Background: Although intermittent androgen deprivation therapy was introduced many years ago to improve patients’ quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that intermittency could be underutilised. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain.Methods: A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants . We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy in reference to the total number of PC patients using hormonal therapy (PIAD) and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy‐associated medications.Results: A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues  administered alone or in combination with anti‐androgens . Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual PIAD along the study was 6.6% in the total population studied, and the overall %IAD during the five‐year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens.Conclusions:  Few prostate cancer patients in Spain use the intermittent androgen deprivation therapy suggesting underutilization of a perfectly valid option for a significant proportion of patients, missing the opportunity to improve their quality of life and to reduce costs for the National Health Service with comparable overall survival rates than continuous therapy. ADT: Androgen Deprivation TherapyATC: Anatomic Therapeutic CodeCAD: Continuous Androgen Deprivation therapyELD: Effect duration of the Last DoseGPC: Clinical Practice GuidelineIAD: Intermittent Androgen Deprivation therapy%IAD: Percentage of time off treatmentIntT: Interval TimeLHRH analogue: Luteinizing Hormone-Releasing Hormone analoguePCa: Prostate CancerIAD: Prevalence of Intermittent Androgen Deprivation therapyPPIIT: Potentially Intermittent Interval TimePSA: Prostate Specific Antigen ranging from the well-known hot flushes, loss of libido, gynecomastia, or erectile dysfunction up to midterm consequences such as bone fractures, depression, diabetes, and hematologic and cardiovascular events., Importantly, all of these undesirable effects increase with the duration of ADT.Androgen deprivation therapy (ADT) is the main indication for Prostate Cancer (PCa) patients with metastatic disease and the most used therapeutic approach to treat patients who experience a biochemical relapse after radical prostatectomy. Reduction of circulating levels of androgen hormones can be achieved either with drugs, such as luteinizing hormone-releasing hormone analogues (LHRH) or with orchiectomy, which is irreversible. Nevertheless, ADT is associated with a wide array of adverse effects Over the years, it has been shown that IAD can improve patients’ quality of life by reducing toxicity, reduce costs and potentially delay the onset of resistance to chemical castration. Recent strong evidence from randomized clinical trials– and systematic reviews, as well as favourable recommendations included in recently updated clinical guidelines,– highlight the potential benefits of IAD, supporting its use as an alternative treatment.In the 1990s, as a response to minimise these negative outcomes, intermittent androgen deprivation therapy (IAD) emerged as an alternative to continuous androgen deprivation therapy (CAD) but not without controversy regarding its feasibility. compared to recent evidence of IAD utilization in Canada. We conducted the current study with the same methodology but covering a much bigger area of Spain (17 million inhabitants from four autonomous communities) to assess the prevalence of IAD with real-world data.Despite the potential advantages of IAD, in a previous study we detected a low use of this approach in Catalonia (Spain)An observational, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities: Catalonia, Madrid, Basque Country and Navarra .Data used for this study were obtained from the health government agencies from each of the four territories in Spain: CatSalut in Catalonia, Servicio Madrileño de Salud in Madrid, Osakidetza in the Basque Country and Servicio Navarro de Salud-Osasunbidea in Navarra. We received all relevant dispensation data from the four respective agencies for the period between 1 January 2011 and 31 December 2016. Databases contained anonymised patient codes, date of birth, dispensing date, prescriber code (anonymised), drug name and anatomic therapeutic code (ATC), total dose per pharmaceutical form, number of dispensed drug units and the corresponding cost. The dispensation of each of the following LHRH analogues was identified: leuprorelin (L02AE02), triptorelin (L02AE04), goserelin (L02AE03), buserelin (L02AE0), histrelin (H01CA0), nafarelin (H01CA02), and the following antiandrogen drugs: bicalutamide (L02BB03) and flutamide (L02BB0), in any pharmaceutical form or dose registered in Spain. We selected ≥ 18-year-old male patients with at least one dispensation of LHRH analogues. We excluded individuals under age 18 based on the high likelihood that LHRH dispensations in this subgroup would be associated with precocious puberty, which was not within our interest. Given the specificity of ADT, we assumed that all other men ≥ age 18 were prescribed these drugs as PCa treatment.The requested data were provided under the requirements of the Spanish data protection laws and no personal data was available to the investigators.To distinguish between the CAD and IAD regimens, we identified all the periods during which patients received no LHRH analogue or Potentially Intermittent Interval Times (PIIT). We first identified all interval times (IntT), defined as the period between any two consecutive dispensations for each patient, together with the effect of the last dose (ELD), identified as the time period during which the patient was covered by the medication, as shown inIAD), calculated as the number of patients with ≥1 PIIT per year, divided by the total number of patients treated with LHRH analogues in the same year. Nevertheless, it should be noted that the PIAD for the first year of data (2011) was underestimated due to the prior three-month intermittency requirement . Because of that, the data from 2011 was not included in the specific analysis of intermittency. We present the costs of hormonal treatment, including LHRH analogues and anti-androgenic therapeutic groups, per drug, year, and autonomous community. We excluded the Basque Country for the calculation of the annual expenditure because of its lack of complete 2011 data. To compare the cost between communities, we normalised the data as euros per dispensation. We expressed baseline characteristics, as mean ± standard deviation for continuous variables and frequency (%) for categorical variables with the corresponding 95% confidence interval (95%CI). A chi-square test was used for comparing presence or absence of intermittency (dichotomous) depending on the four communities or the five years of follow-up (2012-2016). P values <0.05 were considered statistically significant. Calculations were performed using SPSS version 26.0 software .One of the two key study variables created to estimate the use of intermittence was the percentage of time off treatment (%IAD). This percentage was calculated by dividing the sum of all the off periods  by the sum of all interval times on any LHRH analogue regimen . The %IAD was calculated overall and for each region along the study period. The other key variable to estimate the number of patients under intermittency was the prevalence of IAD (PFor the full study period (2011-2016), a total of 863,005 dispensations corresponding to a total of 65,752 men, including either LHRH analogues administered alone  or in combination with anti-androgens , were made in Catalonia, Madrid, Basque Country and Navarra. Previously, 309 males under the age 18 were excluded together with 7,731 subjects that were dispensed only with antiandrogens, because complete castration was not guaranteed. Additionally, 2012 data from the Basque Country were considered inconsistent (likely incomplete electronic system introduction in this area) and were also excluded from the analysis. Finally, a total of 44,264 PCa patients were included in the study, as summarized inOf the total men  finally included in the study and taking LHRH analogues alone, 36,775 (83%) were under CAD therapy and 7,489 (17%) under IAD therapy, considering the full five-year period of the study. However, this value of global prevalence represents an overestimation of the actual annual prevalence of IAD, as can be observed inIAD) of patients under an IAD regimen was 6.6% in the total population studied. The global prevalence of intermittency slightly increased from 8.2% in 2012 to 8.4% in 2013, but later decreased to 3.6% in 2016. We also calculated the %IAD during the five-year study period with a total %IAD value of 5.6%, which is rather consistent with the PIAD figure reported earlier.The five-year prevalence , followed by Navarra (8.2%) and Catalonia (5.8%). Peak values obtained were up to 14.2% [2014] in Madrid, 8.5% [2013] in Navarra, 8.4% [2013] in Catalonia, and 3.8% [2015] in the Basque Country; thereafter, the use of intermittent treatment decreased to 4.3% by 2016 in Madrid, 4.0% in Catalonia, 3.4% in Navarra and 2.5% in the Basque Country.IAD distributed per community per year, as well as %IAD for each community.Statistically significant differences (P < 0.0001) were observed in prevalence of intermittency among the four Spanish regions and among the five years of study (2012-2016). The PWe found that the most representative non-treatment period lasted for a median of six months (ranging from 3 to 58 months) considering all four areas. In Madrid and Catalonia, the median of the PIIT intervals was 6.2 months with an IQR of 7.1 and 9.2 months respectively, while in the Navarra and Basque Country the PIIT intervals were shorter and less variable: 5.1 months (IQR 4 months) and 4.0 months (IQR 3.1 months), respectively. In the four areas the global tendency was to increase the duration of the “off” period from four (2012) up to six months (2016).The most prescribed drug in all four communities during the five-year study period was leuprorelin, followed by triptorelin and goserelin  of the total LHRH analogues dispensed.The global mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens for the four regions. Along the study period, the total expenditure in Catalonia, Madrid and Navarra decreased from 34.7 million euros [2011] down to 25.3 million euros [2016].IAD (6.6%) or the %IAD (5.6%) as reference, IAD use was in the range of 6% in Spain. These results are in agreement with our previous estimations from Catalonia (2008-2012): PIAD = 4.2% and %IAD = 1.7% and confirm a low global utilisation of IAD in Spain. Even worse, the IAD utilisation rate has evolved in a progressively decreasing manner along the current study period, ranging from 8.4% (2013) to 3.6% (2016). Among the four Spanish regions, the %IAD showed that Madrid had the highest prevalence of intermittency (11.4%), followed by Catalonia (5.2%), Navarra (4.3%) and the Basque Country (1.7%). The PIAD showed a decreasing trend along the study period until 2016 in Madrid (4.3%), Catalonia (4.0%), Navarra (3.4%) and the Basque Country (2.5%). Based on the obtained data, we interpret that the well-known role of intermittent treatment in hormonal