Drosophila point to the MAP3 kinase Ask1 as a molecular hub that integrates several signals at the onset of regeneration. It has been discovered that reactive oxygen species (ROS) produced in damaged imaginal discs and gut epithelia will activate the MAP3 kinase Ask1. Severely damaged and apoptotic cells produce an enormous amount of ROS, which ensures their elimination by activating Ask1 and in turn the pro-apoptotic function of JNK. However, this creates an oxidative stress environment with beneficial effects that is sensed by neighboring healthy cells. This environment, in addition to the Pi3K/Akt nutrient sensing pathway, can be integrated into Ask1 to launch regeneration. Ultimately the activity of Ask1 depends on these and other inputs and modulates its signaling to achieve moderate levels of p38 and low JNK signaling and thus promote survival and regeneration. This model based on the dual function of Ask1 for early response to damage is discussed here.One of the main topics in regeneration biology is the nature of the early signals that trigger the damage response. Recent advances in  Regeneration, involving the repair or replacement of body parts, is widespread across the metazoans . The extDrosophila , which predominates in the mitochondria, is the result of the reduction by one electron to oxygen. Two-electron reactions that reduce oxygen to hydrogen peroxide (H2O2) also occur in mitochondria (2O2 is required for inflammatory cell recruitment (Xenopus tail or zebrafish fin lesions are required for regeneration (2O2 is generated by the activation of NADPH oxidases (DUOX) and is important for rapid recruitment of pro-inflammatory cells to the wound  and p38 . In mammneration .Because imaginal discs do not show significant apoptosis, the ectopic activation of pro-apoptotic genes in discrete zones is a suitable technique for neatly testing tissue recovery . This appuckered (puc) is expressed downstream of the JNK pathway and acts as a negative regulator of the pathway . Among the MAP3 kinases that operate upstream from JNK and p38, ASK1 is particularly sensitive to oxidative stressors . ASK1 isDrosophila Ask1. Ask1 can induce apoptosis in a JNK-dependent manner  embedded in a consensus that is highly conserved from sponges to mammals and that can be phosphorylated by Akt  to modulate different signals that foster proliferation and survival and prevent apoptosis. One of the canonical signals upstream from Pi3K/Akt is the insulin/insulin-like growth factor signaling pathway (IIS) that, upon activation of its tyrosine-kinase receptor, PIP2 is converted to PIP3 by Pi3K . PIP3 reOne of the central mechanisms that organisms use to sense nutrients and their own nutritional status is the highly evolutionarily conserved insulin/insulin-like growth factor signaling (IIS) and the target of rapamycin (TOR) pathways . The decDrosophila epithelia, from embryo to adult, have contributed to our understanding of the early signals that respond to damage in an organism. A central feature is Ask1, a kinase initially associated with promoting cell death that has now emerged as being pivotal in regeneration. We foresee Ask1 as a signaling hub that integrates early moderate Ca++/ROS signals and phospho-Akt survival signals to divert Ask1 towards the p38-regeneration response   . In addive cells . The pre++. But once the phospho-Akt diverts Ask1 towards the survival pathway, JNK activity is restricted to protecting the tissue from further damage. This is an attractive hypothesis as it implies that the onset of stress-induced repair has two phases: one more dependent on JNK and a second on p38. Further research will be needed to elucidate whether the activity of these kinases overlaps.An exciting suggestion would be that JNK responds rapidly to the first flashes of ROS or CaDrosophila members of the interleukin-6 family), which are capable of activating the JAK/STAT pathway for growth control (Gadd45, involved in DNA repair (Ets21c, a JNK-dependent transcription factor key for disc blastema cells (The transcriptional signature downstream of the damage response includes the program for regenerative proliferation and repatterning  and the  control . Also, n control , Hippo s control , Gadd45,A repair , and Etsma cells . Further


