogations for up to 36 months after enrollment.After a blanking period of 3 months, regular ICD interrogations [with intracardiac electrogram (EGM) storage of VT/VF or appropriate shock or ATP] will be prospectively collected for patients treated by VT-ART at 6, 9, 12, 18, 24, 30, and 36 months after the VT-ART procedure.The ICD interrogation will collect the events along the last 3 months ahead of each follow-up evaluation.Patients prospectively enrolled within the consortium and treated by RFA will undergo the same follow-up schedule if possible according to the clinical patient’s need and compliance.Patient data retrospectively collected within the consortium and treated by either RFA or VT-ART will be retrospectively extracted at the same time points of prospective follow-up.The final analysis will be performed only for patients with available data for the mentioned time points, either retrospectively or prospectively collected.Quality of life will be assessed before the procedure (for prospectively enrolled patients candidate to VT-ART and RFA) and at 3, 6, and 12 months after therapy. Improvement in the patient’s quality of life will be assessed compared to the pre-treatment period using the SF36 scale.Patient follow-up will thus, briefly, include:•ICD interrogation (with EGM storage of VT/VF) at 6, 9, 12, 18, 24, 30, and 36 months from treatment.•A total of 12-lead ECG at 3, 6, and 12 months.•Echocardiography at 3, 6, and 12 months.•QoL assessment using the SF36 scale  will be •QoL assessment using the SF36 scale will be performed at 6 months for patients undergoing RFA.The trial is promoted by Fondazione Policlinico A. Gemelli IRCCS, Rome . The clinical and investigational procedures will be based on approval from the local ethics committee. Each interested center will submit the protocol to its ethics committee for approval before accrual. After approval, the center will receive a dedicated electronic case report form (CRF). Eligible participants who provide consent and meet the inclusion criteria are anonymously registered in the CRF by assigning a numerical code. Final stratification of the enrolled patients will be performed globally to enhance the homogeneity and balance of the final dataset.The trial will be conducted in compliance with the approved protocol, Declaration of Helsinki 2008, principles of Good Clinical Practice (GCP), and Italian National Normative for clinical experimentation. Upon signing the protocol, every investigator will provide consent for the procedure and instructions in the protocol and run the study according to the GCP, Declaration of Helsinki, and National Normative. Every amendment to the study will be registered and submitted to the ethics committee. Our trial protocol and its attached material have been approved by the Ethics Commission of Fondazione Policlinico Gemelli IRCCS . Every participant center must submit our protocol to their respective ethics commission before enrolling patients.Sustained monomorphic VT is a potentially life-threatening condition that often affects patients with structural heart diseases. VT recurrence poses a severe threat to health and quality of life. Long-term management of recurring VT relies mainly on ICDs, pharmacological control , and RFA of the pathological arrhythmogenic substrate.New long-term solutions are currently being sought for patients in whom VT is refractory to conventional treatment strategies or in whom it cannot be performed. In patients with structural heart disease, the rate of VT recurrence after RFA has been reported to be between 25 and 50% . IntrinsCuculich et al. first investigated the efficacy and safety of stereotactic radiation for the ablation of VT in a five-patient case series, which was later followed by the publication of a phase I/II prospective study by the same authors, including 19 patients . Both stOverall, VT-ART has been proven to be an effective and adequately safe intervention in other studies , 11. Itsvia subgroup stratification into dynamic cohorts of two groups of patients with or without VT-ART in a multicentric consortium.Our trial will provide insight into the efficacy and safety of VT-ART through a matched pair analysis, by an observational, multicentric study (with prospective and retrospective data collection) This study was reviewed and approved by the Ethics Commission of Fondazione Policlinico Gemelli IRCCS . Written informed consent will be obtained from all participants for their participation in this study and every participant center must submit our protocol to their respective ethics commission before enrolling patients.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.