therapy, based on sound evidence from randomised controlled trails– and systematic reviews,, does not appear to be influencing actual clinical practice in a significant proportion of cases. It seems that the necessary trade-off between benefits and adverse effects could be much improved in those situations where IAD is as effective as CAD, since adverse effects of IAD should be lower for a broad range of morbidities.,,,– An international survey conducted in 19 countries asking 441 physicians currently treating PCa patients, showed that 23% of non-metastatic patients treated with gonadotropin-releasing hormone analogues were using IAD. Additionally, the same authors agree with our results that the CAD and IAD use in Spain among men with non-metastatic prostate cancer, was of 35.7% and 6.9%, respectively. Reference countries like France, Italy or Germany showed higher IAD use than Spain , still based on physicians opinions. This fact could be explained by the relatively higher healthcare pressure of physicians in Spain than in France, Italy or Germany . Further evidence suggesting that the use of IAD is low in Spain, comes from data collected in Manitoba (Canada), where 74% (447/601 nonmetastatic hormone-sensitive PCa patients) were using IAD for the management of their relapse.Our results show that, taking either the mean Poff-treatment periods are concordant with the corresponding values reported by Crooket al., that ranged from approximately 20 months in the first non-treatment interval, down to three months in the 6th interval. Globally, there was also a tendency to increase the median duration of the pause period between 2012 (three to four months) and 2016 (five to six months). This may suggest that prescribers using IAD are progressively more confident with the risk/benefit balance of this therapeutic strategy. This is in agreement with the fact that patient-reported outcomes were significantly better in IAD versus CAD at 20 and 38 months of treatment, based on validated quality of life questionnaires in Japan.When analysing the data related to the duration of the “off” periods, or halted medication periods, we observed that the median duration varied between 4 and 6,2 months in all four regions (ranging from 3 to 13 months). These and all kind medication were reduced in the whole country by as much as 12 million per month. However, thereafter the cost increased again up to 213.9 euros per dispensation in 2016. Obviously, the efforts to enhance the use of IAD would produce important cost savings due to the reduction in expensive drug consumption, which some authors estimate in the range of one-third of CAD. In the population studied, we would be talking of around half a million savings per million inhabitants per year.We calculated that the total cost of hormonal therapy in the four autonomous communities was 31.3 million euros per year , which represents a mean of 214 euros per dispensation. The fact that the mean cost per dispensation declined from 214.6 euros in 2011 to 201.7 euros in 2014 could be related to the fact that in 2012, the Spanish health authorities introduced restrictive measures for the sustainability of the National Health System If PCa patients are to be actively involved in their decision process related to hormonal therapy medications, as current clinical guidelines suggest, they should know the existing sound evidence that shows similar overall survival of both CAD and IAD users, but the broader span of morbidities associated to CAD. From the physicians’ point of view, the PSA levels (54%), patient request (48%), desire to maintain sexual function (40%), patient age and comorbidities (38%) were reported as the most frequent reasons for IAD use.The main strength of our study is the capacity to analyse all public health systems electronic dispensations data from the selected Spanish regions, which eliminates any potential selection bias. They constitute a very large sample size, which favours the representativeness of the whole Spanish population. Also, the reliability of the database reduces information bias and missing data problems as previously observed by other authors. and 19 other countries, we could say that the use of IAD in Spain could be significantly increased, leading to the consequent improvement in patients’ quality of life and significant savings for the National Health Service. We plan to conduct an audit in a sample of the electronic records of PCa patients who were potential IAD candidates, to assess if they fulfilled the clinical criteria for having eventually stopped the hormonal therapy.Due to the administrative nature of our data sources, our study is not able to estimate whether patients identified under IAD are clinically appropriate or not. However, taking into account the conservative approach that we used and compared to the real-world utilization in CanadaWe conclude that the IAD use in Spain was relatively low during the study period, although enough time has passed since the related international recommendations were published. As a consequence, an important proportion of hormone-sensitive prostate cancer patients could be currently missing the chance to reduce avoidable adverse effects and to improve their quality of life, apart from the important repercussion that this expense has on the health budget in times of crisis. The population-based method to estimate the IAD prevalence seems to be a quite consistent approach and opens the door to comparable international data to set up reference standards on adequate IAD utilisation.https://doi.org/10.34949/fzzk-ye57. This project contains the following underlying data:-CEIC_PROTOCOLO_Ca prostat.pdf (Study protocol)-IAD_CRF_v1.docx-DataDescription_v1.xlsx-BBDD_Spain_IAD_v4.xlsx (Dispensation data)Project Datasphere: Intermittent hormonal therapy of prostate cancer patients in Spain: a prevalence study,Data Sharing Agreement. Any individuals who wish to access the data will need to register for an account on Project Datasphere.Data are available under the terms of the PDS The authors have appropriately revised the manuscript; I have no reservations about indexing. Thank you for the opportunity to re-review.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:NAI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Abstract, Background: I don't think the first sentence makes logical sense . I think what you are trying to say is that it is being underutilized.Abstract, Methods: Please clarify the denominator. Here I have the impression it is the entire  population but I'd assume it to be patients with advanced/metastatic PCA. In alignment with the study results I'd say that few patients use IADT; secondarily you can state that this likely represents underuse. Introduction: I would state that metastatic disease is the main indication .Reference 20 seems to represent a similar study. You should discuss what this study will add/how it differs?The first part of the discussion appears repetitive. If you present the results clearly, you do not need to repeat them here. Please focus on the big picture take-away points.The RCTs and SRs you cite are likely overlapping bodies of evidence. Citing one recent high quality SR would suffice. Citing relevant guidelines would be even more compelling.  Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:evidence-based medicine, clinical practice guidelines, prostate cancer, urologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Thanks Dr. Dahm for your comments and support."Abstract, Background: I don't think the first sentence makes logical sense . I think what you are trying to say is that it is being underutilized".Agree. Will be corrected in next version.Abstract, Methods: Please clarify the denominator. Here I have the impression it is the entire  population but I'd assume it to be patients with advanced/metastatic PCA." It is correct. The prevalence estimation was referred (denominator) to the total number of patients under hormonal treatment.""In alignment with the study results I'd say that few patients use IADT; secondarily you can state that this likely represents underuse." Agree. Will be corrected in next version.Introduction: I would state that metastatic disease is the main indication ."Agree. Will be corrected in next version."Reference 20 seems to represent a similar study. You should discuss what this study will add/how it differs?"Agree. Basically, extension of the same method of prevalence estimation to other 3 Spanish autonomous communities confirming the same tendency previously observed in the first region . Will be added in next version."The first part of the discussion appears repetitive. If you present the results clearly, you do not need to repeat them here. Please focus on the big picture take-away points."Agree. The first sentence in the discussion will be removed.""The RCTs and SRs you cite are likely overlapping bodies of evidence. Citing one recent high quality SR would suffice. Citing relevant guidelines would be even more compelling."Agree. The older SRs will be deleted. Let me answer step by step: This is a very interesting study to estimate the prevalence of IAD in four Spanish autonomous communities based on electronic dispensation information from 2011 to 2016. The paper is well written; clear and appropriate in it's methods and results. A very high number of data have been recorded so that very consistent results have been obtained. To complete the results I would suggest to perform statistical comparisons of the prevalence values between communities and between the years of follow-up. The study has fulfilled the aims, i.e. to estimate the prevalence values of IAD in different Spanish communities from 2011 to 2016; however, I would have appreciated some discussion about the reasons why the prevalence of IAD in Spain is low.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:My expertise area is biopharmaceutics pharmacokynetic-pharmacodynamic data analysis and statisticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thanks Dr. Colom for your comments and support.To complete the results I would suggest to perform statistical comparisons of the prevalence values between communities and between the years of follow-up." As for your suggestion " Agree. The statistical comparison will be added to the version 2 but very significant differences (p<0.001) among communities and years of follow-up will be expected due to the big size of the sample analysed. We therefore concentrated on comparing the magnitude of the differences summarised in table 2.I would have appreciated some discussion about the reasons why the prevalence of IAD in Spain is low". Agree. This result is quite surprising and we only have conjectures to explain that e.g., Liedeat al. reported important differences in IAD use among European countries due to "clinicians devise individualised treatment courses of optimal length based on patient characteristics while accounting for associated risks and benefits of ADT. This individualised clinical approach is represented in the variation of survey responses as it can become difficult to compartmentalise patients when deciding on treatment strategies." The fact that in Spain we have 4 physicians/1000 inhabitants may explain some extra healthcare pressure than in France, Italy or UK with >4.5 physicians/1000 inhabitants. In any case, the data are fairly consistent when it comes to demonstrating this weak use of IAD therapy in Spain. With respect to your comment that "