A significant proportion of boys with fragile X syndrome (FXS), the most common known genetic cause of intellectual disability, exhibit challenging behaviors such as aggression and self-injury that can cause significant distress to families. Recent evidence suggests that coaching caregivers to implement functional communication training (FCT) with their child via telehealth can help to ameliorate these behaviors in FXS. In the present study, we followed families who had participated in our previous randomized controlled trial of FCT to evaluate the longer-term effects of FCT on challenging behaviors in this population.In study 1, follow-up emails, phone calls, text messages, and letters were sent to caregivers of 48 boys with FXS who had completed our previous study conducted between 2016 and 2019. The main outcome measures administered at follow-up were the Aberrant Behavior Checklist–Community (ABC-C) and the Parenting Stress Index, 4th Edition (PSI-4). In study 2, families who had received FCT treatment but whose child exhibited challenging behaviors daily at follow-up received a 1-h parent training booster session to determine whether the intervention effect could be recovered.Sixteen (66.7%) of 24 families who had received FCT treatment and 18 (75.0%) of 24 families who had received treatment as usual were traced and consented between March and August 2021. The mean follow-up time was 3.1 years . Longitudinal mixed effects analyses indicated that boys who had received FCT were more likely to show improvements on the irritability and lethargy/social withdrawal subscales of the ABC-C over the follow-up interval compared to boys who had continued with treatment as usual. Four of the six boys who had received the booster parent training session via telehealth were reported to exhibit fewer forms of challenging behavior at a 4-week follow-up.Empowering parents to implement behavior analytic treatments with their child in their own home can have durable effects on maintaining low levels of challenging behaviors in boys with FXS. These data further support the need to implement parent-mediated interventions for challenging behaviors in this population at an early age.NCT03510156. Registered 27 April 2018ClinicalTrials.gov,  A significant proportion of boys with fragile X syndrome (FXS), the most common known genetic cause of intellectual disability, exhibit challenging behaviors such as aggression, self-injury, and property destruction that can cause significant distress to caregivers and interfere with the child’s educational and social development –3. PrevaFMR1) gene on the X chromosome at region q27.3 [FXS affects approximately 1 in 3000 to 4000 boys and 1 in 6000 to 8000 girls and is caused by mutations to the fragile X messenger ribonucleoprotein 1  administered via telehealth could ameliorate challenging behaviors in boys with FXS, ages 3 to 10 years , our priAlthough the FCT intervention showed promising results over the 12-week treatment period, it would be important to better understand the longer-term benefits of delivering behavioral treatments via telehealth for this population. In study 1, we re-contacted families who had completed our previous study and examined levels of challenging behavior and family stress at follow-up. For participants who had received FCT treatment but still exhibited daily challenging behavior at follow-up, in study 2, we examined whether delivering an additional booster therapy session via telehealth might help to reestablish the treatment’s effectiveness. A single booster session was delivered via telehealth to reacquaint families with the treatment procedures and outcomes were measured before and after the booster at a 4-week follow-up.FMR1 gene with evidence of aberrant methylation), were aged between 3 and 10 years inclusive, and exhibited at least one form of challenging behavior daily on the Behavior Problems Inventory–Short Form (BPI-S) [In our previous RCT study conducted between 2016 and 2019, boys with FXS were included if they had a confirmed genetic diagnosis of FXS (> 200 CGG repeats on the  (BPI-S) . BecauseFor the present study, caregiver-child dyads who had completed the previous study in each group  were contacted in the order in which they were previously enrolled via phone, email invitations, or text messages. If this was unsuccessful, a letter was sent to the address on file inviting them to participate in the study. All invitations were made from March 2021 to August 2021.Aberrant Behavior Checklist-Community (ABC-C) [The  (ABC-C)  is a 58- (ABC-C)  so that Parenting Stress Index, 4th Edition (PSI-4) [child domain and parent domain, which combine to form a total stress scale. Scores are reported as T-scores with a mean of 50 and a standard deviation of 10. Reliability coefficients for this measure range from .78 to .88. This measure is the most widely used measure of parental stress in the literature and has been employed as an outcome measure in a large number of clinical trials, including our own recently published RCT.The  (PSI-4)  is a 120Finally, the Behavior Problems Inventory–Short Form (BPI-S)  was admid effect sizes were calculated by dividing the estimated slope by the baseline sample standard deviation. For group differences, effect sizes were calculated by dividing the estimated slope difference by the baseline sample standard deviation pooled across the two groups. Finally, to examine whether children who were assessed after a shorter time lapse exhibited fewer challenging behaviors, we computed correlations between change per year on the subscales of the ABC-C and time between baseline and follow-up.For