In men with newly diagnosed, low-volume metastatic prostate cancer, is the addition of prostate radiation therapy to androgen deprivation therapy cost-effective?In this economic evaluation using data from a simulated cohort of 10 000 individuals with low-volume metastatic prostate cancer, a microsimulation model found that the addition of prostate radiation therapy to standard-of-care androgen deprivation therapy was associated with reduced net costs and improved quality-adjusted life-years and was therefore a dominant cost-effective strategy.These findings support the incorporation of prostate radiation therapy as part of initial treatment for men with low-volume metastatic prostate cancer. Prostate radiation therapy (PRT) is a treatment option in men with low-volume metastatic prostate cancer based on the results of the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy Arm H (STAMPEDE-H) trial. However, the cost-effectiveness of this treatment remains unaddressed.To assess the cost-effectiveness of PRT when added to androgen deprivation therapy (ADT) for men with low-volume metastatic hormone-sensitive prostate cancer (mHSPC).This economic evaluation used microsimulation modeling to evaluate the cost-effectiveness of adding PRT to ADT. A simulated cohort of 10 000 individuals with low-volume mHSPC was created. Data from men with low-volume mHSPC were extracted and analyzed from January 18, 2019, through July 4, 2020. Transition probabilities were extracted from the STAMPEDE-H study. Health states included stable disease, progression, second progression, and death. Individual grade 2 or higher genitourinary and gastrointestinal toxic events associated with PRT were tracked. Univariable deterministic and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. Health state utility estimates were based on the published literature.The combination of PRT and ADT using regimens of 20 fractions and 6 weekly fractions.Outcomes included net quality-adjusted life-years (QALYs), costs in US dollars, and incremental cost-effectiveness ratios. A strategy was classified as dominant if it was associated with higher QALYs at lower costs than the alternative and dominated if it was associated with fewer QALYs at higher costs than the alternative.For the base case scenario of men 68 years of age with low-volume mHSPC, the modeled outcomes were similar to the target clinical data for overall survival, failure-free survival, and rates of PRT-related toxic effects. The addition of PRT was a dominant strategy compared with ADT alone, with a gain of 0.16 QALYs  and a reduction in net costs by $19 472  at 37 months of follow-up and a gain of 0.81 QALYs  and savings of $30 229  with lifetime follow-up.In the economic evaluation, PRT was a dominant treatment strategy compared with ADT alone. These findings suggest that addition of PRT to ADT is a cost-effective treatment for men with low-volume mHSPC. This economic evaluation assesses the cost-effectiveness of the addition of prostate radiation therapy to androgen deprivation therapy for men with low-volume metastatic hormone-sensitive prostate cancer. A recent innovation in the management of mHSPC is the addition of prostate radiation therapy (PRT) for men with newly diagnosed mHSPC with low metastatic burden.Prostate cancer is the most common malignant tumor diagnosed in men.10 With a median follow-up of 37 months, the trial found that PRT improved failure-free survival (FFS) but not overall survival (OS) in unselected patients. However, in men with low-volume disease, PRT improved both FFS and OS. In response to the publication of that trial, PRT is now considered a standard-of-care treatment for men with low-volume mHSPC in the US according to the National Cancer Center Network.11 However, PRT introduces additional costs and toxic effects that are not accounted for when OS and FFS are examined in isolation.The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy Arm H (STAMPEDE-H) trial examined the impact of adding PRT to ADT in men with newly diagnosed mHSPC.13 Thus, evaluating the cost-effectiveness of new therapies and projecting their potential financial consequences are instrumental in determining the appropriateness for widespread use. The objective of this study was to perform a CEA to assess the value of adding PRT to ADT for men with low-burden, newly diagnosed mHSPC.For wide implementation of PRT and insurance coverage, cost-effectiveness analysis (CEA) is essential. Health care costs, including expenditures for prostate cancer, are increasing in the US, and there is increasing emphasis on providing value-based care.15 This economic evaluation used no individual patient-level data to inform the model. Therefore, it does not constitute human subjects research and does not require institutional review board review or exemption according to the US Department of Health and Human Services (45 CFR §46). This study followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline.For this economic evaluation, we developed a microsimulation model using TreeAge Pro 2020 software (TreeAge Software LLC) to estimate the cost-effectiveness of adding PRT to standard-of-care ADT among men with mHSPC using model inputs based on published literature. Data from men with low-volume mHSPC were extracted and analyzed from January 18, 2019, through July 4, 2020. Our methods conformed to the Society for Medical Decision Making best practice guidelines for model transparency and validation.10 This multicenter randomized clinical trial assessed 2061 men with newly diagnosed metastatic prostate cancer who were randomized to receive standard-of-care ADT with or without PRT. Prostate radiation therapy was 55 Gy in 20 daily fractions of 2.75 Gy for 4 weeks or 36 Gy in 6 consecutive weekly fractions of 6 Gy. Among 819 patients with low-metastatic burden , OS was improved using either fractionation regimen . Three-year survival was 73% in the control group vs 81% in the PRT group.Clinical data were extracted from the STAMPEDE-H trial.16 Cost-effectiveness was assessed by calculating discounted quality-adjusted life-years (QALYs), cumulative costs, and the incremental cost-effectiveness ratio. A treatment strategy with an incremental cost-effectiveness ratio less than the societal willingness to pay was considered to be cost-effective. In the base case, willingness to pay was defined as $100 000 per QALY gained.17 A strategy was classified as dominant if it was associated with higher QALYs at lower costs than the alternative and dominated if it was associated with fewer QALYs at higher costs than the alternative. The model was run with 10 000 individual trials, and stochastic uncertainty was reported as the 95% CIs around the mean model estimates.We used the microsimulation model to perform a CEA of ADT vs ADT plus PRT from a US payer perspective. The health states were stable disease after initial treatment, progression, second progression, and death . PatientThe time horizon was 37 months to mirror the median follow-up in the STAMPEDE-H trial. The model was then run until all patients died to explore how the additional simulated follow-up time and events affected the model’s results. An advantage of a microsimulation model over a state-transition Markov model is the ability to model and track individual events, such as treatment-related toxic effects. Grade 2 or higher genitourinary and gastrointestinal toxic effects were followed in the model using trackers with individual Monte Carlo simulations.22 Uncertainty in the estimates of the hazard ratios (HRs) were modeled by γ distributions, which are bounded by 0 and infinity.23All model inputs are summarized in 16 A weighted mean was used for systemic therapies for castration-resistant disease after first progression. Cost estimates for toxic effects were derived from a nationwide sample of private claims data of intensity-modulated radiotherapy for prostate cancer using the mean complication costs.21 This sample was the only source of private insurance claims in our study, and it was chosen because it represents the most comprehensive US cost analysis of complications after intensity-modulated radiotherapy, to our knowledge. Costs of end-of-life care were from a national analysis of Medicare beneficiaries with cancer with a poor prognosis.20 Costs were discounted at a 3% annual rate to adjust for inflation and were adjusted to 2020 US dollars using the Consumer Price Index.24This analysis was conducted from a US payer perspective. Costs reflected Medicare rates with the exception of costs related to PRT-related toxic effects. We used institutional Medicare fees for the cost of PRT  trial, which used a slightly higher radiation dose of 60 Gy in 20 fractions.7 we performed an additional analysis of the addition of abiraterone in the upfront setting to ADT and PRT. In addition, probabilistic sensitivity analyses using 10 000 Monte Carlo simulations while sampling with replacement from distributions of all input parameter inputs were performed to explore uncertainty with regard to the transition probabilities, costs, and utilities.Deterministic sensitivity analyses were conducted for all parameters to evaluate the extent to which uncertainty and variability influenced model results. We studied ranges that corresponded to the reported 95% CI or interquartile range around a parameter and used whichever was largest. The base case of our model was calibrated to the STAMPEDE-H clinical trial in which patients received leuprolide acetate as standard of care. Given that therapies such as abiraterone are now being used for mHSPC based on the Long-Acting Therapy to Improve Treatment Success in Daily Life (LATITUDE) and STAMPEDE-G studies,For the base case scenario of men 68 years of age with low-volume mHSPC, the modeled outcomes were similar to the target clinical data with regard to OS, FFS, and rates of PRT-related toxic effects . All other model parameters varied but did not significantly change the preferred strategy because no additional thresholds were encountered  and PRT  arms; however, the net cost savings associated with PRT were similar , and there were gains in QALYs  similar to the base case, likely reflecting similar benefits associated with abiraterone in both arms. The results were stable in probabilistic sensitivity analyses, with an expected increase in probability of cost-effectiveness with decreasing HR for progression associated with PRT and a decrease in cost associated with PRT .25 Cost-effectiveness analyses provide a formalized approach to determine the optimal use of health care resources to maximize benefits with regard to payer value (cost) and patient value (QALYs).26 We performed a CEA that evaluated the addition of PRT to systemic therapy in men with newly diagnosed low-burden mHSPC. The dominant strategy was PRT, which was associated