To support older adults’ preferences to age in place, home and community-based aging-related resources are available, but are often under-utilized. Many barriers prevent individuals from accessing aging-related resources, especially in rural and geographically isolated locations. Therefore, we set out to better understand the perspectives of community members who plan to age in place in rural areas. We administered a survey as part of a broader university-community partnership called Senior Access Points (SAP), which addresses aging-related resource access. Participants were N = 210 individuals living in rural regions across Northern Colorado, ranging from 37 to 94 years old . We assessed hopes and worries about growing older at home, and awareness of available resources. Two independent coders applied a pre-determined coding scheme, then achieved consensus ratings. An overwhelming majority of participants affirmed the importance of being able to remain in their current home (94.8%) or community (95.3%) as they age. Top hopes for aging in place centered around health/medical; housing/home services; and independent rural lifestyle. The top worries were related to health/medical; housing/home services, and transportation. Resource awareness was low: 43.3% of all participants were not aware of any available resources. Overwhelmingly, rural residents hope to grow older at home, but may not know how to connect to resources that support this goal. The resource needs we identified are being used to inform community-driven approaches to improve both awareness and availability of community resources in these rural communities.


Escherichia coli(E. coli) and Salmonella enterica subsp.enterica  were potential antimicrobial-resistantbacteria. In cases of occurrences of human infectious diseases due to the bacteria in foodsderived from livestock, these resistant bacteria could be responsible for reduction or loss ofthe antibiotic treatment efficacy. FSCJ thus conducted a risk assessment of E.coli and Salmonella as identified hazards. FSCJ judged to be low onthe occurrence probability and extent of selection of drug-resistant E. coliand Salmonella, due to the use of colistin sulfate in cattle and pigs, unlessotherwise the use of colistin increases. The chance and extent of human exposure to theresistant bacteria were evaluated low via livestock products including pigs and cattle, as longas proper cooking practice is implemented. The degree of possible reduction or loss of clinicaleffectiveness against E. coli and Salmonella was evaluated asmoderate. The overall estimation of the risk regarding reduction or loss of clinicaleffectiveness of antimicrobials in humans was low. It is necessary to keep up with the latestscientific findings and information.The Food Safety Commission of Japan (FSCJ) updated a risk assessment onantimicrobial-resistant bacteria arising from the use of a veterinary medicinal product,colistin sulfate, in cattle and pigs, according to the “Assessment Guideline for the Effect ofFood on Human Health Regarding Antimicrobial-Resistant Bacteria Selected by Antimicrobial Usein Food-producing Animals” . Both  The Food Safety Commission of Japan (FSCJ) updated a risk assessment onantimicrobial-resistant bacteria arising from the use of a veterinary medicinal product,colistin sulfate, in cattle and pigs, according to the “Assessment Guideline for the Effect ofFood on Human Health Regarding Antimicrobial-Resistant Bacteria Selected by Antimicrobial Use inFood-producing Animals” .Escherichia coli (E. coli)was identified as a hazard1). Basedon the assessment, the Ministry of Agriculture, Forestry and Fisheries (MAFF) withdrew thedesignation of colistin as a feed additive, and placed restriction on its use for veterinarytherapeutics in 2018.In the first assessment (2017), E. coli. in the 1st edition, Salmonellaenterica subsp. enterica  is newly addedas a hazard in the 2nd edition. In fact,monitoring on E. coli and Salmonella derived from livestock,conducted from 2000 through 2017, has suggested the retention of colistin susceptibility inalmost all these bacteria. Some strains were found to contain mcr-1,mcr-3, and/or mcr-5 genes in these samples.In addition to Colistin sulfate is an antibiotic polypeptide that has been used in cattle, pigs and poultryin Japan since 1950s. Colistin’s use had been suspended clinically in humans due to thefrequent adverse effects such as renal dysfunctions, and its role has been covered newlydeveloped substitute antibiotics. In 2015, a formula of colistin methanesulfonate forinjections was re-approved owing to the situation where infections with multidrug-resistantgram-negative bacilli became clinical issues in recent years.E.coli strains harboring a gene (mcr-1) associated withcolistin-resistance on plasmids were reported in China. Up to now, colistin-resistant genefamilies of mcr-1 through 10 have been known within colistin-resistantfamilies. The susceptibilities of E. coli and Salmonellaagainst colistin remain high in Japan, based on the monitoring results of these bacteriaisolated from the livestock from 2000 through 2017. Some strains carrying themcr-1, mcr-3 and/or mcr-5 genes were,however, found among the isolates2).Mechanisms of two-component regulatory systems associated with chromosomal genes have beenknown to operate for colistin-resistance in gram-negative bacteria. In 2015, E. coli and Salmonella were potentialantimicrobial-resistant bacteria to be selected under the use of colistin sulfate in cattle andpigs. In cases of occurrences of human infectious diseases due to the bacteria in foods derivedfrom livestock, these resistant bacteria could be responsible for reduction or loss of theantibiotic treatment efficacy. FSCJ thus conducted a risk assessment of E.coli and Salmonella as identified hazards.Both E. coli and Salmonella is low, due to the use of colistin sulfate in cattle and pigs. The following points were discussed prior to obtaining the conclusion; 1)The prevalence of mcr-gene was 2.0% and below in E. coliderived from domestic healthy livestock and in Salmonella derived from thesick livestock in 2015, although mcr-gene would be transferred amongE. coli and between other bacteria belonging to enterobacteriaceae2), 2) fitness cost of bacteria withacquisition of plasmid harboring mcr-gene was confirmed, 3) the use ofcolistin was currently prohibited as a feed additive, and colistin was recognized as asecond-line drug in 2018, and 4) finally, the increased rates of colistin-resistance amongE. coli and Salmonella derived from livestock will be lowunless otherwise the use of colistin increases.FSCJ judged the probability of selection of drug-resistant E. coli and Salmonella are occasionally detected in meats.However, colistin-resistant strains were scarcely isolated from these products. Consideringproper cooking of the livestock products derived from cattle and pigs, the chance and extent ofhuman exposure to the resistant bacteria were evaluated low via livestock products.Enterobacteriaceae (CRE) infectioncaused by E. coli. Reports of multidrug-resistant gram-negative bacillusinfections such as those by CRE in human cases are limited at present in Japan.Carbapenem-resistant strain has not been found among E. coli derived fromdomestic livestock. Human exposure to both colistin- and carbapenem-resistant E.coli from domestic animals through foods is thus unlikely at present. WhileE. coli or Salmonella may transfer mcr-geneto other bacteria, multidrug-resistant (MDR) gram-negative bacillus such as CRE acquirecolistin-resistance through such mcr-gene transfer. As a result, othereffective antibiotics may be limited. Especially, in the case of MDR Pseudomonasaeruginosa (MDRP), impact on the treatment will be significant, because colistin isoften used to treat MDRP infectious disease in humans. However, transfer ofmcr-gene to MDRP was not determined in conjugal-transfer test usingmcr-gene harboring E. coli as a donor. Therefore, thepossibility that MDRP acquires colistin-resistance by transfer of mcr genefrom livestock derived colistin resistant E.coli orSalmonella is low at present. The influence on clinical effectiveness was evaluated as moderate. Clinical importance ofcolistin is high as it is a recommended drug against multidrug-resistant gram-negative bacillusinfections including carbapenem-resistant Salmonella-induced enteritis. The useof colistin is also not recommended for severe cases of systemic Salmonellainfection under the use of other antibiotics.Antibiotics are not used generally for Considering the hazard identification, the release assessment, the exposure assessment, andthe consequence assessment, the overall estimation of the risk was low. This assessment wasconducted on the premise of risk management measures taken by the MAFF in 2018. It is necessaryto keep up with the latest scientific findings and information.