How do oncologists and a machine learning model compare in predicting 3-month mortality for patients with advanced solid tumors?In this prognostic study, the machine learning model significantly outperformed 74 oncologists in predicting 3-month mortality for 2041 patients with metastatic solid tumors overall and in gastrointestinal and breast cancer subpopulations. Findings were not significant in genitourinary, lung, and rare cancer groups.The results of this study suggest the potential for a machine learning model trained with electronic health record data to support oncologists in prognostication and clinical decision-making to improve end-of-life care. To date, oncologist and model prognostic performance have been assessed independently and mostly retrospectively; however, how model prognostic performance compares with oncologist prognostic performance prospectively remains unknown.To compare oncologist performance with a model in predicting 3-month mortality for patients with metastatic solid tumors in an outpatient setting.This prognostic study evaluated prospective predictions for a cohort of patients with metastatic solid tumors seen in outpatient oncology clinics at a National Cancer Institute–designated cancer center and associated satellites between December 6, 2019, and August 6, 2021. Oncologists (57 physicians and 17 advanced practice clinicians) answered a 3-month surprise question (3MSQ) within clinical pathways. A model was trained with electronic health record data from January 1, 2013, to April 24, 2019, to identify patients at high risk of 3-month mortality and deployed silently in October 2019. Analysis was limited to oncologist prognostications with a model prediction within the preceding 30 days.Three-month surprise question and gradient-boosting binary classifier.The primary outcome was performance comparison between oncologists and the model to predict 3-month mortality. The primary performance metric was the positive predictive value (PPV) at the sensitivity achieved by the medical oncologists with their 3MSQ answers.A total of 74 oncologists answered 3099 3MSQs for 2041 patients with advanced cancer . In this cohort with a 15% prevalence of 3-month mortality and 30% sensitivity for both oncologists and the model, the PPV of oncologists was 34.8%  and the PPV of the model was 60.0% . Area under the receiver operating characteristic curve for the model was 81.2% . The model significantly outperformed the oncologists in short-term mortality.In this prognostic study, the model outperformed oncologists overall and within the breast and gastrointestinal cancer cohorts in predicting 3-month mortality for patients with advanced cancer. These findings suggest that further studies may be useful to examine how model predictions could improve oncologists’ prognostic confidence and patient-centered goal-concordant care at the end of life. This prognostic study compares the outcomes of oncologists vs a machine learning model in predicting mortality in patients with advanced metastatic cancer. The SQ has been used most commonly with a 1-year time frame but also with time frames between 1 week and 6 months with varying performance.41 The SQ has performed better in oncology populations compared with heart failure, kidney failure, and all diagnoses examined in other studies,10 albeit modestly, and further research in this area is needed.Reliable and consistently applied prognostic tools in oncology may enhance prognostic confidence, increase prognostic authority, and improve the clarity and strength of medical recommendations for and against therapies.49 Although there are multiple retrospective evaluations of ML models, there remain few prospective evaluations and even fewer prospective comparisons of clinician and ML predictions.51Institutions have increasingly used machine learning (ML) to identify patients at high risk of mortality at different points from 30 days to 5 years for activating care teams to conduct goals-of-care discussions and engage palliative care.We compared the prognostic performance of medical oncologists using an SQ with a supervised model trained to predict the risk of 3-month mortality. A motivator for this analysis was to improve the acceptability of ML for broader scale use in the electronic health record (EHR) and lay the groundwork to potentially increase prognostic confidence, improving discussions on goals of care between patients, families, and clinicians. This pilot study and the consequent evaluation were steps taken to validate the mortality prediction model and facilitate its acceptability among oncologists before integration in our EHR at the City of Hope National Medical Center.STARD) reporting guideline was followed.52This study was a comparison between predictions made by medical oncologists (57 physicians and 17 advanced practice clinicians) and their advanced practice clinicians at the City of Hope academic center and limited community sites and by a custom model running silently  for 20 months. Institutional review board approval was provided, along with a waiver of consent, by the City of Hope. The research needed a waiver of consent because the investigator does not have a reasonable opportunity to obtain consent and the risk inflicting psychological, social, or other harm by contacting participants is greater than the risk of the study procedures. The Standards for Reporting of Diagnostic Accuracy  within the pathway tool for all patients with metastatic solid tumors in December 2019, worded “Would you be surprised if this patient were to die within the next 3 months?” The answer choices are yes or no.Medical oncologists at City of Hope, a National Cancer Institute–designated cancer center, are adherent in use of a software decision support pathway tool capturing each episode of a patient’s systemic therapy.54 with observations from 28 484 deceased and alive patients and 493 features from demographic characteristics, laboratory test results, flowsheets, and diagnoses collected from the EHR between January 1, 2013, and April 24, 2019. In training and retrospective evaluation, we considered 1 observation per patient. For inclusion in training and evaluation sets, patients needed to have at least 2 encounters as a minimal amount of data; living patients needed a completed visit documented in the EHR at least 1 year postprediction date to avoid observations with potential missing death information. To limit the risk of data leakage, we picked dates of prediction to exclude encounters within 7 days of death. We also avoided overrepresenting observations with prediction dates within 30 days of death to not train the model with a disproportionate number of near-term deceased patients. We extracted hand-crafted features from time series of laboratory test results and flowsheet data in the 180-day temporal window preceding each prediction. We imputed missing values for features only in obvious cases because tree-based classifiers can handle missing data. Clinical variables used by the model, including age, sex, race, and body mass index, and other features extracted from laboratory test and flowsheet time series, are listed in eTable 1 in the 55 of the International Classification of Diseases, Ninth Revision codes. A portion of the observations was used for retrospective evaluation based on a temporal split at a single time point to mimic deployment in the real world, in which past observations are used to train a model to predict in the present.We trained a gradient-boosted trees binary classifier (via the XGBoost library)After hyperparameter tuning via cross-validation and retrospective evaluation, we retrained a version of the 90-day mortality model including the evaluation set and deployed it in a silent prospective pilot, inclusive of all City of Hope patients with accessible EHR data. The resulting model consisted of an ensemble of 357 decision trees with a maximum depth of 6. Since October 2019, the model made batches of predictions from observations automatically queried once a day from our enterprise data warehouse. The presence of new results from laboratory tests noted in eTable 2 in the We identified all medical oncologist and advanced practice clinician (oncologist) 3MSQ answers entered into our pathway decision support tool when any new regimen was ordered for metastatic disease between December 6, 2019, and August 6, 2021, from our enterprise data warehouse. After excluding prognostications not associated with outpatient visits and those entered on or after a death date, we defined a cohort inclusive of oncologist prognostications with a model prediction for the same patient within the preceding 30 days. The cohort consisted of 3099 predictions from both the model and oncologists for 2041 patients with advanced cancer. The EHR data in the community network were not yet fully accessible to the model, which limited predictions for the comparison period. Most 3MSQs were associated with encounters at the academic center (2972 [95.9%]) vs community satellites (127 [4.1%]) . PatientThis prognostic study compared performance of 3-month mortality predictions made by oncologists and a model for patients with metastatic solid tumors. Oncologists’ predictions were made from December 6, 2019, to August 6, 2021, as answers to a 3MSQ. The predictions were paired with the closest model prediction within the preceding 30 days. For the entire study, oncologists and the model were blinded to the predictions of the other. The primary outcome was an in-depth comparison between the performance of oncologists and our model in predicting 3-month mortality for a population of patients with metastatic solid tumors seen in outpatient clinics.The cohort included 3099 pairs of predictions for 2041 unique patients . A prediP < .001) (P = .03) and gastrointestinal  disease subgroups   with a median age of 62.6  years at the time of oncologist prediction. The median lag between a 3MSQ answer and a model prediction was 3 days, with 75% of model predictions made within 8 days from the corresponding answer. We compared model and oncologist performance by setting a decision threshold so that model sensitivity matched the 30% sensitivity of the oncologists. Results showed that the model outperformed oncologists in aggregate   and withence >0) . The PPVence >0) .P < .001 vs PPV difference, 15.9%; 95% CI, 5.9%-26.0%; P = .002)  SQs answered by clinicians, encompassing 1766 predictions (57.0%). We split the cohort between patients with 1 SQ and patients with multiple SQs and included all SQ answers in our analysis. The difference between the PPV of the model and oncologists was larger for the subpopulation with changes in therapy  . We alsoCOVID-19 was associated with population shifts in our organization, especially between March and August 2020 when visits were deferred or switched to telehealth if clinically appropriate. The AUROC of the model over the entire patient population (beyond the metastatic solid tumor cohort in this study) decreased during