the analyses of longitudinal data, we used standard mixed effects modeling , 24, treOf the 48 families who completed the previous study, we were able to contact 43 families by phone, email, or text. Two families subsequently decided not to participate in the study and so 41 families were sent consent forms. Five families did not return the consent form and two signed consent but subsequently withdrew from the study. Therefore, we obtained follow-up data for 34 families, 16 of whom had previously received FCT treatment and 18 of whom had received treatment as usual. The mean follow-up time was 2.8 years (range = 1.4 to 4.2 years) for participants who had received FCT treatment and 3.2 years (range = 2 to 4.2 years) for participants who had received treatment as usual.Figure 95% = − 2.778, − 1.055) for boys who had received FCT and was .068 points  for boys who had received treatment as usual, a significant difference between the groups . On the lethargy/social withdrawal subscale, the mean change per year was − 1.006 points  for boys who had received FCT and was .129 points  for boys who had received treatment as usual, a significant difference between the groups . These data indicated that scores decreased at a faster rate on the irritability and lethargy/social withdrawal subscales from baseline to follow-up for those who had received FCT treatment compared to those who had received treatment as usual. There were no other significant differences between the groups in the trajectory of scores on the other subscales of the ABC-C. There was a significant correlation between change per year on the irritability subscale of the ABC-C and time between baseline and follow-up (r(16) = − .495, p = .026, one tailed) indicating that the treatment gains were stronger closer to the initial treatment.On the irritability subscale of the ABC-C, the mean change per year was − 1.92 points  for boys who had received behavioral treatment and was .059 points  for boys who had received treatment as usual, a significant difference between the groups . There were also significant differences between the groups on the parent domain and the total stress scores of the PSI-4. These data indicated that parenting stress decreased at a faster rate from baseline to follow-up for those who had received FCT treatment compared to those who had received treatment as usual. There were no differences from baseline to follow-up in terms of the proportion of children who were receiving psychotropic medications, speech therapy, occupational therapy, or physical therapy in either group. Five of 16 (31.3%) boys who had received FCT and 4 of 18 (22.2%) boys who had received treatment as usual were reported to be receiving ABA therapy at follow-up.On the child domain, the mean change per year was − 1.276 points (CIχ2(1) = 9.15, p = .002)On the BPI-S, 11 of 16 (68.8%) boys who had received FCT and 14 of 18 boys (77.8%) who received treatment as usual were reported to display at least one form of challenging behavior daily at follow-up. Twelve (75.0%) boys who had received FCT and 15 (83.3%) boys who had received treatment as usual were also taking psychotropic medications at follow-up. A chi-square analysis indicated that boys who displayed daily challenging behaviors were significantly more likely to be taking psychotropic medications . As a result of his property destruction, P10 had made several holes in the walls throughout his house. P10 used vocal language to communicate, with full sentences of 3−5 words and was enrolled in a special education school where he was able to attend until the COVID-19 pandemic began. During the pandemic, P10 was homeschooled with an in-home babysitter who also became his primary caregiver. P10 had begun to display challenging behavior primarily due to constantly being at home and not being able to go to the park, walks or shopping for toys. At this time, his family would often order items online and this led P10 to experience higher levels of anxiety waiting for delivery vehicles which often resulted in challenging behavior. P10’s parents created a padded area in the house for him to de-escalate during severe aggressive episodes. Sometimes P10 would transition himself independently to calm down in this area, but sometimes he would require physical guidance from his parents.P14 was a 9-year-old male who displayed two forms of challenging behavior daily (self-biting and head-hitting). He used vocal language to communicate with full sentences of 5–6 words and attended school in a special classroom in person prior to the pandemic. During the pandemic, P14 began attending school and speech therapy online and began displaying problem behavior by refusing to attend school if his mother was not present to consistently redirect him to attend to the computer screen. P14 also began displaying inappropriate noises during online schooling. In addition, he began biting his arm and hitting himself to get attention