with reduced costs by $19 472 and improved QALYs by 0.16, or approximately 2 months of perfect health gained, using the median follow-up in the STAMPEDE-H trial. We estimate larger gains (0.81 QALYs) and further reductions in net costs ($30 229) with a simulated lifetime time horizon.After the passage of the Patient Protection and Affordable Care Act in 2010, the Centers for Medicare & Medicaid services have sought to transition from fee-for-service to value-based care, for which incentive payments are prioritized for the quality rather than quantity of health care services rendered.To our knowledge, this is the first CEA of PRT in this setting. Sensitivity analyses around model inputs and assumptions suggest that our findings remained robust over a plausible range of values. A central finding of our analysis is that an added up-front cost of PRT may be associated with reduced net costs by improving progression-free survival in the noncurable setting by patients spending less time accumulating costs for more expensive systemic therapies. Supporting this conclusion, the model was most sensitive to the HR for progression, and PRT remained cost-effective at values less than 0.79. Our results suggest that PRT is cost-effective on the basis of data from a randomized clinical trial.31 This finding is particularly relevant in the era of focusing on value-based cancer treatments. Cancer drugs often enter the US marketplace at costs that exceed $10 000 per month and are expected to contribute to 70% of the total cost of care by 2025,32 highlighting the need for alternative payment systems that link the value of cancer treatments to prices. Our study supports the use of PRT as a cost-effective and of high-value treatment because it was associated with lowering payer costs and increasing patient QALYs.The results of our analysis contribute to a broader literature that supports the use of radiation therapy as a cost-effective treatment for cancers with limited spread or oligometastatic disease.33 Nonetheless, our model suggests that improvements in FFS may be cost-effective in reducing costs associated with the use of systemic therapies.This study has limitations. In the STAMPEDE-H clinical trial, the comparison of PRT for low-volume mHSPC was a prespecified analysis with more than 90% power for FFS and 60% power for OS based on 40% of the sample of the comparison population having low-volume disease, which was achieved in the trial. Although all criteria for a high-quality subgroup analysis were met in the STAMPEDE-H trial, this analysis was still underpowered for OS.34 However, these rates likely overestimate toxic effects because the STAMPEDE-H trial (2.75 Gy for 20 fractions or 6 Gy for 6 fractions) used lower radiation doses than the CHHiP trial (3 Gy for 20 fractions). Therefore, this assumption potentially biases the model against PRT by using a conservative toxic effect estimate. However, we found PRT to be a dominant strategy, and varying the rate of toxic effects on sensitivity analysis did not significantly change model results. We also did not find a significant difference between 6 weekly fractions and 20 daily fractions, suggesting that either fractionation scheme may be reasonably cost-effective option.We assumed rates of toxic effects from the CHHiP trial to model more accurate long-term data because toxic effects can manifest 5 years after completion of radiation therapy, which is longer than the median follow-up time of the STAMPEDE-H trial.21 This finding likely overestimates the costs associated with toxic effects relative to Medicare rates because reimbursements from private plans are substantially higher. However, the model was not sensitive to fluctuations in costs associated with complications from PRT. Although the study by Pan et al21 provides the most granular data on intensity-modulated radiotherapy complications, a recent study35 of complications associated with other radiation modalities used for prostate cancer using Medicare fees found similar costs. Furthermore, costs will invariably vary across different health care systems. Costs of cancer treatment vary widely.37 In addition, although a microsimulation model is a widely accepted form of assessing cost-effectiveness, a randomized clinical trial that prospectively collects costs for comparison is the gold standard assessment.Most cost estimates used in this study were Medicare fees with the exception of radiation therapy complication costs, which were informed by private insurance data.16 Although we are not aware of any formal CEAs of apalutamide, its price is similar to enzalumatide, and thus its omission was unlikely to impact our model results with regard to net costs.38 In addition, although our sensitivity analysis assessed the use of PRT when added to abiraterone, it is important to acknowledge that this warrants further investigation in a randomized clinical trial.There are limitations with regard to the systemic therapies used. Some novel therapies, such as apalutamide, were not specifically included in the cost analysis that we used.19 This sample may not be representative of all patients with low-volume mHSPC. However, there were no thresholds found for health state utilities in our study, suggesting patient preferences were not primary factors associated with the cost-effectiveness of PRT.Utilities in our study were extracted from a study of 162 highly motivated men 60 years or older, half of whom had been diagnosed with prostate cancer.For patients with newly diagnosed low-burden mHSPC, this economic evaluation supports PRT as a cost-effective treatment. The findings suggest that adjustments in the HR for progression in the STAMPEDE-H trial were associated with the cost-effectiveness of PRT. Our model was informed by high-quality data, and the addition of PRT to ADT was a dominant strategy compared with ADT alone across a wide range of assumptions. This analysis provides data to help guide the development of future clinical trials in metastatic prostate cancer to increase the value of novel cancer treatments.


The aims of this study were to use functional near-infrared spectroscopy (fNIRS) to determine whether cardiovascular fitness levels modulate the activation of the mirror neuron system (MNS) under table-setting tasks in non-exercise situation, to replicate the study that positive effect of acute moderate-intensity exercise on the MNS and investigate whether cardiovascular fitness levels modulates the effect of exercise on the activation of the MNS.2max), and 5-min cool-down.Thirty-six healthy college-aged participants completed a maximal graded exercise test (GXT) and were categorized as high, moderate, or low cardiovascular fitness. Participants then performed table-setting tasks including an action execution task (EXEC) and action observation task (OBS) prior to (PRE) and after (POST) either a rest condition (CTRL) or a cycling exercise condition (EXP). The EXP condition consisted of a 5-min warm-up, 15-min moderate-intensity exercise (65% VONo significant differences were observed for Oxy-Hb and Deoxy-Hb between different cardiovascular fitness levels in the EXEC or OBS tasks in the non-exercise session. But there were significant improvements of oxygenated hemoglobin (Oxy-Hb) in the inferior frontal gyrus (IFG) and pre-motor area (PMC) regions under the OBS task following the acute moderate exercise. Particularly, the improvements (Post-Pre) of Δ Oxy-Hb were mainly observed in high and low fitness individuals. There was also a significant improvement of deoxygenated hemoglobin (Deoxy-Hb) in the IPL region under the OBS task. The following analysis indicated that exercise improved Δ Deoxy-Hb in high fitness individuals.This study indicated that the activation of MNS was not modulated by the cardiovascular fitness levels in the non-exercise situation. We replicated the previous study that moderate exercise improved activation of MNS; we also provided the first empirical evidence that moderate-intensity exercise positively affects the MNS activation in college students of high and low cardiovascular fitness levels. Mirror neuron system (MNS) was activated when an individual performed action, and observed the same action performed by others . The firIn the field of sport psychology, cardiovascular fitness level was considered as one of the most important factors. Several studies have indicated that high fitness was associated with greater brain volume and functional connectivity . The rolmax) compared with resting state. Furthermore, a recent study used functional near-infrared spectroscopy (fNIRS) also demonstrated that moderate-intensity exercise could improve the activation of MNS in an action understanding social task  of each fitness group was categorized as: low fitness group, moderate fitness group, and high fitness group . All participants were healthy and right-handed (Edinburgh Handedness Inventory score > 0.85), and all had a normal or corrected-to-normal vision. All participants completed four sessions  and were instructed to avoid any intense exercise in 24 h between each session. All participants completed a maximal oxygen consumption test and were then split into three groups based on the American College of Sports Medicine (ACSM) guidelines . The maxss group . Accordiss group . Written2max and were categorized into high, moderate, and low fitness group according to the ACSM guidelines . Participants meeting the inclusion criteria then performed a test of cardiovascular fitness to VOidelines .max), and a 5 min recovery period. Heart rate (HR) was monitored by a wireless HR monitor . The initial cycling workload was 30 W and automatically increased in the warm-up period until HR reached 65% HRmax. The cycle ergometer system automatically adjusts the workload if the HR is higher than target HR to ensure they were exercising at moderate intensity over the 15-min exercise period. Finally, participants were allowed to cool down during the recovery period at 30 W. Under the CTRL condition, participants conducted the same action execution and observation components, but rested instead of performing the exercise  and action observations (OBS) tasks under experimental (EXP) and control (CTRL) conditions. By definition, acute exercise session occurred only in the EXP condition. During the acute exercise session, all participants performed 25 min of exercise on a cycle ergometer  that consisted of a 5 min warm-up, 15 min of exercise at moderate intensity (65% HRexercise .All participants performed the table-setting task before (PRE) and after (POST) the acute exercise session or rest in the EXP and CTRL conditions. If participants individually attended exercise sessions of the experiment firstly, they performed another session on different days.2max was determined if participants met at least three of the following four