There was no significant difference in the treatment strategies, angiographic characteristics and discharge therapy between the groups (p > 0.05). The female patients had significantly higher unadjusted rates of ischemic stroke , cardiac mortality  and MACCE ; female sex was a significant predictor of MACCE in the univariate analysis ; and the cumulative incidence of MACCE was higher in female patients (p = 0.014). After the adjustment, the predictive effect of female sex became non-significant , while there was no difference in the cumulative incidence of MACCE among the propensity score matched cohort (p = 0.177). Female NSTE-ACS patients have worse long-term outcomes compared to their male counterparts. However, the differences disappear after adjustment and propensity score matching. Continuing efforts and health measures are required to alleviate any sex-based differences in the NSTE-ACS population.Previous heterogenous studies show conflicting data about sex-based outcomes of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients. This study evaluated 300 NSTE-ACS patients undergoing a coronary angiography between September 2012 and May 2015 that were managed with all-treatment strategies. The sample was stratified by sex and analyzed for the baseline characteristics and outcomes. The main outcome included major adverse cardiovascular and cerebrovascular events (MACCE), which were a composite of cardiac death, nonfatal myocardial infarction, ischemic stroke or urgent coronary revascularization. The female patients were older (median of 69.0 vs. 63.0 years,  Non-ST-elevation acute coronary syndrome (NSTE-ACS) is one of the leading causes of cardiovascular morbidity and mortality ,2. As suInitial studies reported sex-related inequalities, with female NSTE-ACS patients having worse management and outcomes ,5,6,7. FTherefore, emerging multiple adjusted analyses report against a sex-related disparity among the NSTE-ACS population. Yet, the heterogeneity of studies, population diversity and somewhat conflicting data prevent us from drawing contemporary conclusions. Fluctuation in the follow-up duration, underutilization of coronary angiography and different management strategies are some of the rationales for additional studies. In addition, the lack of systematic risk stratification impairs the comparison of different studies . This haTherefore, this study enrolled NSTE-ACS patients who completely underwent invasive coronary angiography and were managed with all-treatment strategies (percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or conservative management). The aim of this study was to investigate sex-based differences in the characteristics and long-term outcomes of NSTE-ACS patients, while controlling for any potential confounding effects. Additionally, the aim of the study was to determine the prognostic strength of the GRACE risk score in different sex categories.This study was conducted in accordance with the ethical standards and amendments of the Declaration of Helsinki. All subjects were informed about the goal and course of this study. Written informed consent for coronary angiography and informed consent for the use of relevant medical data has been obtained from all participants. The Ethical Committee of the University Hospital of Split, Croatia (No. 2181-147-01/06) has approved the study protocol.This single center observational prospective study enrolled a total of 300 eligible NSTE-ACS patients who underwent a coronary angiography at the University Hospital of Split between September 2012 and May 2015. Patients with active malignant disease and a history of CABG were not considered eligible for the study. A total of 24 patients were lost in follow-up due to their refusal of a further follow-up or loss of adequate communication . All patStudy data were collected using the patient medical records, including electrocardiograms, laboratory reports, procedural data, and angiographic results during index hospitalization. Anthropometric data were collected according to the standard methods. All patients underwent an invasive coronary angiography, followed by the appropriate treatment, including PCI, CABG or conservative management. Treatment strategy was determined by at least 2 interventional cardiologists on a case-to-case basis with respect to the patient’s preferences. Patients with multivessel coronary artery disease or technically challenging lesions were presented to the Heart Team involving cardiac surgeons and interventional cardiologists. The radial approach for an invasive coronary angiography was used in most cases. Irrespective of the treatment strategy, all patients received pharmacological therapy with 12 months of dual antiplatelet therapy, according to the relevant guidelines.The main aim of the study was to evaluate the differences between sex categories in baseline characteristics and study outcomes. An additional aim was to determine the predictive strength of the GRACE score in each sex category. Primary outcome included major adverse cardiovascular and cerebrovascular events (MACCE), which were a composite of cardiac mortality, nonfatal acute myocardial infarction (AMI), ischemic stroke or urgent coronary revascularization. Secondary outcomes included cardiac mortality, nonfatal AMI, ischemic stroke and urgent coronary revascularization. Each outcome was carefully evaluated by a team of experienced cardiology specialists  before the inclusion. Cardiac mortality encompassed each death without sufficient evidence of another non-cardiac cause of death. Nonfatal AMI was defined as a recurrent AMI with or without ST-elevation, according to the relevant guidelines. Unstable angina was also only included among nonfatal AMI events if there was an angiographic confirmation of an unstable lesion and a subsequent revascularization. Urgent coronary revascularization was defined as an urgent intervention, percutaneous or surgical, due to highly symptomatic stable angina.t-test or Mann–Whitney U test were used for continuous data analysis according to parametric or non-parametric distribution, respectively. Categorical variables were expressed as numbers and percentages and analyzed using the chi-squared test. The cumulative incidence of MACCE was estimated using the Kaplan–Meier approach, and the significance was assessed using the Mantel–Cox log-rank test. Cox logistic regression analysis was performed to determine the predictors of MACCE in the multivariate model. The multivariable model included variables that were significantly different between the groups or were previously shown to potentially influence the outcomes . The results of the risk analyses are provided as hazard ratios (HRs) and 95% confidence intervals (95% CI) that corresponds to a 1-unit increase/decrease in each score on a continuous scale. The accuracy of the GRACE score MACCE prediction was determined for each sex category using the receiver operating characteristic (ROC) and area under the curve (AUC). Finally, a propensity score matching analysis was used to account for the confounding variables and control the selection bias. It has been conducted using a SPSS plug-in for R with a nearest-neighbor matching algorithm and a 1:1 ratio, while a caliper of 0.01 has been set to improve the matching criteria. A two-sided p-value of <0.05 was considered significant. Statistical data analysis was carried out using Statistical Package for the Social Sciences (SPSS) software .Statistical analysis was conducted according to standard statistical methods. The normality of data distribution was assessed using the Kolmogorov–Smirnov test. Continuous data were presented as mean ± standard deviation (SD) or as median . Student’s p = 0.008) and had lower values of BMI . When looking at the laboratory parameters, the female patients had lower values of Hgb  and eGFR . Importantly, there was no difference in the follow-up duration between the female and male patients . The other baseline characteristics are presented in A total of 300 patients were initially enrolled in the study protocol, while 276 completed the follow-up, including 71 female and 205 male patients. The female patients were older  and cardiac mortality  during the follow up, while there was no difference in the rates of nonfatal myocardial infarction and urgent coronary revascularization. Importantly, MACCE occurred significantly more often in the female group   .p = 0.014) (p = 0.083)  A. Howeve= 0.083) B.p = 0.014)  .p = 0.177)  .p = 0.372 vs. 0.604, 95% CI 0.502–0,705, p = 0.042, respectively)  .The equality in the management and outcomes of NSTE-ACS patients has been aspired, and numerous studies have been conducted to reveal any sex-related disparities. However, due to population and study heterogeneity, the existing literature is still conflicting and lacks all-supporting data ,16. ThisThe main findings of this study could be summarized. Firstly, the female patients were mostly older. Secondly, when evaluating the unadjusted rates, the female patients had a higher number of ischemic strokes, cardiac mortality and MACCE with significant discrepancy in the event-free survival curves. However, in the propensity score matched cohort, female patients did not have a statistically higher incidence of MACCE. Similarly, female sex was not a significant independent predictor of worse outcomes per se. Finally, the predictive strength of the GRACE score in female patients was inferior compared to in the male population.Consistent with previous studies, the present analysis revealed that female NSTE-ACS patients are generally more prone to adverse outcomes. However, most previous studies had retrospective designs, potentially leading to selection bias and inaccurate data capture . SeveralInterestingly, Kumbhani et al. reported similar sex-based mortality in a PCI-treated NSTE-ACS cohort, but a significantly higher long-term mortality in younger and troponin-negative female patients ,11. HoweWhen looking at the short-term outcomes, data from the J-PCI registry show that a PCI-treated female Japanese NSTE-ACS cohort had a higher rate of bleeding and other complications, but there was no statistically significant difference in the adjusted rates of in-hospital mortality . SimilarA recent meta-analysis of Thrombolysis In Myocardial Infarction (TIMI) trials reported a higher comorbidity burden and a lower utilization of evidence-based treatment in female NSTE-ACS patients, but also a lower adjusted all-cause mortality among female patients. The mean follow-up in the included trials was ~23 months, which is similar (yet shorter) to the present study . AnotherThe preferred access site for invasive management is important as it has been shown that female patients particularly benefit from the radial approach, even after accounting for the smaller vessel diameter . One shoIt is important to highlight several limitations of this study. While there was no difference in discharge therapy, the study coordinators did not record the patients’ adherence to the therapy during the follow-up. However, each of the specialists involved in the follow-up and treatment of these patients was dedicated to titrate and guide therapy, according to the relevant guidelines. Furthermore, this is a single center study that comprised a relatively small sample size and detected a low incidence of events, which could have affected the statistical analyses and prevented additional sub-analyses. As with other studies, the composite outcome in this study was not standardized, which impedes the study comparison. Finally, the study mostly encompassed low-to-medium risk NSTE-ACS patients without previous CAB; therefore, care should be taken before applying these results to a high-risk NSTE-ACS population with prior cardiac surgery. Similarly, the results are not applicable to patients with active malignancy, as they were excluded. Even though the treatment strategy was based on the Heart Team’s decision, a sex-related selection bias could not be fully eliminated. In conclusion, this study showed that female NSTE-ACS patients undergoing all-treatment strategies have significantly worse long-term outcomes. However, the observed disparities are dependent on the differences in baseline characteristics including age, BMI and kidney function. Future studies and global healthcare initiatives are encouraged to improve and equalize the care of the heterogenous NSTE-ACS population.