from his peers online. He was reported to experience higher anxiety levels when he and his family needed to go out of the house into the community. For example, whenever P14 had to attend doctor’s appointments in-person or go grocery shopping with his mother without knowing what to expect, this would often lead to outbursts of self-stimulatory behavior (swinging his arms above his head). His parents began redirecting this behavior to put his arms down, leading to self-injurious behavior.P23 was an 11-year-old male who displayed four forms of challenging behavior . He used an augmentative and alternative communication (AAC) device (Proloquo2Go) on an iPad to communicate, being able to build sentences of three words on the software . Prior to the pandemic, P23 attended school in a special education classroom for children with complex needs. P23 began online school when the COVID-19 pandemic started and this transition had been difficult for him and he had begun displaying challenging behavior daily.P25 was a 13-year-old male who displayed six forms of challenging behavior daily. He used vocal language with full sentences of 3–5 words and was attending school in a special education classroom prior to the pandemic. During the pandemic, P25 stopped receiving speech therapy and began attending school at a reduced level for only a couple of hours per day online. P25 often experienced anxiety levels due to being home with low structure and low activity throughout the day, and he often displayed challenging behavior by biting his knuckles. As P25’s day structure began including more activities throughout the day, he began displaying daily levels of self-biting, particularly when he had to transition across activities.P32 was a 9-year-old male who displayed two forms of challenging behavior on a daily. He used vocal language with full sentences of 6+ words and attended school in a general education classroom in person prior to the pandemic. During the pandemic, P32 and his family moved to a new neighborhood outside of the city where he began attending online school but with a different school district and teacher. P32 began displaying problem behavior during these transitions, particularly grabbing, and pulling others while waiting for their attention or for preferred items while attending online school and other therapies.P49 was a 7-year-old male who displayed three forms of challenging behavior . He used a combination of simple sign language, vocal language with 1-word requests, and picture exchange communication system (PECS) to communicate, with the PECS system being the primary communication method utilizing only one picture exchange. Prior to the pandemic, P49 attended school in person in a special education classroom and attended a clinic to receive 20 h of ABA therapy in person. During the pandemic, however, P49’s ABA therapy was paused and he was not receiving any therapy at the time of the follow-up study.Open-Ended Functional Assessment Interview [Caregivers were administered the nterview  to identTreatment Acceptability Rating Form–Revised (TARF-R) [The (TARF-R)  was admiFinally, the BPI-S was administered prior to the booster session and 4 weeks following the booster session to measure the frequency of the child’s challenging behavior.All participants received the booster session in their homes with minimal environmental modifications required. P10’s mother was advised to remove breakable items from the environment and to have access to the family’s security camera system to be able to remove attention fully while ensuring child’s safety. P10 and P14 were advised to cover the tablet screen to prevent child distractions.Each parent-child dyad was required to have an electronic device with a camera and audio . Most parent-child dyads still had the Bluetooth earpiece  provided in the previous RCT study and were able to utilize it to minimize distractions to the child. Each parent was provided with a video conferencing link to a HIPAA compliant Zoom room under Stanford University’s technology policy. Booster and post-booster sessions were recorded via the Zoom cloud and stored in Box, a HIPAA compliant software storage system for later coding.The booster parent coaching session was provided to each primary caregiver by a Board Certified Behavior Analyst (BCBA) via telehealth. The booster parent coaching session was 1 h in duration and consisted of 2 components: (1) a 30-min PowerPoint presentation, and (2) a 30-min treatment implementation with live coaching with their child. During the presentation, the BCBA reviewed the steps that had previously been trained in the RCT study. After the presentation, the BCBA coached the caregiver to implement the steps with the child providing live guidance and step correction as needed for errors of omission or commission.After 1 week of completing the booster session, a 1-h post-booster session was provided to the caregiver via telehealth. During