criteria: (1) respiratory exchange rate (RER) ≥ 1.15; (2) volitional exhaustion; (3) no increase in HR with increasing intensity; (4) rating of perceived exertion (RPE) ≥ 17 (All participants had their body mass index (BMI) measured in the laboratory. The IPAQ was used to assess participants’ physical activity. Cardiovascular fitness was measured using cardiopulmonary exercise testing . All participants ran on a treadmill  using the Bruce protocol for the maximal graded exercise test (GXT) . VO2max PE) ≥ 17 . ParticiIn the initial period, participants and the experimenter  sat face to face. The storage box was placed in front of the participant and the placemat placed on their right-hand side. The storage box included five table items: a plate, a saucer, a pair of chopsticks, a soupspoon, and a rice bowl. A monitor placed at a 45° angle in front of participants to presented visual cues.In the executive (EXEC) task of the experiment, the participants were instructed to place the table items orderly onto and round the placemat with a normal, natural speed, and rhythm in 15 s after the cue was on the monitor: a picture of a cup. Participants were instructed to only use their right-hand and avoid any other movements. Then, their eyes continued to focus on the monitor that displays a cross to remind participants to remain still and avoid any movements for 20 s; this is block 1. In block 2, the four table items will be restored and placed into the storage box, with the bowl placed in front of the box in the identical order in 15 s, then with 20 s to rest. There were eight blocks in this task, block 3 and 4, block 5 and 6, block 7 and 8 were the same as block 1 and 2. The order of placement was always fixed: plate, saucer, chopsticks, soup spoon, and rice bowl .In the observation (OBS) task of the experiment, the table items, storage box, and placemat were turned toward to the experimenter. The visual procedures were the same as the EXEC task. The experimenter moved the table items, and participants carefully observed the movements. When the experimenter rested and watched the cross on the monitor, participants also focused on the cross and avoided any movements during the whole OBS task.fNIRS data were acquired using the NIRSport system . Probe-channel sets were installed with reference to the international 10/10 system into a NIRS-EEG compatible cap  and then placed on the participant’s head. The cap position was centered at the Cz point, and then thin plastic straps were inserted between probes to ensure that the distance was less than 3 cm between each source and detector. The fNIRS system consisted of eight light sources and eight detectors which formed 14 channels covering most of the MNS region on the participant’s left hemisphere. Channels 1, 2, and 3 consisted of IFG (BA44/45), channels 4, 5, 12, and 13 consisted of PMC (BA6), channels 6, 7, and 8 consisted of rostral IPL (BA40), and channels 9, 10, 11, and 14 consisted of SPL (BA7) . An alreRaw data from each participant were processed within the nirsLAB analysis package . Discontinuities were automatically corrected or deleted by the nirsLAB (std threshold = 5). Spikes were interpolated or manually deleted. A bandpass filter was used; 0.01 Hz was used to remove drift and 0.1 Hz was used to filter respiratory noise. We used the modified Beer–Lambert law  to analy2max) were imported into IBM SPSS Statistics 22 , and then a one-way ANOVA was used to compared characteristics between cardiovascular fitness levels .All descriptive characteristics  level 2 assessed differences in groups to export brain activation maps.The statistical parametric mapping (SPM) level 1 (within-subject) package incorporated into nirsLAB was based on the canonical hemodynamic function (parameters in nirsLAB = [6 16 1 1 6 0 32]) to determine event-related changes in Oxy-Hb, Deoxy-Hb, and total-Hb during action execution and observation. Finally, the beta values of the Oxy-Hb and Deoxy-Hb from each ROI of the participant as the dependent variable were imported to IBM SPSS Statistics 22 . The one-way ANOVA was applied to compare Oxy-Hb and Deoxy-Hb between levels in non-exercise session . Then Oxy-Hb and Deoxy-Hb were subjected to three-way repeated measure ANOVA under different tasks (EXEC and OBS) with three factors: conditions (EXP and CTRL), time sessions (PRE and POST) as within-subject factors, cardiovascular fitness levels  as a between-subject factor. Then when it exhibited main effect on conditions and three-way interaction was significantly different, following two-way repeated measure ANOVA used Bonferroni correction method was applied to the [Post–Pre] Oxy-Hb or Deoxy-Hb contrast (Δ Oxy-Hb and Δ Deoxy-Hb) of EXP and CTRL conditions in these ROIs to compare the effect of exercise on the MNS-related regions that were known as activated by action execution and action observation. We used contrast value of Oxy-Hb or Deoxy-Hb because it would help to eliminate potential variations as different MNS activation may be caused by doing the tasks on different days. All values are presented as mean ± SE. An alpha of 0.05 was used as the statistical significance level for all comparisons.The 2max was significantly different between fitness levels , and post hoc analyses revealed that all three groups were significantly different from each other. The high fitness level group showed the highest VO2max value, the moderate fitness group followed, and the low fitness group had the lowest value . However, it revealed no significant differences between cardiovascular fitness levels with regard to Oxy-Hb and Deoxy-Hb.F = 9.30, P < 0.05, η2 = 0.22], a significant interaction between conditions, time sessions, and cardiovascular fitness levels  in IFG region. It also revealed a significant main effect on conditions  and a marginal significant interaction  in the PMC region. However, there was no significant interaction in the IPL and SPL regions. In order to determine which fitness level of activation of these two ROIs were increased by exercise, two-way repeated measure ANOVA was used to compare the contrast value (Δ Oxy-Hb) of EXP and CTRL conditions. It indicated that was a significant difference in the low fitness level  in IFG region. Also, it exhibited significant difference in the high fitness level  and low fitness level  in the PMC region. However, there was no significant difference in PMC and IFG regions in the moderate fitness level  = 7.92, P < 0.05, η2 = 0.19], a significant interaction between conditions, time sessions, and cardiovascular fitness levels  in IPL region. In order to determine which fitness level of activation of this ROI was increased by exercise, two-way repeated measure ANOVA was used to compare the contrast value (Δ Deoxy-Hb) of EXP and CTRL conditions. It indicated that was a significant difference in the high fitness level  in IPL region. There was no significant difference in the IPL region in the moderate and low fitness levels.With regard to Deoxy-Hb, there was a significant main effect in conditions [In the EXEC condition, the one-way ANOVA was also conducted to each ROI determine whether the Oxy-Hb and Deoxy-Hb were significantly different between levels of fitness in the non-exercise session, which were not affected by exercise. The results revealed no significant differences between cardiovascular fitness levels for Oxy-Hb and Deoxy-Hb.http://dx.doi.org/10.17632/s8tp7d75dw.1.The three-way repeated measures ANOVA was also performed on each of the ROI of Oxy-Hb and Deoxy-Hb, it revealed no significant main effect on conditions or interaction between conditions, time sessions, and cardiovascular fitness levels for both Oxy-Hb and Deoxy-Hb. The data that support the findings of this study are openly available in Mendeley at 2max in the low level of our participants were also higher than those with language developmental disorders relatively. More studies are needed to determine whether cardiovascular fitness level reflects social and language cognition.Our study indicated that there was no significant difference between fitness levels with EXEC or OBS task under non-exercise session, which implied different cardiovascular fitness levels could not reflect different activation of MNS under this table-setting social task and denied Hypothesis 1. Mirror neuron system has been reported to be an action execution and observation matching system. It also played a crucial role in the development of motor and language functions . Our stu2max were used in different studies to categorized different fitness levels . This result can be supported by previous study demonstrated the positive effect of exercise intervention on Parkinson’s disease patients, they showed that exercise increased motor control in early Parkinson’s disease patients . In PetzWe also discuss whether the exercise only improved one of the functions of MNS which is motor control. Or exercise only improved action understanding but not to reach the social cognition function. The present study might be limited because the Oxy-Hb and Deoxy-Hb values within each fitness level between men and women were not categorized identically, this issue due to the limit number of participants in each fitness level. Therefore, these issues may limit the generalizability of our findings and future research should identify the role of sex on exercise and the MNS. However, since the factor of gender has already been counter-balanced in this study , we can assume that effect of gender would not bias the results.Another question is whether we should use measures of Oxy-Hb or Deoxy-Hb to represent behavioral data. Some studies have indicated that the Oxy-Hb signal is often observed to have a higher amplitude than the Deoxy-Hb signal , which mAs our study only used the acute aerobic exercise protocol, and different protocols of exercise have indicated different effects on cognitive performances, expanded researches into effect of long-term exercise, and different exercise protocols of training programs are necessary to determine the effect of exercise on MNS. And more task protocols involve behavioral index associate with social cognition performance should be included into neuroimaging studies since we only used the Oxy-Hb and Deoxy-Hb as the index to indicate the effect of exercise on the MNS.All datasets generated for this study are included in the article/supplementary material.The studies involving human participants were reviewed and approved by the Ethics Committee of Guangzhou Sport University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZX, MH, and M-QX contributed to conception and design of the study. ZX, Z-RW, and JL organized the database. ZX and M-QX analyzed the data. ZX wrote the first draft of the manuscript. MH and M-QX contributed to manuscript revision and read 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.