Background: Microthrombosis and large-vessel thrombosis are the main triggers of COVID-19 worsening. The optimal anticoagulant regimen in COVID-19 patients hospitalized in medical wards remains unknown.Objectives: To evaluate the effects of intermediate-dose vs. standard-dose prophylactic anticoagulation (AC) among patients with COVID-19 hospitalized in medical wards.Methods and results: We used a large French multicentric retrospective study enrolling 2,878 COVID-19 patients hospitalized in medical wards. After exclusion of patients who had an AC treatment before hospitalization, we generated a propensity-score-matched cohort of patients who were treated with intermediate-dose or standard-dose prophylactic AC between February 26 and April 20, 2020 . The primary outcome of the study was in-hospital mortality; this occurred in 23 of 261 (8.8%) patients in the intermediate-dose group and 74 of 783 (9.4%) patients in the standard-dose prophylactic AC group (p = 0.85); while time to death was also the same in both the treatment groups . We did not observe any difference regarding venous and arterial thrombotic events between the intermediate dose and standard dose, respectively . The 30-day Kaplan–Meier curves for in-hospital mortality demonstrate no statistically significant difference in in-hospital mortality (HR: 0.99 (0.63–1.60); p = 0.99). Moreover, we found that no particular subgroup was associated with a significant reduction in in-hospital mortality.Conclusion: Among COVID-19 patients hospitalized in medical wards, intermediate-dose prophylactic AC compared with standard-dose prophylactic AC did not result in a significant difference in in-hospital mortality. In situ microthrombosis has emerged as a key feature of COVID-19, in contrast to an embolus, commonly observed in deep vein thrombosis. Microthrombosis in COVID-19 has been observed in all postmortem lung examinations and could be explained, at least in part, by the large von Willebrand factor (VWF) released following endothelial activation  caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a systemic acquired vascular disease associated with inflammation –8. In sitivation . More sotivation  and the tivation . Therapetivation , intermeData will be made available from the authors on reasonable request.From February 26 to April 20, 2020, consecutive patients with a diagnosis of SARS-CoV-2 infection and initially hospitalized in medical wards were included (none of the patients were directly admitted to ICU). Patients were aged over 18 years and were included in a retrospective, multicenter (24 centers), observational cohort study, which was named the critical COVID-19 France (CCF) study, which initiated by the French Society of Cardiology. Following World Health Organization (WHO) criteria, SARS-CoV-2 infection was determined by a positive result from a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test of nasal or pharyngeal swabs, or lower respiratory tract aspirates (confirmed case), or by typical imaging characteristics on chest computed tomography (CT) when laboratory testing was inconclusive. The CCF study was declared to and authorized by the French data protection committee (authorization no. 2207326v0), and conducted in accordance with the ethical standards established in the Declaration of Helsinki and its later amendments (NCT04344327) , 15.via the REDCap® software  hosted by a secured server from the French Institute of Health and Medical Research at the Paris Cardiovascular Research Center. Baseline information of the patient included demographic characteristics, coexisting medical conditions, cardiovascular comorbidities, and chronic medications. Clinical parameters and biological findings were recorded at admission. On the chest CT scan, the degree of pulmonary lesions with ground-glass opacities and areas of consolidation were categorized as low/moderate (<50% involvement) or severe (≥50% involvement). Data on pharmacological therapies, mode of respiratory support, complications, and final vital status were also gathered throughout the hospitalization. Patients who had an AC treatment (whatever the regimen) before hospitalization were excluded from the analysis.All data were retrospectively collected by local investigators in an electronic case-report form The AC regimens analyzed during hospitalization were categorized into two groups: standard-dose prophylactic  or intermediate-dose prophylactic . The exact dosing of AC was not reported in the database and was reported according to the treating clinician. During the study period, the dose of the AC regimen was based on the International Society on Thrombosis and Haemostasis  and the n (%). Patients were compared according to the AC regimen during hospitalization (intermediate-dose or standard-dose prophylactic AC). In the multivariable analysis, we used conditional logistic regression to assess the association between the AC regimen and outcomes. The interactions between the AC regimen and specific subgroups were assessed via the Cochran–Mantel–Haenszel X2 test. For the survival analysis, the start of the study was triggered by the diagnosis of SARS-CoV-2 infection and hospitalization in a medical ward. The end of the study was defined either by the death of the patient during the hospitalization or by discharge alive from the hospital. We used the Cox proportional hazard (PH) model to investigate the relationships between AC regimen and outcomes. Missing data were handled using multiple random forest imputations using chained equations (10 sets of imputations). All analyses were two-sided and a p < 0.05 was considered statistically significant. Statistical analysis was performed using R studio® software including R version 3.6.3 .To address confounding and other sources of bias arising from the use of observational data, we estimated a propensity-matched analysis for the likelihood of treatment with intermediate-dose prophylactic AC. We estimated the propensity score by running a logistic regression model where the outcome variable is a binary variable indicating treatment status (intermediate-dose or standard-dose prophylactic anticoagulation), including as covariates the following: age, sex, body mass index, high blood pressure, diabetes mellitus, dyslipidemia, current smoking status, and history of cancer. Then a 1:3 match was performed using Greedy matching techniques. All analyses were performed on matched populations. We used standardized mean difference (SMD), which is the most commonly used statistic to examine the balance of covariate distribution between the two groups (intermediate-dose or standard-dose prophylactic anticoagulation). Continuous data were expressed as median  and categorical data as During the study period, 2,878 consecutive patients were hospitalized for SARS-CoV-2 infection in medical wards and were included, as previously described , 15. We p = 0.85); while time to death was also the same in both treatment groups . Moreover, the 30-day Kaplan–Meier curves for in-hospital mortality, shown in p = 0.99). Furthermore, we did not observe any difference regarding venous and arterial thrombotic events between intermediate dose and standard dose . We finally performed a subgroup analysis and found that no particular subgroups were identified in which the use of any AC regimen was associated with a significant reduction in the primary outcome , the authors reported the absence of efficacy, and an increase in the frequency of the bleeding event was demonstrated . SimilarEven though AC has been shown to prevent macrothrombotic complications , 24, intWe acknowledge some limitations in the present study. Despite efforts to control confounders by using different analytical strategies such as propensity score matching, some potential biases may have been disregarded such as the number of major bleeding events and the timing of AC therapy initiation after admission. All efforts were made to adjust the analyses for relevant variables, including cardio-vascular comorbidities, patient characteristics, and severity clinical features. We acknowledge that patients who received intermediate prophylactic dose had significantly more extensive lung damages, rates of endotracheal intubation, rates of high-flow nasal cannula use, and higher levels of CRP when compared with patients in the standard prophylactic group. Thus, it seems that intermediate prophylactic dose was started in more severe COVID-19 patients in medical wards. Moreover, in these patients, the higher prophylactic regimen of AC did not improve the outcomes.All in all, our results highlight the futility of intermediate-dose prophylactic AC, for modification of in-hospital mortality, compared with standard-dose prophylactic AC, in patients admitted to medical wards. Our results confirm data recently published in critical patients with COVID-19. In the future, AC and its different regimens may be tested in ambulatory patients in a multicenter, randomized, controlled, open-label trial, stratified on the timing of the disease more than disease severity in already hospitalized patients.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 French Data Protection Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.DS and RC designed the present study and wrote the manuscript. RC performed statistical analyses. AC and GB designed the trial. All authors reviewed the paper and have substantially contributed to the paper.DS, NG, OS, AC, and RC acknowledge the following without any relation with the current manuscript. DS received consultant, lecture fees, or travel awards from Aspen, Bayer, Carmat, Alliance BMS-Pfizer, LEO-Pharma, and Boehringer-Ingelheim. NG discloses consulting fees by Boehringer-Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, and LEO-Pharma. OS received grants, personal fees, or nonfinancial support from Bayer, Alliance BMS-Pfizer, Sanofi Aventis, Daiichi Sankyo, MSD, Boston Scientifics, and Chiesi. AC received a research grant from RESICARD (research nurses) and consultant and lecture fees from Amgen, AstraZeneca, Bayer Pharma, Alliance BMS-Pfizer, Novartis, and Sanofi-Aventis. RC received Consultant fees from Aspen. The remaining 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.