this post-booster session, the BCBA asked the caregiver to implement the protocols covered during the booster session without reviewing the protocols and without live coaching. The BCBA collected data on parent treatment fidelity and child challenging behavior. If the parent procedural fidelity scores did not reach 80% during the post-booster session, the BCBA would review any errors during protocol implementation with the caregiver and would offer a second post-booster session. However, none of the caregivers made errors during the post-booster, and they were all able to implement treatment with 100% fidelity.During FCT treatment, procedures were matched to the sources of reinforcement identified from the Open-Ended Functional Assessment Interview. For challenging behavior maintained by social-positive reinforcement (access to tangible items or attention), the caregiver was coached to sit near the child in the same room with moderately preferred toys and provide them with attention or the highly preferred tangible item for 30 s. The caregiver was then coached to provide a natural warning that the attention or the tangible item was going to be unavailable . If the caregiver had more time available to engage with the child, or the child was allowed to play with the tangible item, the caregiver was coached to provide a reminder to the child . However, if there was not more time available, the caregiver was coached to provide the child a reminder on when he could access the attention or tangible again in the future . The caregiver was coached to prompt any communication when more time was available if the child didn’t request the attention or tangible item independently and to prompt the child to engage with alternative and moderately preferred items while waiting for the attention or highly preferred tangible item, simultaneously providing a natural visual signal . If the child displayed any problem behavior, the caregiver was coached to ignore and block it, while providing the natural visual signal for the waiting skill. If the functional communication response occurred independently or without problem behavior, the caregiver was coached to provide the corresponding reinforcement (attention or tangible) for 20 s with social praise.For challenging behavior maintained by social-negative reinforcement (escape from academic or transition demand), the caregiver was coached to make the necessary environmental modifications for safety purposes and provide a moderately preferred item to the child without presenting any demands for 30 s. Once 30 s had elapsed, the caregiver was coached to provide a natural warning to complete a task or to transition to another activity . After the child had completed the task, the caregiver was coached to provide praise for task completion and to provide a reminder that the child could have a break . If there was more time available for the child to engage with the current activity, the caregiver was coached to provide a natural reminder to the child of more time available . If the child displayed any problem behavior, the caregiver was coached to ignore and block it, while providing a natural visual signal for the task or transition completion skill. If the functional communication response occurred independently or without problem behavior, then the caregiver was coached to provide the corresponding reinforcement (break from academic or transition demand) for 20 s with social praise.The mean age of the participants in study 2 was 10.35 years (SD = 2.0 years) and the mean expressive communication age equivalent on the Vineland Adaptive Behavior Scales, 3rd Edition  was 2.7 In terms of the functions of challenging behavior identified, five of the six participants displayed two functions of challenging behavior. In all five cases, one of the functions was to gain access to attention. The median number of forms of challenging behavior displayed daily prior to the booster session was 3.5 (range = 2 to 6). At the 4-week follow-up following the booster session, the median number of forms of challenging behavior reported decreased to 2 (range = 0 to 3). Four of the 6 participants evidenced a decrease in the number of forms of challenging behavior displayed, with one participant (P10) no longer showing any forms of challenging behavior on a daily basis following the booster. For two participants (P14 and P32), the forms of challenging behavior reported daily stayed the same. These data indicated that the booster session may have facilitated implementation of the intervention for at least four of the six cases and led to subsequent improvements in their behavior.Table Scores on the reasonableness, effectiveness, and willingness subscales were high, indicating that the acceptability of the treatment was good. Scores on the cost and side-effects subscales were low, indicating that those factors did not impact the acceptability of the treatment. The score on the disruptiveness