To evaluate the utility of teleconsultation in the provision of eye care services during the COVID-19 lockdown. Disparities in the consultation burden of sub-specialities and socio-demographic differences in teleconsultation utilization were also assessed.Al-Shifa Trust Eye Hospital Rawalpindi began audio and video teleconsultation using broadband telecommunication services during the lockdown. Patients’ and consultations’ data gathered during the first three weeks after the commencement of this programme were compared with data from the four weeks prior to lockdown. The weekly consultation ratio and overall consultation burden of sub-specialities were measured. Chi-Square tests of association determined the relationship between different variables (socioeconomic status and consultation characteristics) and consultation modality (on-site vs online).In total, 17507 on-site consultations (4377/week) were conducted compared to 1431 teleconsultations (477/week), which maintained 10.89% of the weekly pre-lockdown eye care services. The post-lockdown teleconsultation programme saw a relatively higher percentage of service utility among female (47.09% vs 44.71%), younger-age (31.33±19.45 vs 41.25±23.32 years) and higher-socioeconomic-status (32.21% vs 0.30%) patients compared to pre-lockdown on-site consultations. The most common indication for teleconsultation was red-eye (16.70%). While cornea and glaucoma clinics maintained most of the pre-lockdown services (30.42% and 29% respectively), the highest dropout was seen in optometric and vitreoretinal services supporting only 5.54% and 8.28% of pre-lockdown services, respectively.Digital initiatives could partially maintain eye care services during the lockdown. Focused strategies to improve teleconsultation utilization are required during the pandemic and beyond. With the ever-maturing development of several digital technologies that address clinical problems and diseases, 2020 should have been the harbinger of an exciting decade in medicine and science. These digital technological advancements included big-data analytics , blockchThe use of telecommunication technology to provide clinical services remotely is known as telemedicine –10. TeleTelemedicine also provides an opportunity for ophthalmologists to conduct consultations in far-flung and underserved areas that may not otherwise have access to specialized eye care , 12, 26.Currently, smartphones have become an integral part of our daily life . A high During the COVID-19 pandemic, some individuals could be more vulnerable to severe disease and might take a much longer road to recovery due to their limited access to healthcare facilities. Health equity is the pledge to lessen disparities in health outcomes and their determinants, including sociodemographic aspects –43. WhilThis study is aimed to estimate the magnitude and determinants of the audio and video teleconsultations’ utility for the provision of eye care services in Pakistan during the COVID-19 pandemic. We studied the sociodemographic characteristics of the patients and utilization trends of the sub-speciality services before and during the lockdown in order to identify factors that may hamper eye care equity and access during the COVID-19 pandemic. These factors can then be targeted with focused strategies to expand and ensure the equitable utility of teleconsultation services.2, it is divided into four provinces  [Pakistan is a minimally resourced, low middle-income country situated in South Asia . With antunkhwa) . Amongstrd March 2020, the Al-Shifa Trust Eye Hospital Rawalpindi started an online audio and video teleconsultation programme on 24th March 2020 to maintain eye care services. Using mobile connectivity and broadband services, the virtual teleconsultation programme connected patients with the consultants through social networking applications, such as Skype, for video assessment and patient-doctor interactions as well as by audio phone-calls. Eight consultants of different sub-specialities were designated an hour every day six days a week (Monday to Saturday) to provide audio and video teleconsultation. The Skype ID, consultants’ schedules and teleconsultation information, such as booking procedure and contact details were advertised through the social networking platforms, such as Facebook and Instagram, as well as through short message service (SMS). One thousand SMS were sent out every day after the lockdown to random patients from the hospital’s data repository. The patients could also visit the hospital’s website  to gather information regarding the teleconsultation programme or book a tele-appointment. On the website, the patients were asked to fill in an electronic questionnaire regarding symptoms and registration status (new or follow-up). These teleconsultations also provided prescriptions and ensured emergency referrals, if deemed necessary , and during the lockdown.The consultation burden was evaluated based on the weekly consultation ratio (WCR), which was the total number of general and sub-speciality consultations during the study duration/total study duration (weeks). The relative decrease in the sub-speciality WCR was measured by calculating the change in WCR as a proportion of the total WCR for the pre-lockdown study duration. The mathematical formula for calculating percentage decline in sub-speciality specific WCR is given below:th February 2020 to 22nd March 2020 (4 weeks) was carried out to calculate the consultation burden classified for different sub-speciality departments. Age and gender distribution, registration day, registration status (new or follow-up), patients’ socioeconomic status  as well as the consultation indication of the patients during the study period were reviewed.A retrospective analysis of Al-Shifa Trust Eye Hospital Rawalpindi’s record from 24After the commencement of the teleconsultation programme, information related to abovementioned study parameters was prospectively gathered for three weeks. Subsequently, the collected data were analysed to calculate the consultation burden. During the teleconsultation, the patients were also asked about how they came to know about the programme. The number of patients requiring an urgent referral during the teleconsultation programme was also determined.A cost analysis was conducted to determine the weekly expenses (48 hours/week) of the hospital for both consultation modalities (on-site vs teleconsultation). The details, such as hourly consultation charges/consultant, internet expenses, utility and publicity expenses, equipment maintenance and repair charges, and equipment and building depreciation charges, for both components of the study duration were obtained from the audit department of the hospital in the form of financial records. The costs, which were equivalent for both consultation modalities, were excluded from the final analysis. Weekly expenses were calculated on an hourly basis and obtained after dividing the weekly expenses of every category by the total number of working hours/week (48 hours). Moreover, the hourly consultancy charges/consultant for 1 week were calculated by dividing the total hourly salaries of the participating consultants (on-site vs teleconsultation) in 1 week by the number of consultants for each consultation modality.All analyses were carried out in Statistical Package for Social Sciences (SPSS) version 17. For descriptive analysis, the frequencies and percentages were used for categorical variables. The arithmetic mean and standard deviation with ranges described the quantitative variables. A Chi-square test with a 95% confidence interval was applied for the inferential analysis to show relationships and trends regarding the modality of consultation (online vs on-site) in categorical variables. On the other hand, an independent samples Student’s t-test was applied to the quantitative variable to determine its association with the modality of consultation (online vs on-site) at a 95% confidence interval.In total, 17507 on-site consultations were conducted at Al-Shifa Trust Eye Hospital Rawalpindi during the four weeks prior to lockdown compared to 1431 teleconsultations that were conducted in three weeks following the commencement of lockdown. Hence, the teleconsultation programme maintained 10.89% of the pre-lockdown weekly eye care services. The predominant mode of teleconsultation was through video calls , whereas the remainder were audio calls.The predominant gender during the pre and post-lockdown study duration was male, although an increase in females from 44.71% pre-lockdown to 47.09% post-lockdown was observed .An age-wise comparison of the study participants revealed that the participants of the post-lockdown teleconsultation programme were younger than the pre-lockdown participants (p<0.001), with a mean age of 31.33±19.45 years (5–68 years) and 41.25±23.32 years (1–100 years), respectively .While more than thirteen thousand patients  were registered in the “Free Treatment” hospital category during the pre-lockdown study, the teleconsultation programme saw a total of 474 33.12%) consultations in the same category. Conversely, the number of private patients increased from 0.30% (n = 53) of pre-lockdown duration to 32.21% (n = 461) of post-lockdown study duration (p<0.001), which accounted for an ~9-fold increase in the absolute number of private patients (n) utilizing the teleconsultation service  and were conducted during weekdays (Monday to Thursday)  . There wThe most common indication for consultation during the pre-lockdown study was refractive error  followed by cataract  while it was red-eye  for the post-lockdown study. More than 150 patients  were referred to the Emergency Department of the hospital facility during the teleconsultation program while 13.77% patients (n = 197) were advised a deferred evaluation once the lockdown restrictions were relaxed. The details of the consultation indications are given in The General Ophthalmology department carried out the majority of the consultations pre-lockdown  and post-lockdown . However, it could only maintain 8.05% of the pre-lockdown services , Table 4The automated short message service (SMS) spread the most awareness (52.42%) followed by social media platforms (39.00%). The remaining patients (8.58%) became aware of the teleconsultation programme through the official website as well as their relatives, neighbours and friends.In our study, the weekly cost of the on-site programme was found to be ~56 times higher than that of the teleconsultation programme. The hourly cost of the on-site consultation modality was 2,76,125 PKR /week, while it was 4,894 PKR (29 USD)/week for the teleconsultation programme. Moreover, there were no expenses in the teleconsultation programme due to equipment maintenance and repair, hospital building depreciation, equipment depreciation as well as salaries of optometrists and other paramedical staff .Our study showed that the teleconsultation programme could maintain 10.89% of the weekly pre-lockdown eye care services. Although the post-lockdown consultation burden was not on par with the pre-lockdown data, eye care services could still be maintained to some extent with teleconsultation during the COVID-19 pandemic. Our pilot study findings also highlight the sociodemographic  and consultation characteristics  of the patients together with the sub-specialities  that could be targeted with focused and inclusive strategies to ensure the equitable utility of teleconsultation services during the pandemic and beyond.The current study provided evidence that male gender, younger generation and individuals with a higher socioeconomic background were more likely to benefit from teleconsultation. A gender-wise comparison between pre and post-lockdown data demonstrated increased participation of females (~3%) in the teleconsultation programme. This could be attributed to the prevailing conservative cultural traditions in Pakistan that make it difficult for females to travel to healthcare facilities by public transport . The meaOverall, the current study demonstrated that more consultations were conducted during weekdays  compared to weekends  in the lockdown. This is contrary to the trend seen by the Paediatric Ophthalmology department of our hospital, where a significant patient-burden was observed on weekends, as patients’ parents had job obligations and other social duties during the weekdays. Thus, the teleconsultation programme could provide an opportunity for parents to acquire consultation for their children from home, even on the weekdays, without visiting the hospital.The most common indication for the teleconsultation during the lockdown was red-eye , which was associated with seasonal ocular allergic disorders  and was managed by the corneal service. In addition, trauma and infectious keratitis-related consultations comprised 9.36% (n = 134) and 4.33% (n = 62) of the post-lockdown consultations, respectively. Most of these patients had a history of vegetative trauma that could be linked to the ongoing wheat-harvesting season. Amongst sub-specialities, the teleconsultation programme maintained 29.01% of the pre-lockdown glaucoma department services. While glaucoma is a chronic disease, and the majority of patients require a lifelong therapy for its treatment, these patients found the programme very useful, as they could obtain regular advice regarding issues that occasinally emerge with the use of topical medicines, such as drug allergies or ocular surface problems. They could also inquire about alternatives if some medicine were not available due to the lockdown. However, the requirement of an occasional detailed physical evaluation to monitor the disease progression limits the concept of virtual consultation for the majority of glaucoma patients. Contrarily, optometry along with vitreoretinal and oculoplastics departments’ services were the least utilized during the lockdown . Middle-aged and elderly patients with problems, such as cataract, presbyopia and stable posterior segment pathologies , likely preferred to wait until routine outdoor services were restored, since their refractive errors and posterior segments could not be evaluated through a teleconsultation. Teleconsultation could be quite a useful way to diagnose and plan the management of many oculoplastics disorders due to their gross appearance ; howeverSome countries such as China are now relaxing the lockdown restrictions since they have attained satisfactory control of SARS-CoV-2 transmission by adopting strict social distancing measures . Such soThe surge of digital technology in Pakistan, allowing a wide array of options, may be utilized to promote inexpensive and equitable eye care in remote underprivileged areas . In our While economic broadband services and mobile connectivity would make teleconsultation affordable and accessible, targeted-marketing strategies  may also be adopted to expand the outreach and scope of digital initiatives. Using teleconsultation, “Home Clinics” could be arranged for females and elderly patients who might find it challenging to come to healthcare premises due to various social issues and cultural sensitivities , 53. MobIn this study, a detailed assessment of the sub-speciality burden in ophthalmology was conducted, which determined the utilization trends of different sub-specialities and identified factors that may hamper eye care equity and access during the COVID-19 pandemic. A multivariate binary logistic regression analysis was performed, but it was not included in the final results because of minimal predictive power and a very limited set of available possible predictors. Moreover, patients’ feedback regarding the teleconsultation programme that could have better described the utility of this service could not be collected. Future work studying this aspect is underway.In conclusion, teleconsultation utility in ophthalmology is a relatively unexplored frontier, especially in developing countries such as Pakistan. The current study showed that teleconsultation could partially maintain eye care services during a lockdown. It also identified the key sociodemographic characteristics of the patients along with the sub-specialities that could be targeted with policy-based interventions to advance equitable eye care and promote teleconsultation utilization. In the words of sages, "a crisis provides an opportunity"; the pandemic too provides an opportunity for the further fusion of the global health sector with optimal digital technology. Effective and immediate utilization of digital initiatives to combat this colossal global health challenge would, in all likelihood, increase the general acceptance of such technologies for other sub-specialities of healthcare in the future.S1 Appendix(SAV)Click here for additional data file.