late spring 2020 but then increased in the following summer months. However, in this metastatic cohort, we observed fluctuations in the monthly performance of the model and oncologists without clear temporal patterns, perhaps owing to the homogeneity of the cohort over time. eFigure 3 in the P < .001) to predict 3-month mortality with 15% prevalence. Stated differently, the model matched the sensitivity of the oncologists but flagged nearly half of the instances (7.7% vs 14.1%). Looking forward, we anticipate tuning the model threshold to increase sensitivity or PPV depending on the clinical application but, more importantly, augmenting oncologists’ prognostic capability while tempering overestimation of prognosis.In this prognostic study, we compared the performance of medical oncologists and their advanced practice clinicians with an ML model to predict 3-month mortality for a cohort of patients with metastatic solid tumors at City of Hope. At a sensitivity of 30% (matching the oncologists’ performance), the model outperformed the oncologists in PPV  and gastrointestinal (P = .002) cancer. The model AUROC was consistent across all groups  SQs in oncology populations achieved an AUROC in the 66% to 82% range, with a 75% mean.56 None of the studies limited the population to patients with metastatic solid tumors, and few had oncologists prognosticating. The study most similar to ours was by Vick et al,40 wherein 81 oncologists answered 4617 twelve-month SQs for a mixed population of patients with metastatic and nonmetastatic cancer, achieving a 74% AUROC. The oncologists in our study achieved a 59.8%  AUROC, but for a population of patients exclusively with metastatic disease. We believe that for a mixed population, oncologists would have achieved a higher AUROC. The AUROC for evaluation of binary (yes vs no) decisions has limitations because the ROC curve is defined only by 3 points  exclusion of patients near death, (2) different disease group subpopulations, and (3) presence and absence of therapy changes. Besides improved performance in predicting near-term mortality, the model was more consistent in predicting 3-month mortality compared with the widely varying performance seen for individual oncologists B, which 49We show the PPV-to-prevalence ratio as a potentially helpful metric for comparing the performance of binary predictions (surprised or not surprised) across subpopulations with different prevalence. In a situation of random guessing, the PPV-to-prevalence ratio would tend to 1. Several publications evaluating SQs and even clinical ML did not report prevalence with PPV by omitting it, leaving its extrapolation to the reader or presenting results close to random guessing  as instances of good performance.This study had limitations. The cohort (n = 3099) excluded most prognostications made at clinical network sites because the model was designed to work with laboratory tests performed at the academic cancer center but ordered infrequently at clinical network sites. Model upgrades will enhance coverage of patients receiving care at clinical network sites.Communication of external deaths may be delayed by up to 6 months, with consequent underestimated prevalence and adjustments of performance results. For instance, the 3-month mortality rate for the cohort increased almost 1% in the span of 1 month. We observed a slow widening of the PPV difference between model and oncologists as death information was updated.This blinded study evaluated the performance of the model and clinicians separately. To estimate the impact of model predictions in clinical practice, we need to evaluate how clinicians prognosticate once given the model predictions. Even a perfect model would have no benefit if it were not trusted by clinicians.58 Further evaluation is ongoing to study the performance of oncologists given model prognostications and whether use of the model improves prognostic confidence, patient engagement, and use of resources at the end of life.In this prognostic study, we noted that an ML model trained with EHR data outperformed clinicians in predicting 3-month mortality for a cohort of patients with metastatic solid tumors, with a 95% CI of 18.5%-31.9% for the difference in PPVs at 30% sensitivity. The model was trained on a relatively small population (n = 28 484) and yet achieved an 81.2% AUROC on the cohort. This finding could encourage other centers to develop custom models based on internally available patient data. This study was a step to validate the model before integration in the EHR of our organization.


Regular participation in resistance exercise is known to have broad-ranging health benefits and for this reason is prominent in the current physical activity guidelines. Recovery after such exercise is important for several populations across the age range and nutritional strategies to enhance recovery and modulate post-exercise physiological processes are widely studied, yet effective strategies remain elusive. Vitamin K2 supplementation has emerged as a potential candidate, and the aim of the current study, therefore, is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults.The current study is a two-arm randomised controlled trial which will be conducted in 80 (40 young (≤40 years) and 40 older (≥65 years)) adults to compare post-exercise recovery in those supplemented with vitamin K2 or placebo for a 12-week period. The primary outcome is muscle strength with secondary outcomes including pain-free range of motion, functional abilities, surface electromyography (sEMG) and markers of inflammation and oxidative stress.Ethical approval has been granted by the College of Medical Veterinary and Life Sciences Ethical Committee at the University of Glasgow (Project No 200190189) and recruitment is ongoing. Study findings will be disseminated through a presentation at scientific conferences and in scientific journals.ClinicialTrials.gov NCT04676958. Prospectively registered on 21 December 2020. The order of the items has been modified to group similar items  and menaquinones (vitamin K2s). Vitamin K was discovered by the Danish biochemist Henrik Dam in the 1930s, and he demonstrated that the product was involved in coagulation. Dam received the Nobel Prize in 1943 for his work on vitamin K. The vitamin K2s or menaquinones (MK-[n]) were discovered in the 1960s, of which MK-4 and MK-7 are the most studied. Vitamin K1 is regarded as the major dietary source of vitamin K, found in green vegetables such as broccoli, cabbage and spinach. Vitamin K2 is found in low quantities in cheese, egg yolk, meat and curd. The richest natural food source of vitamin K2 is the traditional Japanese natto made by fermented soybeans, providing a good source of MK-7. Natto is a popular food in Japan but is not highly appreciated elsewhere due to the taste. The MK-4 is registered as a drug in Japan for the treatment of osteoporosis. In Europe, two forms of vitamin K exist today in food supplements: vitamin K1 and vitamin K2 as MK-7.One nutritional supplement which may be effective but which has very little research is vitamin K2. Although there has been little exercise and vitamin K2 work, there is evidence that vitamin K2 has important roles in redox balance and also in mediating inflammation. Vitamin K is an essential cofactor for gamma carboxylation of glutamic acid residues in many vitamin K-dependent proteins (VKDPs), required for the effective function of a range of proteins  includinThe main aim of the current study, therefore, is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults.Our primary aim is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults.The current study is a two-arm randomised controlled trial comparing placebo with vitamin K2 supplementation. Eligible participants will be identified from local advertisements. Baseline data will be measured prior to randomisation, and follow-up data will be collected 12 weeks after randomisation adjusted for any delays in the start of the intervention post-randomisation.There was no patient and public input in the design of the study protocol.This is a single-centre, University of Glasgow, two-arm randomised controlled trial.Potential participants will receive a mailed prestudy invitation which will provide details on study information and details around eligibility. If still interested, potential participants will be invited to the research site where eligibility will be determined based on the inclusion and exclusion criteria Table .Table 1IWritten consent will be obtained by a member of the study team during a visit to the research site for the baseline assessment, with no study procedures taking place until consent has been obtained. At the baseline visit, a member of the study team will confirm eligibility.Not applicable.The comparator chosen is a placebo capsule without the active ingredient.Participants in the control group will consume one 380-mg micro-crystalline cellulose tablet per day.Participants in the vitamin K2 will consume a 380-mg micro-crystalline cellulose tablet containing 240 μg vitamin K2 (MK-7) (K2VITAL® 0.2% DELTA powder) per day.In accordance with the Declaration of Helsinki, participants can withdraw from the trial at any time for any reason. Furthermore, the investigator can withdraw a participant from the trial at any time if a withdrawal is considered in their best interest. Participants who have stopped the intervention prior to completion will be asked to follow study visits according to the protocol. Participants who choose to withdraw from the trial will be asked the reason why. However, it is emphasised that they are not obliged to state the reason.Participants will be sent a text message every 2 weeks to check how they are getting on taking their supplements and to serve as a reminder to do so.Participants will be asked to maintain their usual physical activity and nutritional habits throughout the trial. Usual healthcare will also be maintained.There are no specific provisions for post-trial care within this study, other than access to usual healthcare.Baseline characteristics will be collected—age, sex, blood pressure, weight, height, BMI, habitual diet, habitual physical activity levels, current medications and comorbidities.All outcome measures will be assessed at baseline and 12 weeks in all participants. Where the post-exercise recovery of outcomes is detailed, these will be measured fasted at baseline (pre-exercise) after which an exercise bout will take place. The exercise will involve bilateral leg extension exercises at 70% of one-repetition maximum (1RM), with 5 sets of 15 repetitions performed. Each repetition will be performed for 4–2s in the concentric and 2s in the eccentric phase. If necessary, the concentric phase can be assisted. Following this, the same protocol will be performed for the bench press. A standardised snack will then be consumed. Further measurements will be made at 3h, 24h, 48h and 72h post-exercise.The primary outcome measure is the overall change in post-exercise recovery of knee extensor muscle maximal isometric torque from baseline to 12 weeks as shown in growth curve models.Pain-free range of motionTime to complete 5 chair risesKnee extensor surface electromyography (sEMG)Systemic markers