Lateral spine images for vertebral fracture assessment can be easily obtained on modern bone density machines. Abdominal aortic calcification (AAC) can be scored on these images by trained imaging specialists to assess cardiovascular disease risk. However, this process is laborious and requires careful training.Training and testing of model performance of the convolutional neural network (CNN) algorithm for automated AAC-24 scoring utilised 5012 lateral spine images , with trained imaging specialist AAC scores. Validation occurred in a registry-based cohort study of 8565 older men and women with images captured as part of routine clinical practice for fracture risk assessment. Cox proportional hazards models were used to estimate the association between machine-learning AAC (ML-AAC-24) scores with future incident Major Adverse Cardiovascular Events (MACE) that including death, hospitalised acute myocardial infarction or ischemic cerebrovascular disease ascertained from linked healthcare data.The average intraclass correlation coefficient between imaging specialist and ML-AAC-24 scores for 5012 images was 0.84  with classification accuracy of 80% for established AAC groups. During a mean follow-up 4 years in the registry-based cohort, MACE outcomes were reported in 1177 people (13.7%). With increasing ML-AAC-24 scores there was an increasing proportion of people with MACE , as well as individual MACE components . After multivariable adjustment, moderate and high ML-AAC-24 groups remained significantly associated with MACE , compared to those with low ML-AAC-24.The ML-AAC-24 scores had substantial levels of agreement with trained imaging specialists, and was associated with a substantial gradient of risk for cardiovascular events in a real-world setting. This approach could be readily implemented into these clinical settings to improve identification of people at high CVD risk.National Health and Medical Research Council of Australia Ideas grant and the Rady Innovation Fund, Rady Faculty of Health Sciences, University of Manitoba.The study was supported by a  We searched Google Scholar twice up to July 28, 2022, for literature published up to June 30, 2022, with no language restrictions, using the keywords “abdominal aortic calcification” and “vertebral fracture assessment”, and “machine learning” or “artificial intelligence”. The literature was scarce with only three published studies and a preprint (2020) retrieved. All studies utilised lateral spine imaging from a single bone density machine manufacturer, had 1300 or fewer labelled images for development, validation and testing, and all reported internal performances of the abdominal aortic calcification (AAC) algorithms without external validation.AAC scoring from bone density machine images is laborious and requires careful training. As a result, AAC scoring is not routinely performed when these images are acquired in clinical practice. Our study developed, validated and tested machine learning algorithms for AAC assessment and evaluated it in a real-world setting using a registry study of 8565 older men and women. We demonstrated greater ML-AAC-24 scores were associated with substantially higher cardiovascular disease risk and poorer long-term prognosis.This ML-AAC-24 scoring demonstrated promising performance, that may seamlessly add screening for cardiovascular disease risk in people undertaking bone density assessment where more costly, time-consuming or invasive tests may not be warranted.Thoracolumbar lateral spine images can be easily obtained at the time of bone densitometry on modern dual-energy X-ray absorptiometry machines, with substantially lower radiation than standard radiographs. Increasingly, these images are obtained at the time of bone mineral density (BMD) testing for trained imaging specialists to identify clinically unrecognised vertebral fractures.,,,In addition to the identification of vertebral fractures, abdominal aortic calcification (AAC) can be visually identified and semi-quantified using either an 8 (AAC-8) or a 24-point (AAC-24) system,A major impediment to the use of AAC more widely has been the time-consuming nature of assessment, exacerbated by the lack of availability of trained readers. As such, recent efforts have focussed on whether machine learning (ML) may be applied to these images to identify and assess the extent of AAC. To date, these efforts have been limited to lateral spine images from single manufacturers, with relatively small datasets of available images annotated by trained imaging specialists.We therefore sought to train and test ML algorithms for the automated assessment of AAC. We used a large collection of lateral spine images with AAC-24 scored by an imaging specialist, with over 15 years of experience reading these images. Moreover, we assessed the performance of our model on test image sets acquired from various generations of Hologic and GE machines, comprising the majority of DXA machines in clinical use. We then investigated whether these machine learning AAC-24 (ML-AAC-24) scores were associated with clinical cardiovascular outcomes in a real-world setting, where these images are captured as part of the routine clinical care.De-identified labelled (AAC-24 scores) and unlabelled images were sourced for the ML (Project number: 03349 LEWIS) from a number of existing studies collecting VFAs. For the Perth Longitudinal Study of Ageing Women, written informed consent was obtained from all participants for the study and follow up of electronic health records at baseline. The Human Ethics Committee of the University of Western Australia approved the study protocol and consent form . The Human Research Ethics Committee of the Western Australian Department of Health also approved the data linkage study . For other Hologic images the HealthPartners Institutional Review Board [IRB] [#A20-149]) approved the use of the de-identified Hologic images or the ethics approval for the study was granted by the Edith Cowan University Human Research Ethics Committee (Project number: 20513 HODGSON). For the GE images the study was approved by the Health Research Ethics Board for the University of Manitoba . The Manitoba Health Information Privacy Committee approved access to