The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes severe respiratory tract infections in humans (COVID-19), has become a global health concern. Currently, several vaccine candidates against SARS-CoV-2 are in clinical trials but approval of these vaccines is likely to take a long time before they are available for public use. In a previous report, the importance of passive immunity and how immunoglobulin (Ig)G collected from recovered coronavirus patients could help in the protection against COVID-19 and boost the immune system of new patients was reported. Passive immunity by immunoglobulin transfer is a concept employed by most mammals and bovine IgG has a role to play in human therapy. IgG is one of the major components of the immunological activity found in cow's milk and colostrum. Heterologous transfer of passive immunity associated with the consumption of bovine immune milk by humans has been investigated for decades for its immunological activity against infections. This short review focuses on passive immunity and how microfiltered raw immune milk or colostrum collected from cows vaccinated against SARS-CoV-2 could provide short-term protection against SARS-CoV-2 infection in humans and could be used as an option until a vaccine becomes commercially available. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes severe respiratory tract infections in humans COVID-19), has become a global health concern 9, has be. Most coCurrently, different academic institutions and pharmaceutical companies worldwide have started programs to develop and test vaccine candidates against SARS-CoV-2 in clinical trials. An S-glycoprotein-based vaccine is a promising approach that has attracted the attention of scientists, since S-glycoprotein can be directly recognized by the host's immune system . For theIn a recent report, I emphasized the importance of immunoglobulin (Ig)G collected from recovered coronavirus patients in protecting against COVID-19 and boosting the immune system of new patients . SubsequIt is well-known that bovine colostrum and cow's milk are highly rich in IgG that binds to many gastrointestinal and respiratory pathogens that infect humans, supporting cross-species activity between bovine and human IgG . Cow's mPassive immunity through ingestion of colostrum and bovine milk is essential for the survival of newborn animals. For this purpose, the vaccination of pregnant cows ahead of calving has been shown to be effective in transmitting protection against infections to the newborn calf. In contrast to human milk, in which the principal immunoglobulins are IgA, IgG1, IgG2, and IgM, IgG1 is the major immunoglobulin in cow's milk, in particular in colostrum, whereas IgM, IgA, and IgG2 are present at lower concentrations . The conThe vaccination of cows against new pathogens before collecting their milk or colostrum can increase the specificity of IgG in the milk or colostrum and the new pathogen should be neutralized after consumption of hyperimmune colostrum or cow's milk. Different experimental and clinical studies have explored the effect of oral bovine IgG in the prevention or treatment of viral infections, including the use of IgG-derived hyperimmune colostrum or cow's milk –26. HypeCryptosporidium, Campylobacter, and Amoeba  produced from cattle immunized with a MERS coronavirus vaccine and single infusions of this IgG antibody, up to 50 mg/kg, appeared to be safe and well-tolerated in healthy participants , 40. In SJ drafted this review.The author declares 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 appearance of histology images stained with H&E can vary a lot as a consequence of changes in the reagents, staining conditions, preparation procedure and acquisition system. In this work we investigated whether color preprocessing—specifically color deconvolution and color normalization—could be used to correct such variability and improve the performance of automated classification procedures. Experimenting on 11 datasets, 13 image descriptors and eight color pre-processing methods we found that doing no color preprocessing was the best option in most cases.Histological evaluation plays a major role in cancer diagnosis and treatment. The appearance of H&E-stained images can vary significantly as a consequence of differences in several factors, such as reagents, staining conditions, preparation procedure and image acquisition system. Such potential sources of noise can all have negative effects on computer-assisted classification. To minimize such artefacts and their potentially negative effects several color pre-processing methods have been proposed in the literature—for instance, color augmentation, color constancy, color deconvolution and color transfer. Still, little work has been done to investigate the efficacy of these methods on a quantitative basis. In this paper, we evaluated the effects of color constancy, deconvolution and transfer on automated classification of H&E-stained images representing different types of cancers—specifically breast, prostate, colorectal cancer and malignant lymphoma. Our results indicate that in most cases color pre-processing does not improve the classification accuracy, especially when coupled with color-based image descriptors. Some pre-processing methods, however, can be beneficial when used with some texture-based methods like Gabor filters and Local Binary Patterns. Digital pathology plays a fundamental role in cancer diagnosis, treatment and follow-up ,6,7,8,9.Among the problems that so far have limited the adoption of digital pathology on a wide scale are differences in the protocols, materials and procedures for image acquisition and the little availability of large datasets of annotated images . Such vaThis work presents a quantitative evaluation of color deconvolution and color normalization on automated (patch-based) classification of histology images stained with hematoxylin and eosin from breast, prostate, colorectal cancer and malignant lymphoma. The present study extends the preliminary results presented in  and the We considered nine datasets of H&E-stained histological images representing different types of neoplastic diseases as detailed below. Samples images of each dataset are illustrated in Histological images from breast carcinoma collected within the ‘Agios Pavlos’ Department of Pathology at the General Hospital of Thessaloniki . The dataset includes 300 images  of invasive ductal carcinoma  from 21 patients.Histological samples of breast carcinoma collected at the Pathological Anatomy and Cytopathology Laboratory  . This coHistological images from patients with prostate cancer collected at the Cedars-Sinai Medical Center  . The datHistological samples from 109 subjects with breast ductal carcinomas who received a biopsy at the Department of Pathology, University Hospital of Patras, Rio, Greece, between 2000 and 2007 . The datA dataset of histological images of colorectal cancer collected at the University Medical Center Mannheim, Heidelberg University  ,42. The n = 113), follicular lymphoma (n = 139) and mantle cell lymphoma (n = 122). The dimension of the images is 1388 px × 1040 px. Since the samples come from different centers there is a large amount of staining variation.Histological images of malignant lymphoma from different institutions ,44. ThisBreast cancer histology images from a population of 248 patients. The images were collected at the Netherlands Cancer Institute  ,46. FromThis dataset has the same structure as the one described in n = 74) and malignant tissue (n = 91). The samples were collected at the University Hospitals Coventry and Warwickshire  [This dataset includes a total of 165 images representing colorectal tissue and is organized in two classes: benign (Kingdom) ,48. The er 2015) .One important factor that can affect the colors of histological images are the specific conditions of the acquisition laboratory. To assess the effects of inter-laboratory variability, we generated two additional datasets by merging Agios Pavlos and HICL  chromaticity representation (‘chroma’ in the remainder), (2) grey-world normalisation (‘gw’) and (3) histogram equalization (‘heq’) ,58. The  toolbox   on the other . The firThe three-dimensional probability distribution in the color space as described in . We usedThe concatenation of the three one-dimensional probability distributions of the intensity level in each color channel . We usedTexture features from 12 co-occurrence matrices computed using three distances  and four orientations . From each matrix we extracted five statistical parameters: contrast, correlation, energy, entropy and homogeneity  for a tofeatures .Texture features from a bank of 24 Gabor filters with four frequencies and six orientations. From the absolute value of each Gabor-transformed image we computed the mean and standard deviation giving a total lization Histograms of rotation-invariant (‘ri’) Local Binary Patterns  computedFrom the grey-scale texture descriptors described in We used five pre-trained convolutional networks ‘off-the-shelf’—i.e., without any further re-training or fine-tuning  of the samples of each class  to construct the classifier, and then, the remaining samples  were used to calculate the accuracy. Thus, the accuracy was the percentage of samples of the test set classified as correct. To obtain a stable estimation, we repeated the random subdivision of the train and test sets hundred times and the results were averaged. We repeated the experiments using To test the effectiveness of each combination of color pre-processing/image descriptor  we condu®  and carried out on a laptop PC equipped with Intel® coreTM i5-3230M CPU@ 2.60GHz, 8 GB RAM and Windows 7 Professional 64-bit. Feature extraction was based on the freely available Color And Texture Analysis Toolbox for Matlab (CATAcOMB) [The experiments were implemented using MatlabATAcOMB)  for the ATAcOMB)  for the The results for the best and second-best combinations of image descriptor and color pre-processing method for each data set are presented in The methods based on texture proved fairly resilient to color pre-processing , as it wTo reduce potential sources of bias related to the samples distribution in the training and test sets, we repeated the classification experiments using a lower train ration  and (2) pre-trained CNN from the ResNet family are the descriptor of choice. Otherwise, if there are enough data enough to carry out some domain-specific tuning, we recommend the color pre-processing method(s) be always evaluated along with the image descriptor(s) used.In conclusion, the results suggest that the application of color pre-processing methodologies for patch-based classification of H&E-stained images should be considered with care. Although our results show some dependence on the dataset used, on the whole our findings indicate that in the absence of enough data for domain-specific tuning, (1) doing nothing (no color pre-processing) is likely to be a good option in most cases (