subscale indicated that caregivers did not find the treatment to be disruptive to the family.The goal of the current study was to conduct a follow-up of families included in our previous study who had received either FCT treatment or continued with treatment as usual to examine the longer-term effects of administering FCT treatments for challenging behaviors in young boys with FXS. Results showed that boys who had previously received 12 weeks of FCT via telehealth were more likely to show improvements in rates of challenging behavior over the follow-up interval than the boys who had continued with treatment as usual. Admittedly, the mean change in score on the irritability subscale of the ABC-C was relatively small (a decrease of 2 points per year). However, given that the mean follow-up time was 3 years, this would equate to a decrease in score of 6 points over that period. Given that the mean score on the irritability scale on the ABC-C at baseline in our RCT was 19.5 points, this amounted to a 30% decrease. These data suggest that implementing behavioral treatments that empower parents with the strategies to manage their child’s challenging behavior can result in the maintenance of treatment effects over several years.Differences were also found between the groups in terms of changes in levels of parental stress. Both groups of caregivers experienced high levels of parental stress at baseline in the previous study, but these stress levels decreased at a faster rate over the follow-up interval for those who had received FCT treatment. One potential factor that could have influenced these results is the onset of the COVID-19 pandemic. Our previous study was conducted between 2016 and 2019  whereas the present study was conducted approximately 1 year into the pandemic (March–August 2021). The number of hours spent at home, socially distanced from others, would therefore have dramatically increased in all families at the follow-up point. However, families who had participated at the beginning of the previous study in 2016 (and therefore had longer follow-up times) would have experienced most of the follow-up period under “normal” pre-pandemic conditions whereas families who had participated at the end of previous study in 2019 (and therefore had shorter follow-up times) would have experienced the majority of their follow-up period under pandemic conditions . The results of the study therefore need to be set in this context. Interestingly, we found that boys who were followed-up after a shorter time lapse exhibited greater decreases in challenging behavior over the follow-up interval. These data provide additional support for implementing booster sessions on a regular basis.At follow-up, we found that 11 of 16 boys with FXS who had received FCT treatment and 14 of 18 boys who had received treatment as usual still exhibited at least one form of challenging behavior on a daily basis. For participants in the FCT treatment group, we invited families to receive a subsequent booster training session. We also interviewed caregivers to identify the potential function(s) of their child’s challenging behavior. Six of the 11 families agreed to participate in the booster training and four of the six boys evidenced a decrease in the number of forms of challenging behavior displayed daily following the booster training. Although these effects were important, the benefits of the booster training were likely limited due to the short duration of the training as well as the short follow-up time (4 weeks). Future research is warranted to determine optimal titration of treatment dosage for long-term maintenance. For example, older patients with a prolonged history of reinforcement may benefit from monthly parent booster sessions for 6 months, prior to discharge. The aim of this type of titration model would be to prevent challenging behaviors from increasing back up to daily occurrences. Future studies will need to determine the optimal length of the booster training and whether further booster sessions are needed to optimize the treatment effect.The results of the functional assessment interview conducted prior to the booster session indicated that in 5 of 6 cases, the child’s challenging behavior was maintained by multiple sources of social reinforcement. In all 5 of those cases, one of the sources of reinforcement was to obtain attention from caregivers. A limitation of the current study was that we were unable to conduct a formal in-home functional analysis of the child’s challenging behavior. This was primarily due to restrictions imposed by the pandemic. However, in all cases, the functions identified in the current study were similar to the functions of challenging behavior identified in our previous study . These dIt is also possible that the reported improvements following FCT (and possibly the improvements at follow-up) could be due to demand characteristics or other forms of bias. Specifically, the