of inflammation (e.g. interleukin-6 and interleukin-1β)Systemic markers of oxidative stress (e.g. peroxiredoxin 3 redox state and F2-isoprostanes)Secondary outcome measures are the change post-exercise recovery from baseline to 12 weeks of:Vitamin K levelsCarboxylated osteocalcinUncarboxylated osteocalcinCarboxylate/uncarboxylated osteocalcinCarboxylated matrix gla-proteinDephosphorylated-uncarboxylated matrix gla-proteinAnd resting levels of:Lean and fat mass Blood glucoseBlood lipidsPlasma insulinVastus lateralis muscle thicknessSubstrate utilisation (carbohydrate and fat oxidation) during submaximal exerciseExploratory outcome measures are the change from baseline to 12 weeks of:The schedule of enrolment, interventions and assessments is shown in Fig. We have based our sample size on being able to (within age groups) detect a physiologically relevant difference in muscle strength of 10% with an SD of 10%, based on data from within our laboratory, with a power of 80% and alpha level of 0.05. This would require a sample size of 17 in each group and so we will aim to recruit 20 participants to each group (within age groups) to account for dropout.Glasgow Evening Times and via social media such as Twitter and FacebookUsing advertisements via multiple media outlets that include local newspapers such as the Flyers will also be distributed, and posters placed in local public places such as supermarkets, clubs, churches, bowling centres and community centresVia local organisations, such as University clubs and local older adult groupsOlder and young people will be recruited using various strategies.sealedenvelope.com) randomisation sequence with randomly permuted blocks. Randomisation will be stratified by age group  and by sex. The randomisation sequence will be generated by an independent statistician.Following the baseline assessment, patients will be randomised to the control or vitamin K2 groups (1:1 ratio) using a computer-generated  who will be blinded to the group assignment. Participants’ characteristics will be described using mean and standard deviation  for continuous variables and frequency tables for categorical variables. The primary analysis would be based on multilevel growth curve models including baseline and all post-exercise recovery period measurements. The time variable will be modelled as a penalised spline if a nonlinear association between time and outcome was found. The group × time interaction would be the primary variable of interest, indicating overall differences between the recovery process. Additionally, for each of the outcomes and time points, two-sample No interim analysis is planned in the current study.Subgroup analysis will be conducted for sex and age group (younger vs. older) and interactions between these subgroups and treatment groups will be tested.Adherence to supplements will be determined by capsule count following the completion of the intervention period. Non-adherence will be handled through the use of intention-to-treat analysis in the primary analysis, and we will also add an additional instrumental variable analysis to examine effect sizes if the participant is fully compliant with supplementation . MissingThe data sets analysed and the codes used for these analyses will be available from the corresponding author on reasonable request.Design and conduct of the trialPreparation of protocol and revisionPreparation of study materials and case report formsOrganise steering committee meetingsPublication of study reportsAgreement of the final protocolAll lead investigators will be membersRecruitment of patients and liaising with principal investigatorsReviewing the progress of the study and if needed agreeing to changes to the protocolStudy planningAdverse event reportingResponsible for trial master fileBudget controlData verificationNot applicable.There are unlikely to be major safety issues with our nutritional supplement interventions. However, if any safety concerns or incidents arise, we will follow our standard operating procedures for reporting adverse events in a non-Clinical Trial of an Investigational Medicinal Product (non-CTIMP) study.Formal audits will occur every 6 months.Any amendments to the protocol will be approved by the local ethics committee prior to implementation. All investigators and patients enrolled in the trial will be informed.The study findings will be disseminated primarily via conference presentations and scientific papers.The current trial is a single-centre, two-arm randomised controlled trial. It has been designed to test the effect of vitamin K2 supplementation on recovery after a bout of resistance exercise. We will also investigate the effects on the inflammatory and oxidative processes after resistance exercise. Such information will be of importance to adults, young and old, who are interested in modulating these processes and the speed at which they recover after a single session of resistance exercise—a form of exercise recommended in the current physical activity recommendations.The study began recruitment in May 2021 and will be ongoing until August 2022 (anticipated). Current protocol: version 1 (03.06.2020).


Satisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity.RILUSCI is a phase 1b–2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI.In this multicenter double-blind trial, adults (aged 18–65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period.To the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI.NCT02859792.The clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number Assistance Publique–Hôpitaux de Marseille. Spasticity, one of the most disabling motor impairments, has several pathological causes  –3 and afThe most fruitful basis for the discovery of a new drug is to start with an old drug”. In line with this statement, we must be able to identify new therapeutic opportunities for treating spasticity based on previously existing approved drugs.When spasticity becomes troublesome, the therapeutic options available include various pharmacological and non-pharmacological approaches , 11, 12.“plateau potential” [+ current (INaP) is largely expressed in the spinal locomotor network [INaP, leading to muscle spasms and hyperreflexia in both humans and adult rats [2+-activated proteases recruited after SCI, typically cleave both sodium (Nav) channels, increasing INaP, and KCC2, disinhibiting motoneurons [INaP might be suitable therapeutic targets for reducing spasticity after SCI. Interestingly, we have established that low concentrations of riluzole specifically and potently block INaP, and we have provided strong preclinical evidence in favor of the application of this drug to chronic SCI subjects [Maladaptive mechanisms promoting a generalized spinal hyperexcitability take place after SCI, and typical signs of spasticity then appear –19. Impatential” , 25. Thetential” , 24, 26. network –32 and p network . SCI uprult rats –39. In ault rats –42. We roneurons . We havesubjects , 38. Morsubjects . In addisubjects –46. The The primary objectives of the trial will be to define the minimal effective dose of riluzole for treating spasticity, and to assess how effective it is as a means of reducing spasticity. The secondary objectives will be to examine the possible dose/effect relationship and to determine the safety and the pharmacokinetic profile of riluzole, as well as its impact on muscle spasms, pain, health-related quality of life and the mobility of SCI participants.Fig 1. Fig 2 is a flowchart of the participants in the study based on the CONSORT guidelines [RILUSCI is an adaptive phase 1b–2b trial conducted on spastic patients with chronic SCI in order to determine the potential benefits of administering riluzole as compared with placebo. The protocol has been designed in keeping with the SPIRIT and CONSORT statements  of riluzole recorded in 75% of the patients tested. The phase 1 trial will be conducted at the Physical Medicine and Rehabilitation departments of Marseille’s public hospital group.Phase 2b will be a parallel placebo-controlled multicentre randomised double-blind trial designed to compare the effects of a BID per os treatment with riluzole (daily dose to be defined during Phase 1b) versus placebo in participants with chronic SCI. Double-blind conditions will apply to both participants and investigators. The phase 2b trial will be conducted at 7 hospitals all over France. The participating centres include the Physical Medicine and Rehabilitation departments of Marseille’s public hopitals and the Valmante University Institute of Rehabilitation in Marseille (UGECAM), the University Hospitals of Limoges, Montpellier, Nantes, the Propara Rehabilitation centre in Montpellier, and the Saint Martin Rehabilitation Centre in Marseille.Participants will be screened and recruited among outpatients consulting for SCI at the various centres participating in the trial during a period of 36 months. Patients’ associations will be contacted by the OrphanDev network (FCRIN) and patients referred by these associations will benefit from a phone interview to check the main inclusion/non-inclusion criteria before being referred to the nearest investigation centre. Participants must meet the following inclusion criteria at the time of the screening visit:◦ Lasting for at least 12 months◦ Level C4-T12◦ Complete or incomplete SCI ◦ With spasticity  or be stable for at least 30 days before the screening visit (phase 2b) and must remain stable throughout the protocol.The intake of all other medications, including painkillers, must have been stable for at least 30 days prior to the screening visit.The number of rehabilitation sessions and the methods used should not vary during the 15 days prior to the screening visit.Participants must give their prior informed written consent to the procedure used in the trial.The exclusion criteria include:Occurrence of spinal cord injury less than 12 months previously,Any associated brain lesion liable to be the cause of spasticity,MAS≤1 or = 5 in at least adductor muscles and/or sural triceps muscles or NRS < 4Presence of urinary infection, fever, pressure ulcer or other spasticity-aggravating factors.Presence of other significant neurological or mental disorder or other illness liable to prevent accurate evaluation,Recent history (less than 1 year) of chemical substance dependency or any significant psychosocial disturbance,Insufficient fluency in the local language for the patient to be able complete neuropsychological, global and spasticity assessments.Active liver disease or clinically proven jaundiceActive malignancy or history of invasive malignancy within the last five yearsClinically significant neutropenia in the investigator’s opinion, Liver enzymes (ALT/SGPT or AST/SGOT) twice the upper normal limit at screening visit, Baseline elevations in several liver function tests  which are clinically significant in the investigator’s opinion.AIDS or AIDS-related complex,The systolic blood pressure measurements > 190 or < 85 mm Hg and/or the diastolic blood pressure measurements > 105 or < 50 mm Hg at screening.An abnormal ECG at screening judged by the site investigator to be clinically significant.Treatment with any investigational drugs or devices less than 60 days before