Acute coronary syndromes (ACS) secondary to coronary vessel plaques represent a major cause of cardiovascular morbidity and mortality worldwide. Advancements in imaging technology over the last 3 decades have continuously enabled the study of coronary plaques via invasive imaging methods like intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The introduction of near-infrared spectroscopy (NIRS) as a modality that could detect the lipid (cholesterol) content of atherosclerotic plaques in the early nineties, opened the potential of studying “vulnerable” or rupture-prone, lipid-rich coronary plaques in ACS patients. Most recently, the ability of NIRS-IVUS to identify patients at risk of future adverse events was shown in a prospective multicenter trial, the Lipid-Rich-plaque Study. Intracoronary NIRS-IVUS imaging offers a unique method of coronary lipid-plaque characterization and could become a valuable clinical diagnostic and treatment monitoring tool. Coronary artery disease (CAD) has continued to be a major cause of morbidity and mortality worldwide, despite recent advances in medical and interventional therapies . The patIntravascular Ultrasound provides 2-dimensional cross-sections of arterial vessels which enables the visualization and characterization of not just lumen and stent struts, but the vessel wall dimensions and the presence of plaques within it. In spite of the usefulness of IVUS in the study of plaques and vessel remodeling, it remains limited in the visualization and quantification of certain plaque characteristics mainly due to the inherent properties of sound waves . NIRS imWe will review the present and potential clinical and research utility of NIRS-IVUS imaging in the study of coronary lipid plaques in the context of CAD.Near-infrared diffuse reflectance spectroscopy is a technique that relies on the property of substances to absorb and scatter NIR light  at different intensities as a function of wavelengths . NIRS asin-vivo use of diffuse reflectance NIRS in imaging the lipid content in human carotid plaques exposed during surgery  had been studied for possible intravascular applications toward the study of atherosclerotic plaques. The Raman near-infrared spectroscopy (NIRS) which was widely used several disciplines was based on the inelastic scattering of photons following collision with molecules and while it was suggested to have the potential to identify vulnerable plaques, was limited by signal-to-noise problems –14. The  surgery , 16In the early days of NIRS, 2 pivotal studies were carried out to validate its accuracy for the detection of lipid core plaques (LCPs) in human vessels. The first study by Gardner et al. made use of 84 human heart specimens- 33 hearts were used to develop NIRS algorithms and produce predefined endpoints while the remaining 51 hearts were used for prospective validation of algorithm, in a double-blinded study design, to evaluate the accuracy of NIRS in detecting LCPs. In order to have a quantitative target for constructing the algorithm and validating the findings, an LCP of interest was defined as a “fibroatheroma” (FA) with a lipid core >60° in circumferential extent, >200 μm thickness, and with a fibrous cap of mean thickness <450 μm.” The primary analysis which was done by comparing NIRS information presented on block chemogram readings vs. the classified histologic findings showed a “receiver operating characteristic (ROC) area under the curve (AUC) of 0.80 (95 % CI: 0.76–0.85),” confirming the ability of the NIRS system to accurately identify the LCPs  study which was the first catheter-based technique to use NIRS in humans for percutaneous application was performed to validate the applicability of the autopsy-based LCP detection algorithm in patients. The study, in addition to showing that the NIRS imaging catheter had a similar safety profile to that of IVUS, demonstrated that the spectra obtained from imaging the epicardial vessels of living patients were similar to those from previously validated spectra from autopsy specimens, thereby supporting the use of NIRS for detection of LCPs in human patients .ex-vivo studies had examined the ability of NIRS to identify histological features of lipid-rich atherosclerotic plaques in human blood vessels obtained at autopsy. These studies reported >90% sensitivity and specificity for the identification of characteristic features suggesting lipid-rich plaques including the rupture-prone thin-cap fibroatheromas (TCFAs) seen in ACS patients. More recent studies have corroborated these findings as well as pointing to the additive value of NIRS to IVUS-derived PB in detecting vulnerable plaques . In later years, a dual modality system which combined IVUS with NIRS was developed to provide in a single catheter information on both vessel structure and plaque composition in a single acquisition. The NIRS-IVUS systems have continued to evolve and now exist in the form of a dual frequency, dual modality system.  The NIRS-IVUS system comprises a scanning NIR laser, a pullback and rotation unit, and a traditional IVUS-sized catheter. The 3.2F rapid exchange catheter has an entry profile of 2.4F and a shaft profile of 3.6F and is compatible with 6F guiding catheters. The NIRS-IVUS can be inserted over a 0.014-inch guide wire while its passage through the lesion is facilitated by the hydrophilic coating present on the flexible distal 50 cm end. The IVUS images are acquired during an automated pullback with simultaneous co-registered NIRS measurements. In the latest generation, the Makoto system, the catheter's imaging core pulls back at speeds of 0.5, 1.0, or 2.0 mm/s and rotates at 1800 rpm with a maximum imaging length of 15 cm, acquiring up to ~130,000 NIRS per 100 mm , 24 Fig.NIRS lipid core data are automatically displayed on a “chemogram” which displays the probability of the presence of a lipid rich plaque with the millimeters of pull-back on the x-axis and the circumferential position on the y-axis. Areas containing lipid core are displayed as yellow and those without any significant lipid core as red. A quantitative image metric is automatically reported as a numerical lipid-core burden index (LCBI), which represents the fraction of the chemogram yellow pixels whose probability of lipid exceeds 0.6, per 1,000. The LCBI provides a quantitative metric of the lipid core plaque present in a scanned vessel and can be computed over the entire length of a vessel scan, segments of scans, or defined width windows within segments   Figure .Prior autopsy studies have shown that lesions with a thin fibrous cap(<65 mn of cap thickness) overlying a large necrotic core are most frequently prone to rupture , 25, 26.The PROSPECT  Trial, a landmark study which included 697 acute coronary syndrome (ACS) patients was a natural history study that sought to provide in vivo evidence of the hypothesis that the histopathological characteristic of plaques and not the degree of stenosis on angiography was responsible for the development of ACS. The study investigated the non-culprit coronary lesions in patients with ACS who underwent three-vessel gray scale and VH-IVUS imaging after successful PCI of culprit lesion demonstrated that “independent predictors of non-culprit-related events were the presence of VH-IVUS thin-cap fibroatheroma , a PB ≥70% , and a minimum lumen area ≤ 4.0 mm2 ” (1–6.42)” .COLOR registry prospectively observed a positive association between plaque morphology evaluated by NIRS and the degree of coronary artery stenosis. It demonstrated that increasing degree of stenosis seen by angiography was associated with more vulnerable plaque morphology as assessed by NIRS-IVUS system. Also, one of the first prospective human studies which evaluated high LCP by NIRS vs. cardiovascular events- The ATHEROREMO-NIRS  trial, a sub-study of the ATHEROREMO-IVUS study of nearly 600 patients  produced promising results regarding the possibility of the technology. The relationship of LCBI value with the primary endpoint composite was found to be similar in both stable angina and ACS patients. In a more recent study, Matsumura et al. employed NIRS-IVUS in examining the features of coronary lesions with intraplaque hemorrhage (a key culprit in coronary lesion progression) in a histopathological validation study and demonstrated the presence of more FAs, greater IVUS PB and NIRS lipid core burden present in intraplaque hemorrhage segments compared to segments without intraplaque hemorrhage  identified patients and coronary segments at risk of future major adverse coronary events using NIRS-IVUS system. Patients with known or suspected CAD undergoing cardiac catherization with possible PCI were examined via NIRS-IVUS imaging in non-culprit arteries when possible. The study showed that 9% of the patients had subsequent non-culprit-major adverse cardiac events (NC-MACE) and out of these patients, higher event rate was associated with analyzable maxLCBI4mm > 400 , pointing to the diagnostic value of the NIRS-IVUS  , 55.Several other studies , 56, 57 With the evolution of pharmacological therapies in addition to the performance of the present lipid-lowering therapies, NIRS-IVUS offers a tool for monitoring the effects of medications such as statins and PCSK9-inhibitors on the coronary vasculature lipid burden. Already, studies have investigated the effect of lipid-lowering medications on reducing necrotic-core containing plaques. The YELLOW (Reduction in Yellow Plaque by Aggressive Lipid-Lowering therapy) trial was a randomized clinical trial (rosuvastatin 40 mg daily vs. the standard-of-care lipid-lowering therapy) which recruited patients with multi-vessel CAD (including at least 1 severely obstructive [FFR ≤ 0.8] non-culprit) undergoing revascularization by PCI. The non-target lesions in both groups were evaluated at baseline and following 7 weeks of therapy with fractional flow reserve (FFR), and NIRS-IVUS, comparison between baseline and follow up results for NTLs demonstrated that reduction in LCBI4mm max was significantly higher in intensive statin group as compared to standard group  In a folThe findings of Waksman et al. in the recent LRP study  stronglyClinicalTrials.gov Identifier: NCT03067844) is examining the effects of PCSK9-inhibiting monoclonal antibody, alirocumab on coronary atherosclerosis in acute MI patients via NIRS, IVUS and OCT. Also, the FITTER  Trial , will be enrolling patients to investigate the impact of evolocumab plus statins on FFR of non-infarct related arteries (non-IRAs) in multivessel disease patients and correlating baseline NIRS-derived lipid core burden with changes in FFR in the non-IRAs.Notably, the effects of newer LDL-lowering medications are currently being studied in ongoing trials. The PACMAN AMI (Vascular Effects of Alirocumab in Acute MI-Patients) trial , patients with high risk plaque were randomized to receive Absorb BVS alongside the standard of care, optimal medical therapy (OMT) or vs. OMT alone and changes in the plaque will be evaluated by IVUS and NIRS at follow up. Lastly, The Preventive Coronary Intervention on Stenosis With Functionally Insignificant Vulnerable Plaque (PREVENT) study, is presently recruiting patients to determine the effect of preventive PCI on functionally insignificant coronary lesions with vulnerable plaque characteristics using NIRS, IVUS, OCT and virtual histology-IVUS modalities .In a study design which integrates a natural history study and a randomized trial, the PROSPECT II and PROSPECT ABSORB, ex-vivo studies could represent a huge breakthrough in vulnerable plaque studies in the near future.While the value of NIRS-IVUS and other intracoronary imaging techniques are being shown in various imaging trials, there are still limitations in assessing plaque characteristics which could explain some of the conflicting study results. Multimodality imaging may be critical in overcoming these limitations, thus emphasizing the need for co-registration of NIRS-IVUS with other imaging including angiography and as well as OCT or in the form of hybrid imaging catheters . FinallyOne of the main limitations of NIRS-IVUS is the invasiveness of the technique which precludes its use in primary prevention in symptomatic patients with subclinical disease. Presently, NIRS imaging does not have the capability to detect the depth of the lipid core or vulnerable plaque features such as the thinness of the fibrous cap.NIRS in conjunction with IVUS is certainly a diagnostically useful tool for the detection of vulnerable plaques and can help identify patients at risk of future coronary events. While there is a wide spectrum of clinical applications for this technology, its viability for demonstrating the effects of present and forthcoming lipid-lowering therapies could significantly influence clinical perspectives and practice in the years to come.All authors made a substantial contributions to the conception or design of this review paper, including the drafting and revisions. All authors have granted their approval for all aspects the manuscript and its submission.RW has served on advisory boards for Amgen, Boston Scientific, Cardioset, Cardiovascular Systems, Medtronic, Philips Volcano, and Pi-Cardia; has served as a consultant for Amgen, Biosensors, Biotronik, Boston Scientific, Cardioset, Cardiovascular Systems, Medtronic, Philips Volcano, and Pi-Cardia; and has received grant support from AstraZeneca, Biotronik, Boston Scientific, and Chiesi; and has participated at a speakers bureau for AstraZeneca and Chiesi; is an investor in MedAlliance. 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.