control group had previously received treatment as usual, and therefore had a very different experience in many ways from the experimental group. Caregivers who were coached to implement FCT with their child may also have had a conscious or unconscious bias to please the experimenters, resulting in greater improvements than the control group. Placebo effects in the experimental group are also possible. In future studies, it would be important to equate the demand characteristics of the two groups, for example, by asking caregivers in the control group to complete online learning modules concerning their child’s challenging behavior. These psychoeducation sessions could be conducted at a similar frequency to the treatment group. To limit potential bias in the behavioral ratings, direct observations of challenging behaviors could also be conducted using trained observers who are blinded to treatment status.This study fills a significant gap in the literature by examining the extent to which behavioral treatment effects may be maintained in FXS and further informs the field concerning the longer-term benefits and impact of behavioral treatments administered via telehealth in general. We believe that the results of our study provides valuable information on how well and how long treatment effects can be maintained and how effectively treatment effects can be restored, which has been rarely studied in the field of behavioral intervention.


Among several combinations tested, remdesivir with either azithromycin or ivermectin synergistically increased the antiviral activity with no increase in cytotoxicity, improving the therapeutic index and lowering the LIC100 of every one of the drugs to levels that are expected to be achievable and maintained in the lung for a therapeutically relevant period of time. These results are consistent with recent clinical observations showing that intensive care unit admission was significantly delayed by the combination of AZI and RDV, but not by RDV alone, and could have immediate implications for the treatment of hospitalized patients with COVID-19 as the proposed “drug cocktails” should have antiviral activity against present and future SARS-CoV-2 variants without significant overlapping toxicity, while minimizing the onset of drug resistance. Our results also provide a validated methodology to help sort out which combination of drugs are most likely to be efficacious in vivo, based on their in vitro activity, potential synergy and PK profiles.Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant constraints and are not indicated for hospitalized patients, who are left with few antiviral options. Repurposed drugs have previously shown controversial clinical results and it remains difficult to understand why certain trials delivered positive results and other trials failed. Our manuscript contributes to explaining the puzzle: this might have been caused by a suboptimal drug exposure and, consequently, an incomplete virus suppression, also because the drugs have mostly been used as add-on monotherapies. As with other viruses  identifying synergistic combinations among such drugs could overcome monotherapy-related limitations. In a cell culture model for SARS-CoV-2 infection the following stringent criteria were adopted to assess drug combinations: 1) identify robust, synergistic antiviral activity with no increase in cytotoxicity, 2) identify the lowest drug concentration inhibiting the virus by 100% (LIC Despite new antivirals such as molnupiravir and PF07321332-ritonavir have been recently approved, they suffer from significant shortcomings: 1) they carry a high pill burden (6 to 8 pills daily); 2) molnupiravir could induce genetic mutations and its efficacy is limited . In addiAntiviral drug monotherapies have already failed while drug combinations have already been successful against Human Immunodeficiency Virus, Hepatitis C Virus, and other viral epidemics by completely inhibiting viral replication, avoiding the onset of mutant viruses and drug resistance, preventing disease progression, and sometimes leading to virus eradication and cure –16. Simiin vitro failed to work in vivo.Our suggested highly active broad-spectrum antiviral drug cocktails may have applications for the treatment of patients hospitalized with COVID-19. These patients have the highest need for effective antivirals for several reasons: 1) they carry a substantially higher viral load compared to non-hospitalized patients, 2) a higher viral load appears to be associated with more severe clinical outcomes and its reduction is most likely required for efficacy  and 3) tRemdesivir  was purchased from MedChemExpress . Azithromycin , ivermectin , umifenovir  and nitazoxanide , hydroxychloroquine , homoharringtonine , camostat , darunavir (S5250) and lopinavir  were purchased from SelleckChem .2. 