During the last decades, neurofeedback training for emotional self-regulation has received significant attention from scientific and clinical communities. Most studies have investigated emotions using functional magnetic resonance imaging (fMRI), including the real-time application in neurofeedback training. However, the electroencephalogram (EEG) is a more suitable tool for therapeutic application. Our study aims at establishing a method to classify discrete complex emotions  elicited through a near-immersive scenario that can be later used for EEG-neurofeedback. EEG-based affective computing studies have mainly focused on emotion classification based on dimensions, commonly using passive elicitation through single-modality stimuli. Here, we integrated both passive and active elicitation methods. We recorded electrophysiological data during emotion-evoking trials, combining emotional self-induction with a multimodal virtual environment. We extracted correlational and time-frequency features, including frontal-alpha asymmetry (FAA), using Complex Morlet Wavelet convolution. Thinking about future real-time applications, we performed within-subject classification using 1-s windows as samples and we applied trial-specific cross-validation. We opted for a traditional machine-learning classifier with low computational complexity and sufficient validation in online settings, the Support Vector Machine. Results of individual-based cross-validation using the whole feature sets showed considerable between-subject variability. The individual accuracies ranged from 59.2 to 92.9% using time-frequency/FAA and 62.4 to 92.4% using correlational features. We found that features of the temporal, occipital, and left-frontal channels were the most discriminative between the two emotions. Our results show that the suggested pipeline is suitable for individual-based classification of discrete emotions, paving the way for future personalized EEG-neurofeedback training. Vann. A decade later, there is still much to discover about the neurophysiology of complex emotions, which, according to some, represent a combination of basic emotions  scenario with audio input to elicit complex emotions. Music has been proven to be an effective stimulus in evoking genuine feelings in the laboratory setting Scherer, . MoreoveTo date, research in emotion classification using EEG signals mostly focused on distinguishing emotion based on psychological models Russell, , primariRecently, a growing body of research investigated emotion-recognition with deep learning algorithms. Particularly convolutional neural networks showed promising results, outperforming traditional ML models in distinguishing emotional states , which is characterized by high generalization properties, low computational capacity, and sufficient validation in real-time application. We extracted both FAA and time-frequency, together with correlational features across the whole scalp. We tested the model's performance and generalization properties by applying a trial-specific cross-validation procedure. Furthermore, we applied a feature-ranking algorithm to reduce our dataset's dimensionality and to investigate which channels and frequency bands were the most discriminative between the two emotional states. We hypothesized that tenderness and anguish have different electrophysiological correlates, not reducible just to the FAA and that they can be distinguished using an ML approach. Finally, we calculated Spearman's correlation coefficient between subjective ratings and subject-specific classification accuracy to understand whether the SVM performance was associated with the self-evaluation of the emotional intensity, the mantras' utility, the fatigue, and concentration levels that subjects felt throughout the experimental blocks.We recruited 14 healthy adults or young adults  with no history of psychiatric disorder or neurological illness for this proof of concept experiment. Before analysis, we discarded EEG recordings from three participants  due to the presence of excessive artifacts. The average age of the 11 remaining participants was 27 years (SD = 7), ranging from 19 to 46. All participants had normal or corrected-to-normal vision and had Brazilian nationality, except one German participant who fluently spoke Portuguese.We implemented a multimodal stimulation with a virtual scenario, an edited version of the Unity 3D asset Autumnal Nature Pack, accompanied by emotion-specific musical excerpts. The virtual environment displayed the first-person view over a landscape of hills and cornfields, differently colored according to the emotion elicited: purple for anguish and orange for tenderness .http://www.audacityteam.org). For all tenderness trials, we played a piece of soft, harmonic, and gentle music. In contrast, we electronically manipulated the anguish trials; unpleasant stimuli from the originally pleasant tunes used for the tenderness condition. We used four new sound-files, in which the actual melodic excerpts were simultaneously played with two pitch-shifted versions of the same excerpts. The pitch-shifted versions were one tone above and a tritone below the original pitch (samples of the stimuli are provided at http://www.stefan-koelsch.de/Music_Emotion1), resulting in dissonant and distorted music. For the neutral condition, the landscape was typically colored, and no background music was presented.Together with these visual stimuli, participants listened to eight different instrumental musical excerpts of 46 s. Music excerpts were fixed for each trial type  and normalized with the root mean square feature on the software Audacity , the Beck's Depression Inventory (BDI), and The Positive and Negative Affect Schedule (PANAS). After the EEG cap setup, we instructed participants to use mantras and personally recalled memories to facilitate emotional self-induction during the experiment. As guidance, we provided a list of suggested mantras , but theAt the end of each emotional block, participants had to fill a short self-assessment questionnaire in which they had to rate on a 5-point Likert scale: (i) the emotional intensity (from 1 = very mild to 5 = highly intense), (ii) the utility of mantras (from 1 = not useful to 5 = very useful), (iii) the concentration and (iv) the fatigue levels (from 1 = very low to 5 = very high) they felt throughout the experimental block.EEG data were recorded using the Brain Vision Recorder software. The signal was acquired from the BrainAmp amplifier and the standard 64 channels EEG-MR Plus cap  at a sampling rate of 1,000 Hz and a bandwidth of 0.01–250 Hz. All the electrodes had sintered Ag/AgCl sensors placed according to the standardized international 10/20 EEG placement system, and their impedance was kept under seven kΩ. We used one of the 64 channels to record the ECG signal, and we set channel FCz as the reference electrode and channel AFz as the ground. We programmed the entire processing pipeline on Matlab .We performed the offline analysis of EEG data using the EEGLAB toolbox  is a complex-valued sine wave tapered by a Gaussian window described by the following equation:et−2/2s2 is the real-valued Gaussian and ei2πft is the result of the Euler's formula combined with a sine wave . Within each window and for all the 63 channels and the seven frequency bands, the features extracted were the mean power, the standard deviation of the mean, and the frontal alpha asymmetry (FAA). The FAA coefficients were calculated for the channel pairs Fp1-Fp2 and F3-F4 in both low-alpha (8–10 Hz) and high-alpha (10–12 Hz) bands. The resulting feature array consisted of 2,912 samples for both classes  with a total of 886 features.After CMW, we extracted each channel's amplitude information for each frequency component in the range of 1-45 Hz. We then applied the sliding-window approach again. Within each of the 91 windows and for each of the seven frequency bands aforementioned, we calculated the Spearman correlation coefficient of the 63*63 channels matrix. This time-frequency correlational analysis allows characterizing both the time-varying and frequency-varying properties of non-stationary signals such as electrophysiological signals. To eliminate redundant information and reduce the feature array's size, we only selected all the coefficients in the upper triangle of the correlational matrices. The resulting high-dimensional feature array consisted of 13,671 features (pairwise channel correlation coefficients for each frequency band) and 2,912 windows as samples for both emotional classes.We used the MATLAB R2019b Statistics and Machine Learning Toolbox for classification and visualization of the data. We opted for a linear Support Vector Machine (SVM) algorithm for high-dimensional data for binary classification of the feature arrays. SVMs are supervised learning algorithms that define a hyperplane as a decision boundary, such that the margin of separation between two classes is maximized. Herewith, SVMs provide a measure that allows scaling the certainty to which a window sample is assigned to one of the two classes: the sample's distance from the separating hyperplane. Regarding future applications in NFB, SVM allows for scaling the feedback  and, thus, more precise response to emotional intensity changes.We applied 8-fold cross-validation to train and validate the classifier. Therefore, we assigned all windows of one trial to the same fold. Thinking about possible future applications in NFB studies, we chose this method to estimate event-specific markers' impact on classification accuracy. As the model will be trained before the NFB session, we aimed at testing its performance on an entirely unknown set of trials. The four trials' windows  were thus kept as test sets, while the classifier was trained with the remaining 28 trials. We iterated the 8-fold cross-validation ten times and averaged across classification runs.To visualize the datasets and understand the variability in performance across participants, we used t-Distributed Statistic Neighbour Embedding (t-SNE) . Finally, we computed Spearman's correlation coefficients between participants' self-assessment questionnaire and SVM accuracy to assess whether there was a relationship between subjective ratings and differences in performance.First, we investigated through ML whether the two complex emotional states could be accurately differentiated in a subject-wise manner using time-frequency/FAA and correlational features extracted within 1 s windows. To ensure that classification performance did not depend on the high feature-to-sample ratio, we performed a feature-ranking procedure and we repeated classification with a drastically reduced number of features. Furthermore, we aimed at comprehending the inter-subject variability by visually inspecting the data distribution of individual subjects by using the t-SNE method. Then, we investigated the common highest-ranked features across subjects to shed light on the spatial and spectral properties that allowed discriminating between tenderness and anguish. Finally, we explored whether subjective emotional experience  showed any association with subject-dependent classification performance.p-values.The results of all cross-validation runs for each participant are presented in p < 0.0001). These results show that it is possible to discriminate between anguish and tenderness within-participants, despite the presence of a high inter-subject variability across both feature sets.For the whole feature array extracted with the time-frequency/FAA analysis, we reported accuracies ranging from 59.2% up to 92.9%  when applying cross-validation .Then, due to the high-dimensionality of both feature sets, we performed a feature-ranking procedure and we repeated the 8-fold cross-validation with the selected subsets of 100 features. The subset of selected features significantly improved the model's predictive power for time-frequency/FAA features  when comparing channels Fp1/Fp2, AF3/AF4, AF7/AF8, F1/F2, F3/F4, F5/F6, and F7/F8. In p > 0.05).We assessed emotional intensity, the usefulness of mantras, fatigue, and concentration levels at the end of each block. An overview of subjective ratings is presented in Our study demonstrated the feasibility of using EEG and ML tools to distinguish complex emotional states using a near-immersive emotion-elicitation paradigm. We selected stimuli, such as VR with music, that potentially serve as BCI for NFB experiments. We showed that, despite low spatial resolution and the inability to infer activity in subcortical structures, EEG is a suitable tool for classifying discrete emotions, such as tenderness and anguish. We performed cross-validation using SVM and we reached moderate to high accuracy using time-frequency/FAA and correlational features calculated in short time-windows. Furthermore, we were interested in identifying the most relevant features for classification that were shared among participants. To do so, we performed a feature-selection procedure and we repeated cross-validation using a subset of 100 selected features. We found that the most discriminative features belonged to channels of the