This computational process was used to predict both the primary and secondary pharmacological activities for a selection of 857 diverse small molecule drugs for which extensive secondary pharmacology data are readily available (456 discontinued and 401 FDA approved). The OTSA process predicted a total of 7,990 interactions for these 857 molecules. Of these, 3,923 and 4,067 possible high-scoring interactions were predicted for the discontinued and approved drugs, respectively, translating to an average of 9.3 interactions per drug. The OTSA process correctly identified the known pharmacological targets for >70% of these drugs, but also predicted a significant number of off-targets that may provide additional insight into observed in vivo effects. About 51.5%  and 22% (900) of these predicted high-scoring interactions have not previously been reported for the discontinued and approved drugs, respectively, and these may have a potential for repurposing efforts. Moreover, for both drug categories, higher promiscuity was observed for compounds with a MW range of 300 to 500, TPSA of ~200, and clogP ≥7. This computation also revealed significantly lower promiscuity  for compounds with MW > 700 and MW<200 for both categories. In addition, 15 internal small molecules with known off-target interactions were evaluated. For these compounds, the OTSA framework not only captured about 56.8% of in vitro confirmed off-target interactions, but also identified the right pharmacological targets for 14 compounds as one of the top scoring targets. In conclusion, the OTSA process demonstrates good predictive performance characteristics and represents an additional tool with utility during the lead optimization stage of the drug discovery process. Additionally, the computed physiochemical properties such as clogP , molecular weight, pKa and logS  were found to be statistically different between the approved and discontinued drugs, but the internal compounds were close to the approved drugs space in most part.Most small molecule drugs interact with unintended, often unknown, biological targets and these off-target interactions may lead to both preclinical and clinical toxic events. Undesired off-target interactions are often not detected using current drug discovery assays, such as experimental polypharmacological screens. Thus, improvement in the early identification of off-target interactions represents an opportunity to reduce safety-related attrition rates during preclinical and clinical development. In order to better identify potential off-target interactions that could be linked to predictable safety issues, a novel computational approach to predict safety-relevant interactions currently not covered was designed and evaluated. These analyses, termed Off-Target Safety Assessment (OTSA), cover more than 7,000 targets (~35% of the proteome) and > 2,46,704 preclinical and clinical alerts . The approach described herein exploits a highly curated training set of >1 million compounds (tracking >20 million compound-structure activity relationship/SAR data points) with known  The drug discovery process for small molecules typically starts with large screening campaigns using institutional or commercial compound collections in order to identify chemical matter for lead optimization efforts Drews, . The pasSmall molecule drugs have been shown to bind on average to a minimum of 6-11 distinct targets excluding their intended pharmacological target  approved drugs to assess whether they would predict reported known interactions. In addition, 15 internal molecules with well-characterized off-target interactions were evaluated.in vitro and in vivo testable off-target binding targets that may be adverse as well as therapeutic.The overall OTSA computational process is described in The full OTSA workflow is comprised of a number of 2-D target prediction methods and 3-D protein structure-based approaches including 3Decision, a web-based protein structure application utilizing public as well as proprietary structures, co-developed by AbbVie, Inc.  and Discngine S.A.S . The predicted off-targets from these orthogonal target prediction methods are ranked using normalized pseudo-score, which is the sum of the linear combination of scores from the different ligand-centric methods. Pseudo-score of 1.00 reflects certainty: it is assigned when the test molecule is present in the training set with that mechanism of action (MoA) or if most of the methods predict a particular target as a likely binding partner. In order to choose reasonable pseudo-score cut-off values, 15 well-studied marketed kinase inhibitors were used as a training test. The predicted score values for these inhibitors were analyzed within the context of available pharmacological as well as other off-target information. Most of the known off-targets, as well as the pharmacological target were predicted with a score value ≥0.6 . Thus, pThe key steps involved in the off-target prediction workflow are described below:in vitro metabolite profiling is available, these data are combined with the predicted metabolites to create a Meta-List. Metasite , Bioclipse  were used to profile potential targets for both the parent molecule and its metabolites. The six different cheminformatic methods used in the present study are Similarity Active Subgraphs (SAS) Willett, , SAS basSAS: Given a biological target, a SAS is defined as the simplest active subgraph containing the minimum pharmacophoric features needed  to achieve activity. SAS screening allows for the identification of similar pairs of molecules previously categorized as dissimilar, expanding the applicability domain and improving prediction Willett, . In addiSAR: SAR facilitates the development of large-scale QSAR models  Pharmacophoric Fragments (PHRAG), (2) Feature-Pair Distributions (FPD), and (3) Shannon Entropy Descriptors (SHED). PHRAG and FPD calculate the similarity between two chemical structures that account for the overlapping portion of their active profile . MLM is a consensus score of the three MLMs; if the consensus score results are positive, the corresponding ligand-target link is considered to be likely.XPI: This public domain availability of cross-pharmacological data for thousands of small molecules on many different biological targets enables an in-depth cross-pharmacology analysis  , 2-D methods or ligand-based  and lastly a protein-ligand interaction pattern. For the current work, we focused on using only 2-D methods. The first method is the ligand fingerprint based, in which Extended-Connectivity Fingerprints (ECFP6) was used to calculate tanimoto similarity between the probe molecule and the ligands extracted from all public and proprietary X-ray crystal structures. The second method is the ligand pharmacophore which utilizes a fuzzy 3D pharmacophore representation of ligands to compare a pair of ligands. This method does take the conformation of the ligands in account and calculates root mean square deviation (RMSD) of superimposition. The third and last method in the 2-D category is ChEMBL profiling, which calculates the similarity between compounds from various assays and the probe molecule. Users can choose the sensitivity of these searches and ensure stringent or loose searches.The top scoring off-targets from this 3Decision (3-D binding site comparison search approach) step are generally combined with the 2-D predicted off-targets (six methods) to create a master off-target list (component 2 of OTSA process). This step was not used for the approved and discontinued drug lists evaluated in the current study, as the 3Decison method is not high-throughput and would not be practical for such a large collection of molecules. However, for the internal 15 compounds, the 3-D method (3Decsision) was used in addition to the 2-D methods.3count) to increase molecular complexity  compounds satisfy both clogP  at four concentrations centered around their respective clinical human Cmax concentration value  and toxicity (off-target binding) is not the binding affinity, but the residence time of the drug molecule within the binding pocket of on/off-targets. Several examples confirm the role of residence time in prolonged target-mediated in vivo outcomes  are generally screened against the target of interest to discover novel lead molecules. It is not possible to work on the chemical optimization of each and every lead identified. Therefore, at this stage, the inclusion of key physicochemical property filters  can bias the odds in favor of finding successful leads. The current work suggests the physicochemical properties of approved drugs  are statistically different from those of discontinued drugs, in agreement with other published reports  predictive value for confirmed interactions in each compound set is promising considering that (1) our OTSA process includes metabolites in the prediction, which are not assessed by CEREP  and (2) not all of the predicted interactions were included in the CEREP screens and, as such, may also be accurate predictions. Finally, this study indicated that the computed lipophilicity (clogP), charge (pKa) and MW of the discontinued drugs are generally in higher range compared to the approved drugs. This work also suggests that the effective use of these computed simple physiochemical properties together with the OTSA predicted adverse interactions may form an integrated framework that can be used in lead optimization and preclinical studies.All authors are aware of the manuscript and have contributed significantly to its completion. In addition, all authors are employed at AbbVie and the appropriate disclosures are included on the title page along with keywords.All authors are employed by AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.