screeningAny myorelaxant medication including intrathecal baclofen taken by the subject during the last 14 days prior to screening (step 1)Patient’s condition not stable under intrathecal baclofen or per os myorelaxant medication for at least 30 days prior to screening (step 2)Patient’s condition not stable under any other chronic medication, including analgesics, for ≥ 30 days prior to screening.Injection of BTX-A into striated muscle less than 3 months previously (apart from BTX-A injection into the detrusor)Subject is currently using, and will continue to use for the next 14 days, any of the following medications, which are classified as Inhibitors of CYP 1A2  or inducers of CYP 1A2 (rifampicin and omeprazole)Ongoing pregnancy and women with childbearing potential not using any form of efficacious contraception during the study and 3 months after the end of the study.Ongoing lactation and during the 3 months after the end of the study.Known hypersensitivity to riluzoleAfter checking the inclusion and exclusion criteria, each participant will receive extensive information about the treatment tested, the assessment procedures, the objectives and risks associated with the trial. Prior to the start of medication in the study, participants’ informed consent must be obtained in writing by the investigator. Subjects will be free to withdraw from the study at any time without having to give any explanations or being penalized in any way.In phase 1b, we will use an adaptive Bayesian design in order to minimize the number of subjects to be included. Because of the characteristics of the continuous reassessment method with Bayesian inferences, the inclusion of 30 subjects has been found to suffice for studies of this kind , 50. StoFig 1 will be the same in both 2 phases of the study. Subjects will participate for up to 5 weeks. The first 2 weeks will constitute the screening period, starting on the day the subject signs the Informed Consent Form. At the end of the screening period, participants will be randomized (1:1) to either the riluzole or the placebo groupsfor a 2-week period of treatment. Block randomisation stratified per center will be performed. A 1-week post-treatment period will ensue. It is planned to carry out three follow up visits on each participant: on day 3 after the beginning of treatment, at the end of the 2-week period of treatment, and one week after withdrawal of the medication. Details of the assessments and interventions occurring at each visit are presented in Fig 1.The timeline of the trial summarized in At the screening visit, experimental drugs prepared by the coordinating pharmacy will be distributed to the investigating pharmacy at each study site. For phase 1b, riluzole oral suspension (5 mg/ml) will be prepared in 300 ml vial + syringe. For phase 2b, riluzole oral suspension will be diluted in Orablend SF* with a view to administering the same volume (20 ml) of oral suspension to each group. The investigating pharmacy will prepare clinically indiscernible galenic forms of riluzole and placebo. After being prescribed by the investigator, the treatments will be dispensed to patients at the second visit. All the documents required for drug traceability will be completed by the investigating pharmacist. The pharmacist will report the name of the drug, the dosage and the specific number of allocated drugs dispensed to each patient.In phase 1b, four doses of riluzole will be tested: 25 mg BID, 50 mg BID; 75 mg BID, and 100 mg BID. The four dosage levels were chosen based on previous studies on amyotrophic lateral sclerosis and acute SCI patients treated with riluzole in the standard regimen . The staDuring phase 2b, the minimal effective dose defined in phase 1b will be administered to the patients. The CIC-EC 1426/FCRIN PARTNERS platform will inform the pharmacist  about the treatment to be prepared and delivered to each participant. Patients included in the treatment group will take riluzole orally, BID, for 2 weeks at the established ME dose. The same administration schedule will be applied to the placebo patients. Each investigator, participant and pharmacist will be blinded about the identity of the participants in the intervention.In phase 1 and 2, two 5-ml blood samples for the riluzole PK study and baclofen observance will be consistently collected prior to riluzole intake and 2 h postdose in order to determine the trough and peak concentrations, respectively, on days 0, 3 and 14 after the initial dose . If possible, samples will be sent on the same day to the laboratory in charge of the pharmacokinetic tests. If this is not possible, all the samples will be frozen and stored at -20°C after the pre-analytic process.All the drugs currently used to treat chronic SCI participants will be recorded, specifying: the name, dose, regimen, dates of start and end of intake. In step 1, participants will need to stop oral myorelaxant medication 14 days prior to screening and during the study. In this step 2, oral myorelaxant medication of participants should be stable for at least 30 days prior screening. Other treatments, including analgesics should be stable for ≥ 30 days prior to screening. Due to the risk of drug interactions, any drugs that interfere with CYP1A2 will be withdrawn at least 5 half-lives before the patients’ inclusion.The primary outcome will be the efficacy of riluzole as a means of reducing spasticity. The description of this main outome will be binary (success or failure). Success has been defined as follows: “Improvement of the Modified Ashworth Scale (MAS) score by more than 1 point, or improvement of the 0–10 Numerical Rating Scale (NRS) spasticity score by more than 20% between Week 0 and Week 2”.The MAS is the most commonly used clinical method of measurement for assessing spasticity . This scThe 0–10 NRS score (0 = “no spasticity” to 10 = “wo8rst possible spasticity”) is a participant-reported outcome measure designed to reflect participants’ perception of their spasticity. This score has been previously used on SCI participants and has been validated for Multiple Sclerosis spasticity assessment purposes . The 20%These two scales assessed by either the participant (NRS) or the clinician (MAS) will allow us to have a clearer picture and a greater sensitivity to the changes in spasticity before versus after the treatment period.Secondary outcomes will include neurological, functional, and pain outcomes such as:Penn Spasms Frequency Scale: This is a self-reported perception of patients’ spasticity based on frequency ratings (from 0 = no spasms to 4 = spasms occurring more than ten times per hour) and severity ratings (1 = mild to 3 = severe) of their spontaneous muscle spasms. This tool is widely used to complement clinical assessments of spasticity and provide a more comprehensive understanding of an individual’s spasticity status .Participant Global Impression of Change: This scale is a 7-point categorical scale rated by the participant from 1 (very much improved) to 7 (very much worse). Participants are asked to assess the overall change in their condition since joining the study.Visual Analog Pain Scale: This scale is an 11-point continuous scale rated by participants from 0 (no pain) to 10 (worst possible pain).Neuropathic Pain Symptom Inventory: This questionnaire can be used by clinicians to classify various types of neuropathic pain and assess the changes induced by pharmacological treatment. This scale includes: 10 descriptors of various symptoms and 2 items quantifying the duration of spontaneous ongoing and paroxysmal pain. A total intensity score can be calculated as the sum of the scores obtained on the 10 descriptors .DN4 questionnaire: This questionnaire can be used by clinicians to discriminate between nociceptive and neuropathic pain. This scale has been validated with a high level diagnostic accuracy for use on individuals with SCI . A scoreInternational Spinal Cord Injury Basic Pain Data Set: This questionnaire contains a minimal amount of clinically relevant information about pain that can be collected in the everyday practice of healthcare professionals’ with experience of SCI. This questionnaire applies to all the effects of pain  rating from zero (no interference) to six (extremely strong interference), specifying the number of pain-related problems and a description of the worst 3 .Spinal Cord Injury Independence Measure: This measure addresses three specific types of functional problems in participants with SCI, including an assessment of self-care problems , respiratory and sphincter management, and the participant’s mobility levels (getting in and out of bed and going indoors/outdoors) . The parPersonal therapeutic objectives: Personal objectives will be determined at baseline  by the clinician along with the participant.Electrophysiology: A nerve conduction study and an Electromyography (EMG) will be performed using standard techniques. The tibial nerve will be stimulated at the ankle and popliteal fossa, and compound muscle action potentials (M-Wave) will be recorded over the abductor hallucis. Measurements include negative peak duration, baseline-to-peak amplitude, mean F-wave amplitude and soleus H reflex. The maximal H-reflex and M-wave responses can be used to compare maximum H-reflex amplitude and maximum M-wave amplitude (Hmax/Mmax) ratios between subjects under different recording conditions. Surface EMG will be performed at experienced centers only. Subjects will be seated in an adjustable chair with their test foot securely strapped to an instrumented footplate attached to a mechanical fixture. Surface electrodes will be attached to the skin above the muscle in order to measure the activity in the right and left tibialis anterior and soleus muscles. The EMG signal will be amplified and filtered . Electrophysiology examinations will be performed before drug intake and 2h post dose on Day 1 and Day 14.Riluzole pharmacokinetics (PK): Riluzole concentration in plasma is quantified by performing a high performance liquid chromatography assay with U.V. detection, adapted from Chow et al. , after aSafety and tolerability: to be assessed by the occurrence of Adverse Events (AE). All suspected unexpected serious AE are to be notified immediately to the sponsor.haematology , biochemistry , serologies  and urinalysis . All analyses will be performed by a local laboratory.Laboratory safety parameters: Participants will undergo laboratory screening analysis including Bladder diary: The participants will record in a diary the frequency of urinary probing and urinary leakages during 1 day during the 3 days preceding visit 2 (randomization) and during the 3 days preceding visit 4 (end of treatment).Results of previous studies on patients with amyotrophic lateral sclerosis have shown that the overall tolerability of riluzole is good  and thatIf any cases arise in which the spasticity worsens under treatment, the investigator will search for an intercurrent condition that is likely to explain this aggravation, including: infection, lithiasis, fecaloma, bedsores, etc. In the case of patients undergoing intrathecal baclofen infusions (phase 2b), the investigator will first check the pump. These conditions have first to be treated. In cases where no specific