frontal left hemisphere, of the temporal, and the occipital lobes. The feature-selection procedure also highlighted the importance of high-beta and gamma bands to distinguish between anguish and tenderness trials. Finally, we calculated the Pearson correlation coefficient between subjective ratings  and classification performance across participants to investigate the relationship between the self-reported ratings and inter-subject variability in SVM performance. We reported no significant association between self-assessment measures and accuracy distributions.One crucial challenge of neuroimaging studies on affective processes has usually concerned participants' difficulty in engaging and sustaining valid emotional states in an experimental setting, especially when trying to elicit complex emotions. Here, the use of a multimodal realistic virtual environment (VR) may have eased and encouraged the participants' involvement in the experiment by providing an engaging setup, as proven by previous studies  is helpful for a broad range of mental health and neurological issues  may have influenced sensory processing and classification results. At the same time, using identical musical tracks for all subjects may have influenced participants' emotional elicitation differently due to variances in individual taste in music. For future work on emotion elicitation, choosing personalized musical tracks could improve individuals' induction of emotional states. Another interesting future perspective would be to evaluate whether the combination of visual and auditory stimuli is more efficacious in inducing the desired emotions than either one sensory modality alone. Moreover, the dominance of a sensory domain at evoking emotions could be investigated by exposing participants to either only visual or auditory or mismatched stimuli. Another limitation of our study, as already stressed above, is the high inter-subject variability we found in the two affective states' classification. Although we assessed emotional intensity at the end of each block, we do not have any fine-grained assessment of the duration of the emotional experience throughout the experiment. Since emotions, both at experiential and neurophysiological levels, cannot be reduced to constant patterns across individuals (Barrett et al., This proof of concept study showed that a multimodal near-immersive emotion-eliciting scenario is a feasible approach to evoke complex emotions, such as anguish and tenderness, in a laboratory setting. We proposed a pipeline that may be applicable for EEG-based BCI and NFB applications that require real-time data processing. Our findings indicate that the SVM classification of discrete emotions using EEG signals is achievable in a subject-wise manner, using short time-windows as in an online experimental setting. We identified features from the temporal, occipital, and left frontal sites as the most discriminative between the two emotions. Remarkably, we found a different involvement of left frontal and right frontal features, particularly in channel AF7 compared to channel AF8. The high-beta and gamma frequency bands appeared to have a substantial role in differentiating between anguish and tenderness. Together our results suggest that the EEG is a suitable tool for classifying discrete emotions, and that the proposed pipeline may be implemented in real-time to enable EEG-based NFB.The dataset analyzed and the codes used in this study are available upon reasonable request from the corresponding author.The studies involving human participants were reviewed and approved by D'Or Institute Ethics and Scientific Committee. The patients/participants provided their written informed consent to participate in this study.ED: methodology, formal analysis, data curation, writing—original, draft, review, and editing. MW: formal analysis, visualization, validation, writing—original, draft, review, and editing. BM: conceptualization, software, and investigation. CT-C: conceptualization, investigation, and supervision. TB: conceptualization, funding acquisition, and project administration. GD: methodology and supervision. JM: funding acquisition, resources, and supervision. All authors contributed to the article and approved the submitted version.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.


Ca-P coatings on Ti implants have demonstrated good osseointegration capability due to their similarity to bone mineral matter. Three databases  were searched electronically in February 2021 for preclinical studies in unmodified experimental animals, with at least four weeks of follow-up, measuring bone-to-implant contact (BIC). Although 107 studies were found in the initial search, only eight experimental preclinical studies were included. Adverse events were selected by two independent investigators. The risk of bias assessment of the selected studies was evaluated using the Cochrane Collaboration Tool. Finally, a meta-analysis of the results found no statistical significance between implants coated with Ca-P and implants with etched conventional surfaces . With the limitations of the present review, Ca-P-coated Ti surfaces have similar osseointegration performance to conventional etched surfaces. Future well-designed studies with large samples are required to confirm our findings. Titanium (Ti) is one of the most widely used materials for the manufacture of dental and orthopaedic implants due to its mechanical properties, chemical stability, and excellent biocompatibility . The quaThe osseointegration of implants has been defined as a direct and functional connection between the bone and the implant, where the macroscopic and microscopic characteristics of the implant surface are of great importance. Lack of osseointegration is often due to poor bone formation around the implant surface, leading to insufficient fixation of the implant .The deposition of calcium-phosphate (Ca-P) coatings on the implant surface has received significant attention due to the chemical similarity to natural bone mineral. Ca-P-based coatings show the ability to adhere directly to bone tissue and to increase the biochemical anchorage between bone and the coating material . Ca-P coCa-P, in the form of apatite, is the main mineral content ~69%) of natural bone . However% of natuUltrastructural observations have shown that Ca-P coatings partially dissolve, saturating body fluids in the peri-implant area and leading to a double precipitation of biological apatite, which could serve as a substrate for bone-forming cells, the only difficulty being matching the dissolution of the coating with the rate of healing to achieve ideal bone apposition on the titanium surface .Although previous reviews on this topic have been published, none of them compared in vivo, Ca-P-coated Ti surfaces with conventional etched surfaces . Therefore, the aim of the present systematic review and meta-analysis was to bring together preclinical studies in experimental animals to determine whether Ca-P-coated Ti implant surfaces possess increased osseointegration capability.This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .A search was carried out for any registered protocols on a similar topic in the International Prospective Register of Systematic Reviews (PROSPERO). No systematic review protocols were found in this database. Therefore, this review was pre-registered in the PROSPERO platform under the identification number CRD-REGISTER-2-ID255185.The Population, Intervention, Comparison, Outcome and Study Design framework (PICOS) was used as a basis to formulate the research question, which was: “Do Ca-P-coated Ti surfaces have a higher osseointegration capacity than etched Ti surfaces?”. (P) Population: animals receiving endosseous Ti implants. (I) Intervention: Ti implants with Ca-P incorporation. (C) Comparison: Ti implants with conventional surface. (O) Outcome: bone formation around the implant surface. (S) Study design: preclinical studies in unmodified experimental animals .-Preclinical studies in unmodified animals , using endosseous implants with Ca-P incorporation;-Studies with at least six animals and 4 weeks of follow-up;-Studies published in English.The inclusion criteria for the study selection were:-In vitro studies;-Narrative and systematic reviews;-Clinical cases;-Studies that did not meet the established inclusion criteria.The exclusion criteria for the study selection were:The following search strategy was used: Two independent researchers conducted electronic searches in the PubMed, Embase, and Web of Science (WoS) databases up to February 2021 with the Medical Subject Headings (MeSH) terms: “Titanium implants”, “biocompatible coated materials”, “osseointegration”, “calcium phosphate”, “animal model”. Boolean operators “AND” and “OR” were used to refine the search .Two independent reviewers  carried out the study selection by obtaining full text data from the selected articles, including general information, animal parameters , methods of Ca-P incorporation, timing of assessment, methods of analysis, conclusions, and implant parameters . After eliminating duplicates, studies were selected according to the inclusion criteria. Cohen’s kappa statistic was calculated to measure the level of agreement between the two reviewers. Disagreement on the eligibility of studies was resolved by discussion between the two reviewers.The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool, an adapted version of the Cochrane RoB tool with specific biases in animal studies), was used to assess the methodology of the scientific evidence in all selected studies .Animal Research: Reporting of In Vivo Experiments (ARRIVE)  guidelin2 value was > 50% [p < 0.05. A funnel plot was used to assess publication bias.Odds ratios (ORs) with 95% confidence intervals (CI) were used for adverse event outcomes. The mean difference (MD) and standard deviation (SD) for BIC were used to estimate effect size. The meta-analysis was performed using RevMan software . The random-effects model was selected because of the expected methodological heterogeneity in the included studies; furthermore, significant heterogeneity was interpreted when the Ias > 50% . The thrThe initial electronic search yielded 107 references. After eliminating duplicates and irrelevant articles based on their title and abstracts , 18 full texts were selected ,30,31,32Although item 2 was mentioned in several studies, the lack of information resulted in a high and unclear risk of bias for most of the included studies .The most commonly used animal model was rabbit ,16,17,202 = 99%)  ). FigureThe experimental studies show graphical signs of publication bias, as can be observed in the funnel plot .The purpose of the present study was to answer the following clinical question: “Do Ca-P-coated Ti surfaces have a higher osseointegration capacity than etched Ti surfaces?”. To quantify the potential effect of Ca-P-containing surfaces on peri-implant bone apposition, a meta-analysis of BIC was performed. Our meta-analysis found no statistical significance between implants coated with Ca-P and implants with conventional etched surfaces (SLA type).Certain thin Ca-P coatings have been shown to be amorphous and readily soluble in simulated body fluids , and sevHowever, many studies have shown that Ca-P coatings improve the biocompatibility and fixation of implants; for example, Vercaigne and colleagues reported that Ca-P coatings are much more effective in stimulating the bone reaction than microroughness of surfaces , emphasiResearch seeks to improve the biomechanics of bone tissue by designing implants with improved biocompatibility, osteoconductivity and osteoinductivity, leading to faster and improved bone healing and turnover ,45.After implantation, the implant surfaces come into contact with biological fluids and tissues, and there are two types of host response: either forming an intermediate fibrous layer that does not guarantee adequate biomechanical fixation or direct bone-to-implant contact, ensuring osseointegration . HoweverNumerous studies have shown that early fixation and long-term mechanical stability of fixtures are improved with rough profiles compared to smooth surfaces ,48; howeAfter implantation of Ca-P-coated fixtures, a layer of biological apatite is released on the implant surface that could serve as a matrix for adhesion and growth of osteogenic cells .The studies included in our meta-analysis used different coating processes: oxidation ,16, micrFinally, it should be added that we encountered some serious limitations related to this meta-analysis: firstly, the small number of studies included and therefore the limited number of implants studied; second, the high risk of bias of all studies; third, the substantial heterogeneity of the selected studies. This did not allow any solid conclusions to be drawn.Within the aforementioned limitations, it can be concluded that Ca-P-coated Ti surfaces have a similar osseointegration power to conventional etched surfaces (SLA or similar). However, in order to confirm our results, well-structured, well-conducted studies with larger samples and longer follow-ups are necessary.