the Manitoba data and waived the requirement for signed consent (HIPC 2016/2017–29). The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Population Health Research Data Repository. The results and conclusions are those of the authors and no official endorsement by Manitoba Health and Seniors Care, or other data providers is intended or should be inferred.,,De-identified bone density machine-derived lateral spine images were available from four different models of bone density machine from the two largest bone density machine manufacturers: Hologic Inc , and GE . Details of the datasets used are summarised in Hologic machines, whereas for GE machines both single- and dual-energy (DE) images were available. We have used a regression network to predict continuous outcome i.e., AAC score, given the image features. •two dense layers with Batch normalisation and Rectified Linear Unit (ReLU) activation function and,•a fully connected final layer with linear activationThe lateral spine images used in this work were pre-processed before being input into the machine learning model with only the AAC-24 scores used for training/validation/testing. Only single-energy (SE) images are available for the n is the total number of training images, Yi and Zi are the ML computed and ground truth scores, respectively. The ML computed scores are further categorised into three classes: low, moderate, and high using the following thresholding strategy:We optimised our network for Mean Squared Error loss, which is formalised as:Our model regresses upon the ground truth AAC-24 scores, i.e., it tries to predict a continuous output value which is as close as possible to that of the given input image. Regression outcome may be preferred over a direct classification (only three possible outcomes) as the approach to map the input images to the ground truth scores (human assessed scores) makes it easier to measure the distance between the predicted values and ground truth. The continuous measure of error can be easily interpreted and compared across different models, making it a better choice for understanding the error of a score compared to classification. The pre-trained EfficientNet-B3 was fixed after pre-training and was not trained together with the regression module. To effectively analyse the reliability and generalisability of our approach, we first trained our model on the SE images from the Hologic-4500A dataset (n = 1914) and then independently tested it on the SE images from the Hologic Horizon (n = 508). The scans from GE have a GE SmartScan feature limiting the field of view to reduce radiation dose. This appears as a black mask on the regions surrounding the spine and aorta. To help our model adapt to GE scans, we fine-tuned it using a combination of 2331 iDXA and Lunar Prodigy scans from the Manitoba bone density registry. To account for the disbalance in the different AAC categories in the training dataset, we performed 10-fold stratified cross validation. 10-fold stratified cross validation involved splitting the sets of images into 10 random sets (folds) such that each set maintains the same distribution of AAC scores. Each time the model is trained on 9 folds and tested on the remaining (10th) one. This process is repeated 10 times and then the average performance of the model is reported. Details of various hyperparameters including, learning rate, batch size, cross-validation technique and the number of neurons in the fully connected layers of our regression network, are given in the Supplementary Text ,Clinical outcome data were available in two studies. The first was a prospective cohort study of Hologic 4500A lateral spine images where labelled images from 1998/1999 and 2003/2004 were available for training/testing and for comparison to imaging expert AAC scores for 15-year CVD and all-cause mortality outcomes. Unlabelled images from 2008  were available for 582 participants to determine the association with 5-year CVD and all-cause mortality outcomes. Cohort characteristics of women with AAC scores have been published previously.Mortality data were retrieved from the Western Australian Data Linkage system from January 1998 to December 31st 2013 as described previously.The primary outcome was major adverse cardiovascular event (MACE) defined as all-cause mortality recorded in Vital Statistics, hospitalisation for acute myocardial infarction, or hospitalisation for non-hemorrhagic cerebrovascular disease occurring after VFA (index date). Secondary outcomes were incident hospitalisations for coronary artery disease, coronary revascularisation, congestive heart failure, or peripheral arterial disease, including a composite of any secondary endpoint. We also identified cardiovascular diagnoses that occurred prior to the index date using a look back to 1984. All diagnoses were based upon hospital discharge abstracts , by examining the Pearson correlation of the ML computed AAC scores (ML-AAC-24) with the ground truth  assessment (AAC-24). When looking at the agreement by Cohen's weighted Kappa (linear) for AAC-24 scores we rounded these values to whole numbers to reflect the imaging specialist scoring and used the results from the dual-energy images for GE machines. We then assessed the performance of our model in terms of accurately classifying images into low, moderate, and high categories, based on their AAC scores. The AAC score thresholds for the three categories were defined as: i) Low (AAC-24 score<2), ii) Moderate (AAC-24 score≥2 to <6) and ii) High (AAC-24 score ≥6) based on previous publications.None of the funding agencies had any role in the conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.The Cohens weighted Kappa for the Hologic-4500A and Horizon test scans were 0.51 and 0.56, respectively. The ICCs were 0.76  and 0.82 , respectively. The trained model had an average classification accuracy of 76–83% for the established AAC groupings  for the two Hologic test sets , Fig. 2.The linear correlations of the models which were independently fine-tuned on DE and SE images of the Manitoba registry, are shown in To determine if ML-AAC-24 scores had a similar association with clinical events we tested the association between in ML-AAC-24 with 15-year CVD (n = 266) and all-cause mortality (n = 419) in 1082 women. Women in the high ML-AAC-24 group (vs. lowest) had a HR for CVD death of 2.17, 95% CI 1.49–3.15 vs. imaging specialist high AAC HR 1.66, 95% CI 1.21–2.29. Similar results were seen for all-cause mortality high ML-AAC-24 group 1.79, 95% CI 1.31–2.45 vs. expert assessed high AAC group HR 1.57, 95% CI 1.22–2.02. In 582 women (mean age 84.7 years ± 2.4 years) with images obtained in 2008 without no imaging specialist AAC-24 assessment women with high ML-AAC-24 score had similarly higher relative hazards of CVD mortality  and all-cause mortality  vs. those with a low ML-AAC-24 score.Baseline characteristics for the outcomes assessment cohort are summarised in Medical image analysis such as segmentation or localisation of lower lumber regions may be useful in accurately predicting AAC 24-point scores. However, such analysis is dependent on the availability of ground truth annotations for the lumber regions, which is very expensive to acquire at scale. The low resolution of VFA scans and presence of artefacts further adds to the complexity of localisation and identification of lumber regions and aortic wall. On the other hand machine learning models leverage data examples to learn the useful features to predict the overall AAC scores, without the need of other intermediate steps. In this study, we found good levels of agreement between imaging specialist and ML-AAC-24 scores across DXA machines from different manufacturers that have been widely used over the last three decades. We also observed high levels of accuracy (76–85%), with only 3% of manually-assessed individuals with high AAC-24 being incorrectly classified as low by the CNN. This is notable as these are the individuals with the greatest extent of disease and highest risk of fatal and non-fatal cardiovascular events and all-cause mortality.,Whilst expert assessed AAC-24 is not routinely performed or reported on lateral spine images from bone density machines, it is being assessed and reported to patients in some institutions (J.T.S. unpublished) as well being reported to individuals in a randomised controlled trial to determine if the knowledge of the presence and extent of AAC may lead to modification of diet and lifestyle behaviours.In the real-world assessment, ML-AAC-24 scoring was able to directly link ML-AAC groups with subsequent cardiovascular outcomes, confirming that the approach identifies large proportions of people at substantially higher cardiovascular risk and poorer long-term prognosis. Higher ML-AAC-24 as predicted by the algorithm were strongly and robustly associated with the primary composite outcome of MACE, as well as all of the individual components of all-cause mortality, hospitalised myocardial infarction or cerebrovascular disease, in addition to a range of secondary cardiovascular diagnoses. These associations remained strong when adjusted for multiple baseline covariates, even after excluding individuals with prior cardiovascular diagnoses. These data demonstrate that the ML approach can accurately classify a patient's extent of AAC, and hence CVD risk when undertaking DXA-based lateral spine imaging currently collected to detect spine fracture.Increasingly, clinical guidelines are recommending performing this vertebral fracture assessment (VFA) imaging at the time of DXA testing to identify asymptomatic vertebral fractures. As such automated assessment of the presence and extent of AAC with similar accuracies to imaging specialists provides the possibility of large-scale screening for asymptomatic CVD. The observed hazard ratios for increased ML-AAC-24 align closely with those that were reported in a recent meta-analysis of 46 cohorts of 36,092 participants.As per Koo and Li's guidelines,We chose to train the algorithm on the largest dataset from a single machine (Hologic 4500A) read by the most experienced expert (J.T.S) and tested on other bone density machine makes and models. This approach was selected given fine-tuning a model which has already learned to map images to AAC scores is more plausible than training from scratch, especially when the size of the datasets with expert assessment are limited. In future if larger datasets of several thousand images with expert assessment are available, training within specific machine makes and models  may be possible.The agreement and accuracies across the different makes and models of bone densitometers were similar to Reid et al.However, whilst these results are promising, there remain many areas for improvements. For example, the ML tended to underestimate the AAC-24 scores compared to human assessment, leading to greater