condition has been identified or the spasticity does not improve after treatment of the intercurrent condition, the administration of the experimental drug will be stopped.Unblinding procedures: the need to unblind participants to their status can arise in the following cases:To make decisions about a patient’s clinical treatment or when an unexpected serious AE occurs and the intervention must be made known. If required, the investigator may apply to the sponsor for unblinding, with the coordinator’s approval,At the request of the Data Safety Monitoring Board,During an unmasked analysis in keeping with the study analysis plan.Only the FCRIN platform and the clinical trial’s pharmacy team at the Timone hospital will be unblinded and will handle the unblinding procedures.In this trial, relevant data, AE, and safety assessments will be documented in both paper and electronic versions of the case report forms. Each participant has a unique numeric identifier. Data will be recorded and managed using a dedicated web-based software REDCap (Research Electronic Data Capture) with secured and restricted access. No personal data will be recorded in the case report forms apart from the unique numeric identifier. Access to the complete final trial dataset will be restricted to the clinical research unit’s statistician, who will analyse the study data for the purpose of reporting and publication of the results.The Data safety monitoring board, with no interests in either the drug tested or research on this drug, will be set up by the sponsor and entrusted with the mission of following up the security data. The Data safety monitoring board will also have an advisory function on points of security such as the tolerance and the reassessment of the benefit-to-risk ratio during the research process. This committee will also be responsible for making sure of the conformity of the protocol with current standards. The DSMB will meet at the end of Step 1. In the event of any anomaly, this committee will meet again as appropriate.Bayesian analysis will be performed by the CIC-EC 1426/FCRIN PARTNERS platform. Secondary analysis and safety analysis will be performed by the CIC-CPCET. Quantitative variables will be expressed as medians (quartiles) or means (standard deviations), depending on whether or not there is a Gaussian distribution. Qualitative variables will be expressed as numbers (percentages). Inter-group comparisons will be conducted using parametric or non-parametric tests, depending on the nature and the distributions of the variables. Unless otherwise specified, statistical significance is defined here as p<0.05. Baseline value will be the last value recorded before randomization. In phase 1b, all participants with whom the primary endpoint has been reached will be analysed with a view to applying the continuous reassessment method. In phase 2b, the probability of a response being associated with the minimum effective dose will be estimated using a Bayesian approach according to a beta-binomial model. Statistical analyses will be performed sequentially per participant at the end of the 2-week assessment period.https://clinicaltrials.gov (n° NCT02859792). The trial will be conducted in keeping with the Helsinki Declaration [This study has received the approval of the local ethical committee  and the authorization of the National Agency for Medicines and Health Products in France on July 10, 2017, as registered in the French National Clinical Portal laration . The replaration . The CONRecent developments have started in the US, focusing on the acute phase of SCI on the basis of the potential neuroprotective activity of riluzole. A phase 1b has been completed (NCT00876889) and a phase 2b/3 double-blinded randomized controlled trial is already in progress (NCT01597518/ RISCIS) . The phaThe most unique aspect of the present RILUSCI trial in comparison with other registered trials is the fact that it involves the administration of riluzole to patients in the chronic phase of SCI. This is also the first time that the chronic administration of riluzole will be studied in patients suffering from spasticity. By acting on voltage-dependent sodium channels, riluzole decreases the persistent sodium current which, in the absence of presynaptic inhibition, favours neuronal hyperexcitability and therefore spasticity after SCI. The main advantage of riluzole is that it is already authorised and marketed in France for the treatment of amyotrophic lateral sclerosis  and cereS1 File(PDF)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOC)Click here for additional data file.S4 File(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.S2 Checklist(DOC)Click here for additional data file.


Spinal bracing is a proven effective treatment for children with adolescent idiopathic scoliosis (AIS). Four factors have been reported to affect brace treatment outcome including (1) growth or curve-based risk, (2) the in-brace correction, (3) the brace wear quantity, and (4) the brace wear quality. The in-brace correction is impacted by spinal flexibility. The quality of brace design also affects the in-brace correction and comfort which indirectly affects the brace wear quantity and quality. A traditional polypropylene spinal brace is bulky and uncomfortable, and its manufacturing process is labor intensive. As 3D printing technology becomes more common and advanced, there is a potential to manufacture spinal braces using 3D printing technology. The objectives of this paper were to report the immediate effectiveness and benefits in using 3D printed brace to treat children with AIS. Six children with AIS , who were new to brace treatment, were recruited. Spinal flexibility and pressure pad locations were acquired using ultrasound assisted method to ensure braces were designed properly. To manufacture the braces, all participants were scanned by a handheld 3D scanner to obtain their body shapes. The 3D braces were then printed with Nylon 12 material. The average in-brace Cobb angle correction was 10 ± 4° (41 ± 18% correction). The 3D brace was 33% thinner, 26% lighter, 37% lower cost and required 3.7 h less labor time to manufacture when compared with the standard polypropylene brace. As a conclusion, the 3D printed brace had good immediate treatment effectiveness, but the long-time effect is still required time to explore. Adolescent Idiopathic Scoliosis (AIS) is a three-dimensional 3D) spinal disorder with a lateral curvature and axial vertebral rotation (AVR) . It affeD spinal A conventional spinal brace is a rigid thermoplastic jacket with multiple foam pads added inside the inner surface to provide directed mechanical loads on the torso to counteract the spinal curvatures. The manual design process can be cumbersome, labor intensive and costly, and requires applying wet plaster wraps on the patient torso to obtain a negative body mold. The body mold is then scanned by a 3D handheld scanner. A 3D torso file is then generated and can be sent to a carver machine to create a positive foam mold. A polypropylene sheet is then thermo-vacuum formed on the foam mold to create the brace shape. Custom trimming the brace edges and adding brace accessories are required before fitting the brace to patient. With the advancement of 3D scanning and printing technologies, a computer-aided design/computer-aided manufacturing (CAD/CAM) system can capture the torso contour using a 3D handheld scanner directly. The scanned torso file is then modified and sent to a 3D printer for manufacturing a brace. Pilot studies had been conducted in developing 3D printed scoliosis braces –13, 15 aAmong many 3D printing methods, fused deposition modeling (FDM) method is the most suitable approach. Furthermore, there are many materials which are suitable and compatible with the traditional polypropylene brace material. Ng et al.  recommenParticipants who were (a) diagnosed with AIS, (b) age between 10 and 16 years old, (c) pre-menarchal or <1 year post-menarchal for female, and had (d) pre-brace largest Cobb angle between 20 and 45°, (e) Risser sign <3, and (f) prescribed with a full time (23 h) thoracic-lumbar-sacral orthosis (TLSO) were recruited from the local scoliosis clinic. Ethics approval was granted from the local health research ethics board, and all participants and their guardians signed the assents and parental consent forms prior to participation.To assess the spinal flexibility, two or three ultrasound (US) images were acquired from each participant. The US scans were acquired at standing, maximal prone left or/and right side bending. The direction of side bending depended on whether the subject had the left-side or right-side curve, bending to the opposite side of the curve. An experienced US operator performed all US scans during this study. All scans started from the vertebral level C7 and terminated at L5 with both levels were marked before scanning. During scanning, the US probe was positioned perpendicular to the participants' back and moved along the path of the curve. For standing position, subjects were asked to stand in a standard upright posture. In maximal side bending, participants were instructed to bend their upper body as much as they could to the left or right side without moving their pelvis. The spinal flexibility index, bending relative to standing index (BRSI), was calculated using Equation (1):More flexible curves have higher BRSI values. A BSRI >1.0 implies overcorrection.Before designing the brace, the pre-brace x-ray and the standing US spinal image were displayed side-by-side to assist the orthotist to decide on pressure pad locations. Participants were asked to don a gown with the back opened and stood inside a custom 3D brace design frame. The orthotist used the design frame to secure bolsters with subjectively determined applied pressure levels against the patient's torso to simulate in-brace correction. After determining the optimal pad location and pressure level, participants were asked to put on a stocking shirt and stand at the same position. A 3D Spectra scanner  was used to capture the 3D torso as shown in All participants returned to the scoliosis clinics ~6 weeks after they started using their braces. In-brace radiographs were taken at the first follow-up visit using an EOS radiography system . The in-brace Cobb angle was measured by an experienced rater who had over 20 years of experience.N) brace and a polypropylene (mpp) brace was calculated using Equation (2):Brace production time  was recorded. Mass ratio between the Nylon12 printed (m3), t is the thickness of plastic sheet (m), H is the height of plastic sheet (m), and L is the length of plastic sheet (m). Both traditional and 3D braces were estimated based on a rectangular volume of a polypropylene sheet.where m is mass, ρ is density  and technician costs (CAD $50/h). Equipment cost included the foam mold carver and the 3D printer.Six participants, 5 females and 1 male, age ranged between 11.4 and 14.9 years, were recruited. All 3D printed braces were well-manufactured and none of the participants were required to use the traditional backup braces. In current practice, a skilled and an experienced orthotist can design high quality of spinal braces. During designing a brace, it