Model inputs were derived from secondary research (peer-reviewed literature and Medicare data). We estimated the population-level diagnostic costs and clinical implications for each testing strategy. The testing strategy that resulted in the greatest project cost savings (including testing and first-line drug cost) compared to next-generation sequencing alone in newly-diagnosed metastatic colorectal cancer was using high-sensitivity artificial intelligence followed by confirmatory high-specificity polymerase chain reaction or immunohistochemistry panel for patients testing negative by artificial intelligence . The high-specificity artificial intelligence-only strategy resulted in the most favorable clinical impact, with 97% diagnostic accuracy in guiding genotype-directed treatment and average time to treatment initiation of less than one day. Artificial intelligence has the potential to reduce both time to treatment initiation and costs in the metastatic colorectal cancer setting without meaningfully sacrificing diagnostic accuracy. We expect the artificial intelligence value proposition to improve in coming years, with increasing diagnostic accuracy and decreasing costs of processing power. To extract maximal value from the technology, health systems should evaluate integrating diagnostic histopathologic artificial intelligence into institutional protocols, perhaps in place of other genotyping methodologies.Rising cancer care costs impose financial burdens on health systems. Applying artificial intelligence to diagnostic algorithms may reduce testing costs and avoid wasteful therapy-related expenditures. To evaluate the financial and clinical impact of incorporating artificial intelligence-based determination of mismatch repair/microsatellite instability status into the first-line metastatic colorectal carcinoma setting, we developed a deterministic model to compare eight testing strategies: A) next-generation sequencing alone, B) high-sensitivity polymerase chain reaction or immunohistochemistry panel alone, C) high-specificity panel alone, D) high-specificity artificial intelligence alone, E) high-sensitivity artificial intelligence followed by next generation sequencing, F) high-specificity artificial intelligence followed by next-generation sequencing, G) high-sensitivity artificial intelligence and high-sensitivity panel, and H) high-sensitivity artificial intelligence and high-specificity panel. We used a hypothetical, nationally representative, population-based sample of individuals receiving first-line treatment for  Oncologic diagnostic algorithms, specifically those involving next-generation sequencing (NGS), financially burden healthcare systems. Just as the advent of NGS was an advancement over polymerase chain reaction (PCR) and immunohistochemistry (IHC) for some applications, artificial intelligence (AI) may be the next innovative oncologic diagnostic agent. From routine histopathology images, AI can recapitulate genetic information with area under the receiver-operator curve (ROC) approaching 0.9 , 2. AI mKRAS, and BRAF status from histopathology , nearly 150,000 cases of colorectal cancer (CRC) are diagnosed annually . In the athology . In the de novo) mCRC population: NGS alone, high-sensitivity PCR or IHC panel (“panel” for short) alone, high-specificity panel alone, high-specificity AI alone, high-sensitivity AI with confirmatory NGS for patients testing negative by AI, high-specificity AI with confirmatory NGS for patients testing positive by AI, high-sensitivity AI with confirmatory high-sensitivity panel for patients testing positive by AI, and high-sensitivity AI with confirmatory high-specificity panel for patients testing positive by AI  for these platforms, as characteristics vary across studies , 9. Our We projected the high-sensitivity AI followed by high-specificity panel strategy to result in the lowest total testing and first-line drug therapy cost, $2.72 billion, compared to $3.13 billion for NGS alone, representing savings of $400 million (12.9%) Table 2.The high-specificity AI-only scenario was associated with the shortest time to treatment initiation (<1 day) (versus 12 days for NGS), with 100% of patients receiving results within the guideline-recommended ten working days (versus 0% for NGS). Compared with the NGS-only scenario, in which all 32,549 (100%) patients received KEYNOTE-177-supported therapy, 31,442 of 32,549 (97%) patients received KEYNOTE-177-supported therapy in the high-specificity AI-only scenario.We estimate that the accuracy of AI is similar to the accuracies of PCR and IHC in determining MSI/MMR status. For the high-sensitivity context , we estimate 98% sensitivity and 79% specificity for AI compared to 100% sensitivity and 81% specificity for PCR/IHC. In the high-specificity context , we estimate 70% sensitivity and 98% specificity for AI compared to 67% sensitivity and 93% specificity for PCR/IHC.The $400 million (12.9%) difference between the most and least expensive scenarios highlights that testing approach can significantly impact costs in the setting of first line mCRC. The least costly scenario, high-sensitivity AI with confirmatory high-specificity panel, comes with the tradeoff of 9% of patients  receiving a first-line therapy not supported by KEYNOTE-177 data (versus 0% with NGS-only). The second-least costly scenario, using high-specificity AI alone, results in only 3% of patients  receiving a non-supported therapy. It is our view that the ability to start therapy earlier due to elimination of treatment initiation delay  may compensate, to some degree, for any reduction in median progression-free survival (PFS) resulting from that 3%. Moreover, the Kaplan-Meier PFS curves from KEYNOTE-177 suggest that PFS for pembrolizumab and chemotherapies are similar for the first eight months of therapy. Only after this timepoint do the curves separate, disease tends to progress (PFS 8.2 months), and patients will likely switch therapy. We could draw the conclusion, then, that chemotherapy offers similar benefit to pembrolizumab in dMMR/MSI-H disease for several months. If we accept this premise, at least in part, then perhaps treating 1,107 patients with a non-KEYNOTE-177-supported therapy, and avoiding additional immunotherapy cost, becomes more reasonable. If we consider where else in the health system the $400 million in savings could be spent, the prospect becomes more palatable still.It is important to acknowledge that established tests are only as powerful as the biomarkers that they assess. While 43.8% of dMMR/MSI-H patients respond to pembrolizumab, health systems would benefit from diagnostic tools that could help avoid using costly immunotherapy in the dMMR/MSI-H patients who will not respond . With potential to consider tumor characteristics beyond genetics , AI could prove to be even more predictive than NGS. In other words, the promise of AI is not to be a cost-effective approximating of existing technologies, but rather an improvement upon them, both in terms of clinical utility and cost.It is important to recognize that applying artificial intelligence to digital histopathology is only one cog in a much broader wheel of strategies to curb healthcare spending. For example, screening for early detection of colorectal cancer is another vital component of a greater program to curb costs, as screening is estimated to be associated with $1.50 to $2.00 in returns for each dollar spent . Uptake The main limitation of our study was the use of a theoretical model, which will require real-world validation. The integrity of our estimates is dependent on the validity of the sources that we used to develop input assumptions. Although we aimed to use as few sources as possible to allow for some standardization among or assumptions, our assumptions are derived from a diverse range of sources. We aimed, too, to use data from high-quality, prospective clinical trials, where possible, but there were numerous cases in which the required data was only available in the form of retrospective analyses. Since the application of AI to histopathology diagnostics has not been widely used in clinical contexts, we do not yet have access to real-world cost and outcomes data. Our model did not consider important aspects like heterogeneity in the population and varying costs by setting and payer, instead assuming a monolithic U.S. healthcare system for demonstrative purposes. Each individual institution’s initial fixed costs associated with implementing digital histopathology are also outside of the scope of our study. These costs might include purchasing or renting hardware  and software  from digital histopathology vendors. On an ongoing basis, additional pathology personnel would likely be required to perform new tasks like internal validation, maintaining hardware and software, and scanning slides. However, multiple previous analyses have suggested that gains in efficiency and productivity associated with implementing digital histopathology more than pay for these upfront and ongoing costs , 18. TheWhile we used first-line therapy for mCRC as an example, we view these findings as relevant across cancers whose diagnostic algorithm involves genetic evaluation – with savings far beyond this sliver of total spending on cancer care. Not only would the initial investment in AI eventually pay for itself, but, because of the nature of the technology, AI improves as the platform “learns” from each sample. In this way, every dollar spent on AI is an investment in a better technology. This valuable characteristic of AI differentiates it and positions it as a vehicle for improving the quality and cost of cancer care.The original contributions presented in the study are included in the article/AK - Performed analysis and wrote manuscript. GS, LS, NL, and NC - Provided analytical advice and edited manuscript. JK - Formulated research question, designed analysis, supervised research, and edited manuscript. AP - Formulated research question, designed analysis, supervised research, edited manuscript, and provided resources and funding. All authors contributed to the article and approved the submitted version.JK is funded by the Max-Eder-Programme of the German Cancer Aid  and the START Programme of the Medical Faculty Aachen . AP is funded by NIH/NIDCR K08-DE026500 and NIH/NCI U01-CA243075, and has research funding from the Adenoid Cystic Carcinoma Research Foundation, Cancer Research Foundation, and University of Chicago Comprehensive Cancer Center. NL is funded by NIMHD R01MD013420 and NIDDK P30 DK092949.