N-octylamine-modified fluorographenes with variable degrees of functionalization are studied and their nonlinear optical properties are assessed using 4 ns pulses. A very strong enhancement of the nonlinear optical response and a very efficient optical limiting action are observed, being strongly dependent on the degree of functionalization of fluorographene. The observed enhanced response is attributed to the increasing number of defects because of the incorporation of N-heteroatoms in the graphitic network upon functionalization with N-octylamine. The present work paves the way for the controlled covalent functionalization of graphene enabling a scalable access to a wide portfolio of graphene derivatives with custom-tailored properties.Fluorographene has been recently shown to be a suitable platform for synthesizing numerous graphene derivatives with desired properties. In that respect,  Herein, we investigate the effect of the amine functionalization of FG via N-octylamine nucleophilic substitution on its nonlinear optical (NLO) response and optical limiting (OL) performance under nanosecond laser excitation. Doping FG with heteroatoms, such as nitrogen, can significantly alter its electronic structure due to tailored defect-induced states, leading to novel 2D materials whose optical and electronic properties can be controlled by modifying the amount of nitrogen (%N) incorporated into the graphenic lattice. For instance, nitrogen doping can tune the electrical properties of some chemically functionalized graphenes, e.g., from a p-type semiconductor )β, the OA Z-scans were fitted by the following equation, described in detail elsewhere [Finally, the mechanism responsible for the nonlinear absorption of the studied FG-OAxs was investigated. As mentioned in the previous section, for the Z-scan measurements carried out under 532 and 1064 nm excitations, they were all found exhibiting valley-shaped “open-aperture” Z-scans, corresponding to RSA behavior, implying the presence of nonlinear absorption. However, depending on the excitation wavelength, the pulse duration and the material properties, the observed nonlinear absorption can arise from two-photon absorption (2PA) and/or excited state absorption (ESA). To evaluate the nonlinear absorption coefficient lsewhere :(1)Tx=1This equation implies nonlinear absorption due to two-photon absorption (2PA). As can be seen from the solid lines of the OA Z-scan curves, corresponding to the best fit by this equation, a very successful fitting was obtained, suggesting that the 2PA process is the main mechanism giving rise to the RSA behavior.β, was plotted as a function of the on-axis peak intensity for all FG-OAxs. If the ESA process is operating, it should cause the depletion of the ground state, leading to variations of the β with the on-axis peak intensity [β was found to be independent of the on-axis peak intensity, under both the 532 and the 1064 nm excitation, thus suggesting that any contribution of the ESA to the nonlinear absorption should be negligible. Therefore, it can be safely concluded that 2PA seems to be the principal mechanism of the observed OL action.Furthermore, the determined nonlinear absorption coefficient, ntensity . HoweverN-octylamine and having different degrees of functionalization, were studied. The NLO responses of the FG and the FG-OAx derivatives were investigated by means of the Z-scan technique, along with their OL action, under various excitation wavelengths ranging from visible (450 nm) to NIR (1750 nm). Their NLO response was turned ON shortly after the initiation of the partial nucleophilic substitution of the FG, leading to strong enhancement with the time of reaction. The FG-OAxs were found to be exhibiting strong nonlinear absorptions, attributed to defect-induced states due to the C–N bonding configuration formed by the incorporation of nitrogen into the graphenic lattice. Their strong nonlinear absorption was found to result in extremely efficient OL action, rendering the FG-OAxs very efficient optical limiters suitable to and attractive for a plethora of OL applications, from the visible to NIR spectral regions. The above experimental findings demonstrate clearly that FG is a useful platform for achieving chemical functionalization, leading to a wide portfolio of fluorographene derivatives, while by controlling the degree of functionalization the nonlinear optical properties of the derivatives can be largely tuned, providing materials with tailored properties throughout almost the entire optical spectrum, which are highly desirable for several photonic and optoelectronic applications.In conclusion, pristine fluorographene (FG) and four FG derivatives (FG-OAx), prepared after the partial nucleophilic substitution of FG with


A high rate of thrombotic complications, such as pulmonary embolism, has been linked to mortality in COVID-19, and appropriate treatment of thrombosis is important for lifesaving. Although heparin is frequently used to treat thrombotic pathology in COVID-19, pulmonary embolism is still seen in severe cases. Although systemic fibrinolytic therapy is a focus of attention because a thrombotic pathology is the cause of death in severe COVID-19, it should be kept in mind that fibrinolytic therapy might be harmful at advanced stage of COVID-19 where the status of disseminated intravascular coagulation (DIC) has been transmitted from suppressed-fibrinolytic to enhanced-fibrinolytic in disease progression of COVID-19. In this respect, inhalation therapy with fibrinolytic substances might be a safe and promising treatment. Some articles suggest several treatment options using fibrinolytic drugs for acute respiratory distress syndrome (ARDS) in severe cases of COVID-19 . ARDS anp < 0.0001) higher in severe cases of COVID-19 (ICU) than in mild cases (Non-ICU). This may indicate that fibrinolysis would be more activated in the advanced phase of COVID-19 [However, great caution is required when systemically administering tPA for severe COVID-19 associated with ARDS. According to a report by Tang et al., levels of fibrin/fibrinogen degradation products (FDP) and D-dimer increased significantly, and fibrinogen increased due to an inflammatory response following hospital admission in patients who died . In thesCOVID-19 .The marked decrease in fibrinogen is extremely dangerous if systemic fibrinolytic therapy is administered at the same time, and it gives rise to concerns about fatal bleeding, including cerebral hemorrhage. Particularly in severe cases of COVID-19, the coagulation and fibrinolysis pathology might change greatly over a short period. In previous reports of coagulation and fibrinolysis testing in COVID-19, the overwhelming focus was on D-dimer, followed by PT and APTT. However, periodic testing of fibrinogen and FDP levels is also important. If the results of these tests indicate the presence of enhanced-fibrinolytic-type DIC, systemic fibrinolytic therapy should not be administered.On the other hand, treatment by inhalation of fibrinolysis-related substances, such as tPA and plasminogen, can be administered at any stage of COVID-19 without concerns about bleeding . AdminisWith systemic fibrinolytic therapy for ARDS in severe COVID-19, there is concern about massive bleeding if the disease stage or coagulation and fibrinolysis pathology is misjudged. Autopsy investigations showed the frequency of both thrombosis and bleeding findings to be the same even if fibrinolytic therapy had not been administered , 8. Take2/FiO2 ratio without the side effect of bleeding. It is noteworthy that no effect on PT, APTT, or bleeding time has been shown [Although systemic fibrinolytic therapy is a focus of attention because a thrombotic pathology is the cause of death in severe COVID-19, it should be kept in mind that there are cases in which such therapy might be harmful. Indeed, five of 62 patients (8%) with DIC caused by severe meningococcal sepsis had been reported to develop intracerebral hemorrhages after systemic tPA administration . In thisen shown . In the Inhalation therapy with fibrinolytic substances should be planned to start at the phase of suppressed-fibrinolytic-type DIC  Fig.  or withoDespite the fact that the coagulation/fibrinolytic condition changes in a short period in the DIC of COVID-19, it is of concern that the DIC in COVID-19 is generally understood to be hypercoagulable DIC in many papers. In the absence of appropriate monitoring of the changing state of DIC, systemic fibrinolytic therapy would be considered dangerous.The clinical efficacy and safety of inhalation of fibrinolytic agents have not been sufficiently investigated, and it is also unclear whether they would be evenly distributed to all alveoli of COVID-19 patients. Moreover, inhalation therapy for patients with COVID-19 may stimulate the production of deleterious aerosols. Even though clinical research is still required, we believe that this new therapy would be good news for COVID-19 patients with ARDS.