is necessary to compromise between the comfort and treatment outcomes. The comfort level is influenced by how aggressively the orthotist designs the brace. On the other hand, the prediction of the treatment outcome is usually based on the immediate in-brace correction. Without an objective evaluation of spinal flexibility, clinicians aim to achieve 40–50% in-brace Cobb correction –20. If tIn term of manufacturing process, the total 3D brace labor time was 3.7 h shorter than the polypropylene brace. Although the actual manufacturing time of the 3D brace was 8.5 times longer, most of the time was the machine and post-processing time (96%) rather than labor time. Machine and post-processing could be done overnight and outside of normal work hours. The reduced labor time not only lower health care cost, but also reduced labor effort which allowed clinicians to provide more time for direct patient contact. The 3D printed brace was 33% thinner and 26% lighter. A thinner and lighter brace will be less noticeable, dissipate heat better, and may thus improve brace wear compliance.Comparing the materials and methods of manufacturing with other studies, Redaelli et al.  used theTwo of the participants were randomly selected and asked to compare the 3D printed brace and the traditional brace. Both wore their prepared traditional brace for a day. Having experience to try both types of braces, both participants preferred the 3D printed braces. They both reported that the 3D printed brace was more comfort to wear because of being thinner and lighter.The limitation of this study is the number of participants is small, and the long-term effectiveness is unknown. It also requires an experienced ultrasound technician during the brace casting to acquire and analyze the data. To overcome this, an automatic ultrasound machine which can scan the back automatically is being considered for future improvements. Also, the custom software developed for the ultrasound imaging measurement needs to be enhanced so that 3D information and automatic measurements can be obtained without requiring significant operator experience.The 3D printed brace was as effective as the traditional polypropylene brace. The immediate in-brace correction was achieved to the target goal level. The 3D printed brace was 33% thinner, 26% lighter, 37% lower in cost, and required 3.7 h less labor time to manufacture than a standard brace.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Health Research Ethics Board of the University of Alberta. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.EL: made substantial contributions to the conception and design of the work, interpretation of data, drafted the work and revised it critically for important intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. KN: made substantial contributions to the conception and design of the work, data acquisition, data analysis, interpretation of data, drafted the work, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DH: made substantial contributions to the conception and design of the work, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.This work was supported by the Women and Children's Health Research Institute and Natural Sciences and Engineering Research Council of Canada.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Research on face recognition with masked faces has been increasingly important due to the prolonged COVID-19 pandemic. To make face recognition practical and robust, a large amount of face image data should be acquired for training purposes. However, it is difficult to obtain masked face images for each human subject. To cope with this difficulty, this paper proposes a simple yet practical method to synthesize a realistic masked face for an unseen face image. For this, a cascade of two convolutional auto-encoders (CAEs) has been designed. The former CAE generates a pose-alike face wearing a mask pattern, which is expected to fit the input face in terms of pose view. The output of the former CAE is readily fed into the secondary CAE for extracting a segmentation map that localizes the mask region on the face. Using the segmentation map, the mask pattern can be successfully fused with the input face by means of simple image processing techniques. The proposed method relies on face appearance reconstruction without any facial landmark detection or localization techniques. Extensive experiments with the GTAV Face database and Labeled Faces in the Wild (LFW) database show that the two complementary generators could rapidly and accurately produce synthetic faces even for challenging input faces . Face recognition (FR) is one of the most important problems in computer vision area as it has a wide range of real-world applications. Conventional FR functions are generally performed with primary facial features such as eyes, nose, and mouth, assuming non-occluded faces . HoweverMFR methods often need large datasets with masked face images to make full use of the learning capability of deep learning technologies. To address this issue, the authors in  have conA two-stage generative model based on cascading two convolutional auto-encoders (CAEs)  is introWith the appearance-based approach described above, the proposed generative model can be practically used for constructing large datasets of masked face images. As demonstrated in experiments, the proposed method is able to process low resolution faces of 25 × 25 pixels with acceptable synthesis results without high loss in recognition rate refer to . AdditioTo cope with the aforementioned limitations, this paper proposes a compact and practical method to synthesize masked face. The main contributions of this paper are twofold:The rest of this paper is organized as follows. The proposed method aims to transfer an unmasked face image (input) to a masked face image (output). Specifically, for a given unmasked face image, a masked face image is generated by overlaying a fake mask pattern on the corresponding face. The proposed method contains two sequential stages, each of which utilizes a CAE. Auto-encoder is a method specialized in unsupervised learning, consisting of an encoder and a decoder. The encoder learns to translate the input into an internal representation. The decoder learns to convert the internal representation into the same form as the input. The best-known neural network for image modeling is CNN which enables to effectively retain the structural information connected between pixels of an image. For this reason, CNN has been successfully applied to an auto-encoder where CNN is deployed in both the encoder and decoder. In the stage of mask region extraction, the secondary CAE takes the output of the masked pattern generation and predicts a segmentation map which localizes the mask region on the face. As illustrated in This section describes in detail the mask pattern generation which is the former stage of the proposed generative model. The CAE used in this stage is called mask pattern generator (denoted by i-th unmasked face (source domain) and Lp is defined as follows:i-th target masked face i-th pose-alike faces denoted by In order to learn led SNOW  is used led SNOW . Figure database . Varioused error  which coAs shown in j-th masked face Lr for learning To learn BA is bitwise and operation used for image masking and ⨁ is image sum operation. Because each segmentation map This section presents extensive experiments for the proposed method using Labeled Faces in the Wild (LFW) database  and GTAVGr, Adam  was used(1)The proposed method was able to generate similar mask synthesis results for the three different facial resolutions of an input face image. This demonstrated that the proposed method was robust to variation in facial resolution.(2)The generated mask pattern fitted accurately the faces with moderate out-of-plane rotations in pitch or yaw. This was because the generator refer to  by utili(3)Thanks to the reconstruction ability of the appearance-based method, the proposed model was able to generate the masked faces even for the faces occluded by a hand see c.This section aimed to investigate the effectiveness of the proposed method under different pose views and resolutions of input faces. GTAV Face database was used in this experiment. The training set consisted of 903 images  from 22 (out of 44) subjects, and the testing set consisted of 397 unmasked face images from the remaining 22 subjects. Seven different pose views were considered: (1) −45~60 degrees; (2) −15~30 degrees; (3) frontal; (4) +15~30 degrees; (5) +45~60 degrees (6) down; and (7) up. For the case of facial resolution, three different pixel sizes were used: (1) 80 × 80; (2) 40 × 40; and (3) 25 × 25. Furthermore, 80 × 80 pixel images were downsampled to obtain 40 × 40 and pixel images. From the results of the masked face synthesis illustrated in The goal of this experiment was to investigate that the encoded pose vector in This section aimed to quantitatively verify that the proposed generative model was robust against variation in facial resolution. For this, the FR accuracies (in recognition rate) were measured for the three different facial resolutions present in The recognition rates for the three facial resolutions were illustrated in To further investigate the effect of using different facial resolutions of masked face synthesis on recognition rate, the masked face images generated from the unmasked face images of 80 × 80 pixels were resized to 25 × 25 pixels and their recognition rate was measured. The recognition rate was 73.54% which was very similar with the result (73.80%) for the masked face images generated from the unmasked face images of 25 × 25 pixels see . These rIn this section, the effectiveness of the proposed method was investigated using another dataset called LFW. LFW was a database of face photographs designed for studying the problem of unconstrained face recognition, which contained real-world face images of faces collected from the web. LFW database was much more challenging than GTAV Face database due to the uncontrolled conditions of the face acquisition. To consolidate training data, in addition to the original training set consisting of 903 images, 397 faces  with masked faces has been becoming increasingly important due to the prolonged COVID-19 pandemic . The pro(1)The generative model was very compact and easy to implement. The two generator networks did not require complicated network settings .(2)As demonstrated in qualitative and quantitative experiments, the generative model could be robust against moderate out-of-plane rotation (up to ± 60 degrees) and resolution variation present in face images .(3)The generative model had very low computational cost for both training and inference. Because it took only 0.28 s to process 397 face images, the model could rapidly generate synthesized masked faces with real-time processing. Furthermore, due to the compact network architecture, the generative model could be easily extended to other mask patterns by simply retraining the generator networks.The proposed method could be practically used for the following reasons:Due to the efficiency of the proposed method, it could also be useful for research of video-based face recognition ,27,28. F