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The development of artificial intelligence and the Internet of things has motivated extensive research on self-powered flexible sensors. The conventional sensor must be powered by a battery device, while innovative self-powered sensors can provide power for the sensing device. Self-powered flexible sensors can have higher mobility, wider distribution, and even wireless operation, while solving the problem of the limited life of the battery so that it can be continuously operated and widely utilized. In recent years, the studies on piezoelectric nanogenerators (PENGs) and triboelectric nanogenerators (TENGs) have mainly concentrated on self-powered flexible sensors. Self-powered flexible sensors based on PENGs and TENGs have been reported as sensing devices in many application fields, such as human health monitoring, environmental monitoring, wearable devices, electronic skin, human–machine interfaces, robots, and intelligent transportation and cities. This review summarizes the development process of the sensor in terms of material design and structural optimization, as well as introduces its frontier applications in related fields. We also look forward to the development prospects and future of self-powered flexible sensors. Multifunctional flexible sensors have been widely used in human health detection, intelligent robots, and other fields in recent years because of their characteristics of high sensitivity, high resolution, and low cost . ScientiIn the context of global sustainable development, energy-storage devices with high performance ,13,14,15This paper summarizes self-powered flexible sensors based on TENGs and PENGs from two aspects: material and structure design. While summarizing their applications in electronic skin, human–machine interfaces, and robots, we also look forward to the direction of future development.Stretchability is one of the important advantages of flexible sensors . Convent(1) Fiber-shaped structure. The structure of a single fiber can achieve excellent stretchability. Highly sensitive and stretchable fibers can be woven into smart fabrics and wearable electronic products. Mokhtari et al.  fabricat(2) Flat-shaped structure. Although the axial stretchability of flat-shaped flexible sensors is not as good as that of single-fiber-shaped structures, flat-shaped sensors have multidirectional stretchability. Wang’s research group  fabricatIt can be seen from Human skin, as the largest organ in the human body, perceives the external environment  and serves as a barrier to protect the body. However, more importantly, the human skin possesses intrinsic self-healing ability to fully recover from physical or mechanical damage by triggering inherent repair mechanisms to alleviate or avert injure and ultimately maintain the integrity of structure and function ,56. GeneConventionally, most existing self-healing materials are polymers , and various physical, chemical, and even physicochemical approaches have been used to establish self-healing systems. By effectively constructing dynamic reversible intermolecular interactions, chemical approaches have been widely adopted to promote self-repair, including introducing reactive chain ends and supramolecular chemistry a. ThereiRecently, Parida et al.  demonstrMost self-powered sensors usually employ two idiosyncratic materials to constitute the elastic layer  and electrode layer . Thus, it is still urgent to realize complete self-healing of fundamental components after fracture. Accordingly, Xu et al.  fabricatx–PA1-x–Zn  elastomers, which could simultaneously and quickly self-heal after fracture and wear at room temperature. By incorporating dynamic metal–ligand coordination and hydrogen bonds into PDMS networks, the self-healing polymer possessed outstanding self-healing ability within 10 min at room temperature (100% efficiency). When the assembled TENG was working in contact-separation mode, the electrical outputs could reach 140 V, 40 nC, and 1.5 μA. Even when stretched to breaking point or scratched to introduce wear, it could recover its electrical outputs within 20 min and 2 h at room temperature, respectively.To enhance the self-healing capability of self-powered sensors, self-healing processes feature hydrogen bonds and other interactions . For example, Han et al.  preparedBenefiting from the outstanding self-healing ability of advanced materials by introducing dynamic reversible interactions, self-powered sensors exhibit superb performance in applications, whether they serve as the power source or the whole system.Degradable materials used in self-powered sensors are widely investigated because of their green and recyclable properties. Since the birth of the world’s first cellulose paper-based piezoelectric nanogenerator (PENG) in 2011 , green aThe use of degradable materials to prepare self-powered sensors is based on paper-based recyclable self-powered sensors. Zheng et al.  reportedAt present, degradable materials used in self-powered sensors can be divided into three categories: animal-based degradable materials, plant-based degradable materials, and artificial degradable materials.(1) Animal-based degradable materials. Currently, the most popular degradable materials used in self-powered sensors are animal-based materials. Among them, proteins and their derivatives, such as silk and egg white ,68, can 3 (C/BT) aerogel paper based on polydimethylsiloxane (PDMS) nanocomposites. Nie et al. [(2) Plant-based degradable materials. At present, self-powered sensors made from plant-based materials are regarded among the main representatives of future green electronic products and are considered to have great development prospects. In particular, PENGs and TENGs based on paper/cellulose materials are a new source of renewable energy with low cost and a rich source of raw materials, attracting the attention of many researchers ,78,80,81l-lactide-co-glycolide) (PLGA) or PVA ((3) Artificial degradable materials. Artificial degradable materials synthesized by various methods have played an important role in self-powered sensors ,83. Rece) or PVA c. The stIt can be shown from Multifunctional flexible sensors, which can effectively solve the problem of the limited application range of single-performance sensors, have been widely studied in recent years . Rao et 3. The excellent structure enabled 3dB-TENG to have shape adaptability and corresponding slight weight changes. It was applied to an intelligent running shoe insole for human motion monitoring and a carpet that automatically identifies identity. It can see from Traditional sensors have defects such as unstable performance and poor sensing capabilities. Moreover, most TENGs have a planar structure, occupy an ample space, and are very unsightly and inconvenient in wearable applications. Dong et al.  reportedA TENG’s performance is greatly affected by the environment’s humidity. Liu et al.  proposed3), zinc oxide (ZnO), and flexible polymer materials that are usually used to prepare high-performance piezoelectric materials. PVDF and its copolymers can be compounded to improve its polarization and obtain high-performance piezoelectric materials by using inorganic nanomaterials as nucleating agents.Conventionally, PENGs consist of an insulation as piezoelectric layer sandwiched between two conductors . InorganWe detailed a complete electrical generation process for a PENG during one pressing and releasing process a. In theAt present, many attempts have been made to simultaneously improve the flexibility and power output performance of nanogenerators ,93,94,953 could be produced by compressing or bending the single-fiber nanogenerator, which was about 1559% higher than previously reported piezoelectric textiles. Razavi et al. [(1) 1D single-fiber-based PENG. The 1D single-fiber-based PENG is the simplest structure of textile nanogenerators, which can be directly fabricated into 2D and 3D PENGs. In recent years, many scholars conducted research and achieved good results. Mokhtari et al.  fabricati et al.  fabricat(2) 2D fabric-based PENG with textile forming structures. Although the simple structure of 1D single-fiber-based PENGs brings great convenience for manufacturing, its electromechanical conversion efficiency and electric energy output do not meet expectations due to the limitations of size and structure. In order to obtain the desired electrical power output, an efficient method is to weave 1D fibers into 2D or 3D fabrics. Zhou et al.  reported3 nanoparticles embedded in PU and polyvinylidene fluoride–trifluoroethylene copolymer (PVDF–TrFE) nanofibers  3D fabric-based PENG with multilayer stacking structures. Fabric-based PENGs can be prepared in the form of traditional textiles by stacking two-dimensional textile structures. A stacked nanofiber mat was alternatively composed of nanocomposite nanofibers of BaTiOnofibers f. The sulectrode g. FurthePENGs can only convert pressure into electrical energy; however, in everyday life, substantial power is lost because it cannot be collected, such as friction energy. In recent years, scholars have focused more and more on the research of devices that can convert friction energy into electrical energy ,103,104.A triboelectric effect exists between any two objects, even if they are of the same material. There are cations and anions that appear when two different materials or irregular surfaces of the same material come into contact. In addition, contact between materials at two different temperatures also produces the triboelectric effect, whereby the hotter one tends to be positively charged, while the cooler one tends to be negatively charged . TherefoTENGs can be divided into four models: the