misclassification into lower AAC groups, suggesting further development is needed. This underestimation may lead to weaker associations with clinical outcomes but will need further investigation in larger datasets with clinical outcomes. When looking at the activation maps of the outliers (>2.5 SD from the mean difference between AAC-24 and ML-AAC-24) we identified a number of cases where the ML-AAC-24 scores failed to identify and score iliac artery calcifications, when these were adjacent to the L4 region. We continue to investigate other potential causes of discrepancies such bowel gas overlying the aorta and the ribs being mistaken for AAC adjacent to the L1 region in people with hyperlordosis. Similarly, we are investigating whether vertebral fractures, scoliosis, osteophytes and rotation leading to the aorta being partly covered by the spine, may be affecting the agreement between AAC-24 and ML-AAC-24 scores. We are also increasing the size of the datasets and adding more granular manually assessed calcification data, such as the adjacent lumbar region where calcifications were observed, and whether these were in the anterior or proximal aortic wall to improve the accuracies of the algorithm. Finally, whilst the algorithm generally had a high level of sensitivity, specificity and accuracy identifying people with high AAC, the performance for identifying individuals with less extensive AAC was lower. This suggests further work is needed to improve these measures.EfficientNetIn this work, we used a state-of-the-art convolutional neural network model We only had access to manually assessed VFA images from the two largest manufactures and the algorithm may not perform as well on other manufacturers' VFA images. However, Hologic and GE account for the vast majority of DXA machine sales. Additionally, we did not have access to real-world examples with long-term clinical follow up for Hologic bone density machines similar to what was available for the Manitoba dataset. However, we did have the long-term outcomes for the Perth Longitudinal Study of Ageing Women where ML-AAC was similarly associated with mortality outcomes to human assessment and predicted mortality outcomes in images that had been captured 5 years after the last human assessments of AAC. Also, we did not look at how patient characteristics such as age, ethnicity, sex and BMI may affect performance. However, the associations between ML-AAC-24 groups and MACE outcomes were independent of these characteristics. Secondly, the Manitoba registry lateral spine images were captured based on age and an increased a priori risk of osteoporosis and fracture and thus may not represent younger individuals and those with better bone structure. Additionally, as we used a MACE composite outcome that includes all-cause mortality this may weaken the association between ML-AAC-24 and the outcome due to non-cardiovascular causes of death. However, despite this we identified strong and robust associations between ML-AAC-24 and the MACE composite outcome as well as all of the individual cardiovascular outcomes.We had access to the largest manually assessed set of VFA images from widely-used bone density machine models in clinical practice over the last three decades. Importantly, these images were read by a globally-recognised expert in assessing AAC-24 (JTS) or people trained by J.T.S. providing reliable and consistent scoring for ML. Further strengths include i) the use of advanced and efficient ML models to quantify AAC, and, ii) the generation of visual explanations  which add to the explainability of the model. We believe that clinical trials comparing patient and physician behaviour, treatment and outcomes based on ML-AAC-24 reporting are now warranted.In conclusion, we found substantial agreement between trained imaging expert and machine-learning AAC-24 scores irrespective of the make and model of DXA machine. Since these images and automated scores can be rapidly and easily acquired at the time of bone density testing this may lead to novel approaches for early cardiovascular disease detection and disease monitoring in routine clinical practice settings.SZG, DS, WDL, JTS, JRL conceived and designed the study; DS, KZ, RLP, DPK, JTS, JRL acquired funding; RLP, KZ, SR, WHL, JRL, JTS, WDL collected the data; NS, MS, SZG, WDL, JRL analysed the data; NS, SZG, DS, BAM, MJJ, WDL, JTS, JRL prepared the manuscript with input from all authors; ZG and JRL verified the underlying data and NS, SZG, WDL, JTS, MS, JRL had the primary responsibility for the final content. All authors provided intellectual input and edited the paper. All authors read and approved the final manuscript.The data that support the findings of this study are available from the relevant Data Custodians, including the Manitoba Population Research Data Repositor, Department of Health Human Research Ethics Committee, and the Department of Health Research Governance Office. Restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. However, data will be made available from the authors upon reasonable request once permission of the relevant Data Custodians have been obtained.DPK has received a grant from Solarea Bio and royalties from Wolters Kluwer. DPK sits on the Scientific Advisory Boards of Solarea Bio, Pfizer and Reneo and has participated on the Data Safety Monitoring Board for the AgNovos Healthcare osteoporosis treatment trial. All other authors have no disclosures to declare.