single-electrode model, lateral-sliding model, vertical contact-separation model, and freestanding triboelectric-layer model . AlthougSince the four models have the same working mechanism, the CS model is used below as the representative to introduce TENG design. Firstly, the dielectric materials of the upper and lower layers touch each other. They generate opposite electrical charges at the contact surface and balance each other such that there is no current in the external circuit b. When tLike PENG, TENG can be divided into three types according to shape and structure: 1D single-fiber-based TENG, 2D fabric-based TENG with textile forming structures, and 3D fabric-based TENG structures.2SO4 wrapped around carbon fiber, and the outer sheath was fibrous. The design constituted a self-powered pressure sensor. In order to improve the power output, as well as promote their wide application, textile-based TENGs usually exist in the form of fabric. Conductive or dielectric fibers can be processed into fabrics via various textile forming techniques. Cong et al. [3 (PZT)/glass fiber fabric as the dielectric layers and Altium as an electrode. The generator had excellent output performance and could simultaneously light up to 1350 LEDS. Wang et al. [Whether the structure is complex or not, its most basic principle involves a charged effect and electrostatic induction. A single fiber/yarn is the smallest design unit for textile-based TENGs. One-dimensional single-fiber-based TENGs are widely designed and applied due to their excellent performance and simple structure. Zhang et al.  reportedg et al.  built ang et al.  applied g et al.  developeg et al.  created 2 and a short-circuit current of 13.3 µA. At a low frequency pressure of 1 Hz, the device could obtain an open-circuit voltage of 150 mV within 80 s. Connecting multiple such devices in series can be used to power small wearable electronic devices. Li et al. [3NPs/PDMS, and a top electrode based on carbon. The bottom electrode and triboelectric layer were integrated as a spacer  base was reported . This OTFurthermore, researchers recently made a flexible and lightweight origami TENG using conductive Ni/Cu nonwoven polyester and Mylar film . The supIn addition to origami structures, kirigami is used to design and develop new types of nanogenerators. The introduction of kirigami TENG (KTENG) structures can improve the energy collection efficiency and stretchability of the device. A highly stretchable, environmentally friendly paper-based TENG with rationally designed interlocking kirigami structures was reported in . The intFurthermore, the kirigami structure is also used for TENGs in electronic skin. Dukhyun et al.  reportedIn addition, a polymer matrix with a kirigami structure can enhance the stretchability of a TENG. A self-powered stretchable wearable photodetector was developed using a kirigami-based honeycomb structure of zinc oxide nanowires and coupled with a TENG . EmbeddiIn addition, the merits of the Miura folding structure, such as light weight, large unfolding area, and small folding volume, have attracted interest for TENG applications. Recently, a novel charge-excitation TENG based on a Miura folding structure was developed by integrating flexible PET (as a folding substrate with a double working side design: one side working as the main TENG (M-TENG) and the other side working as the excitation TENG (E-TENG)); the output performance was largely increased due to this unique structure design, which could increase the TENG working area and reduce its volume . The kirElectronic skin (e-skin) is a flexible electronic device covering the surface of a machine or human body, where the system can give the carrier the ability to sense touch, pressure, temperature, and chemical or biological information. After granting robots the ability to perceive through electronic skin, the application scenarios of robots can be broadened, which includes many actions that require a high degree of interaction, such as caring for the elderly . With thThe emergence of self-powered devices such as PENGs and TENGs has significantly increased the application scenarios of electronic skin. Recently, many novel designs of electronic skins based on self-powered devices appeared. Wang et al.  used PVDIn addition to their important role in the field of electronic skin, PENGs and TENGs also have many applications in wearable devices. PENGs and TENGs have brought about a revolution in wearable devices, replacing traditional rechargeable sensors and bringing great convenience to users. For example, in motion detection, the weight of the battery in the traditional wearable sensor is relatively large, which leads to inconvenience for the user. The use of self-powered sensors can effectively solve this problem and greatly reduce the overall equipment weight.In the medical field, there are currently many reports on the use of self-powered sensors to detect pulse and respiration ,137,138.In terms of motion detection, wearable devices are mainly used to record the number of steps and monitor gait d 141,14,143. ZhuWith the development of flexible sensors, they are becoming more and more important in intelligent prostheses, self-charging power cells for healthcare monitoring, and biological sensors . Ma et aIn the era of artificial intelligence, human–machine interfaces play a particularly irreplaceable role in the diverse interactions between man and machine . Shi et Sensors play a crucial role in robot control. In recent years, TENGs have been applied to robots. In the process of robot motion, it can provide feedback in terms of external force, speed, displacement, and other information to better control robot motion. This section mainly summarizes the application of self-powered flexible sensors in bionic robots, soft robots, and industrial robots.Jin et al.  first apDue to the flexibility of the TENG sensor, it has been applied to many soft actuators or grippers. Chen et al.  designedIn terms of industrial robots, Liu et al.  demonstrImplantable devices can obtain energy through organisms, such as converting the mechanical energy of the heartbeat and intestinal peristalsis or the chemical energy of the glucose redox reaction into electrical energy, which can be applied to physiological sensors or to power cardiac pacemakers.3 of power. Therefore, a self-powered pacemaker can be formed by combining a pacemaker with I-TENG  applications. Zhu et al.  proposedIn terms of AI, Zhou et al.  proposedHowever, an effective and practical approach for real-time sentence recognition of sign language is still lacking, which is more significant for the practical communication of signers and non-signers. Feng et al.  improvedWe presented a brief overview of self-powered flexible sensors in terms of three aspects: material design, structural optimization, and frontier application. The emergence of PENGs and TENGs has been a major discovery in the field of self-powered flexible sensor. Recently, significant progress has been made with respect to self-powered flexible sensor in the fields of healthcare, robotics, industrial application, etc. These application fields also put forward higher requirements for self-powered flexible sensors, which are to be highly sensitive, accurate, stable, and mechanically flexible. Compared with conventional flexible sensors with an external battery, self-powered flexible sensors can effectively address the shortcomings of a battery with a limited lifetime. Moreover, TENGs and PENGs can solve the unpredictability of energy conversion in some special environments. Self-powered flexible sensors can significantly improve the performance of sensing to a certain extent. Therefore, as an effective conversion technology from mechanical energy to electrical energy and signals, PENGs and TENGs can be simultaneously used as sensing devices and energy sources. Self-powered flexible multifunctional sensors based on TENG and PENG have properties such as stretchability, self-healing, and degradability, and they have been applied in many fields, including wearable devices, electronic skin, intelligent prostheses, and human–machine interfaces. Furthermore, implantable devices have great potential in the medical and healthcare fields. Some researchers have achieved expected results in communication with a computer for construction of the mobile Internet of things, which has great value.It is undeniable that huge progress has been made in self-powered flexible sensors, but there is a long way to go to translate existing research into practical value. Self-powered flexible sensors based on PENGs and TENGs with high output performance have a lot of room for improvement. Their higher output performance is conductive to the realization of wireless energy transmission. However, several reports about alternating current (AC)-based TENGs have only described AC–DC conversion by rectification. In the future, it is also urgent to improve TENG technology in terms of output performance and output modes. For example, an inverting TENG (I-TENG) can realize the AC mode through the coupling of triboelectrification and air breakdown (DC mode). Unlike AC-TENG, I-TENG delivers unique characteristics and performance parameters  that can be controlled. Benefiting from its novel output mode and outstanding output performance, the inverting TENG can be useful in self-powered controllers, intelligent systems, etc. Furthermore, several issues need to be studied and improved, such as sensitivity, stability, durability, and industrial production. In the context of artificial intelligence, how to effectively combine self-powered flexible sensors with human–machine interaction, intelligent robots, AR/VR, and other intelligent fields requires more research. TENGs and PENGs mainly convert mechanical energy into electrical energy. At present, there are also nanogenerators that convert wind energy, kinetic energy from seawater, and heat energy into electrical energy. However, the energy formed by these nanogenerators is not stable; therefore, it is of importance to investigate the stable conversion of other energy sources into electrical energy.