24 hours after seeding fetal bovine serum concentration was decreased to 2% to avoid interference with the viral infection.Vero E6 cells  were seeded at a density of 10,000 cells/well into a 96-well plate in DMEM supplemented with 1% glutamine, 1% penicillin/streptomycin and 10% fetal bovine serum  at 37°C and 5% CO0, which is the highest concentration showing 0% cytotoxicity  compared to the untreated control.24 hours after seeding cells reached ~70% confluency and were treated with increasing concentrations of the drugs, alone or in combination, and cultured for additional 72 hours. At the end of the incubation period, the cytotoxic effect was measured through MTS assay  and by observation of cell monolayer integrity under light microscopy. Each compound was tested in duplicate wells to determine the HCC100, which is the lowest drug concentration that 100% inhibits virus replication. The Therapeutic Index (TI) was calculated as the ratio between HCC0 and LIC100.24 hours after seeding cells reached ~70% confluency and the supernatant in each well was replaced with 2% serum CM containing drugs at increasing concentrations, alone with each concentration tested in duplicate wells , or in dual drug combination . 1 hour later cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.01 and cultured for 72 hours. Four strains were used: 1) the human 2019-nCoV strain 2019-nCoV/Italy-INMI1, isolated in Italy (ex-China) from a sample collected on January 29, 2020, kindly provided by the Istituto Lazzaro Spallanzani, Rome, Italy . The 201As a validation of the cytoprotection assay readout, an ELISA test  was performed in monotherapy experiments on supernatants collected at the end of the culture period to measure produced virus through the quantification of the viral NP nucleoprotein .2 for 72 hours. After incubation, cytotoxic effect and antiviral efficacy were evaluated as described previously. The raw data were analyzed using the MacSynergy II software that produces synergy plots representing the statistically significant synergy or antagonism at the level of 95%, 99% and 99.9% confidence, calculated with a Bonferroni adjustment. A 3D plot of the surface was generated using the intrinsic plotting software through Excel [Fig 1 shows an example of Drug A and Drug B combination leading to synergy and lowering the LIC100 that resulting in a several-fold increase in the activity of both drugs. We first ensure that there is no increase in cytotoxicity when drugs are combined; every experiment with increased cytotoxicity in any of the wells analyzed is discarded. Then we compare the activity of two drugs (Drug A and Drug B) as monotherapy or in combination. The matrix allows for the determination of the area of synergy, the LIC100, which is the lowest drug concentration that completely inhibits virus replication and the LIC100 fold increase.For each drug combination the compounds were prepared separately by two-fold serial dilution and mixed in 96-well assay plates to create a two-dimensional matrix of diluted drugs generating up to 49 different combinations of two drugs plus a control without drugs Equal aliquots from the individual drug dilution plate were transferred to the cell-containing plates, cells were infected with the SARS-CoV-2 2019-nCoV/Italy-INMI1 strain at an MOI of 0.01 and incubated at 37°C and 5% COgh Excel . At leasFrom over 100 publications describing at least one drug potentially able to inhibit SARS-CoV-2, we selected 26 drug candidates with well-documented antiviral activity. Each drug was tested as monotherapy for cytotoxicity and antiviral activity using the 2019-nCoV/Italy-INMI1 SARS-CoV-2 strain and 10 of them were further selected as their TI was above 1. These compounds were: hydroxychloroquine, umifenovir, nitazoxanide, azithromycin, ivermectin, homoharringtonine, camostat, remdesivir, darunavir and lopinavir. The acceptability criteria for these compounds were confirmed with the GZ69 SARS-CoV-2 strain. Similar results were obtained when remdesivir was tested against the delta and omicron variants (not shown). This was not unexpected, since immunological variants have emerged to escape the pressure induced by the immune system and not to become resistant to drugs.0), 2) the Lowest 100% Inhibitory Concentration (LIC100) and 3) the calculation of synergy by a rigorous and well-established model [in vitro are prerequisites to look for maximal safety and antiviral efficacy in vivo and are expected to bear clinical relevance.We analyzed all potential double combinations of the 10 selected antivirals by using stringent criteria: 1) the Highest Concentration with 0% Cytotoxicity  based double combinations, as RDV was the only approved anti-SARS-CoV-2 drug among the selected antivirals. Both azithromycin (AZI) and ivermectin (IVM) showed synergistic inhibition of SARS-CoV-2 replication with RDV in the absence of any antagonism, as illustrated in 100 , meaning that a much lower concentration of each drug  was needed to achieve the complete inhibition of virus replication when the drugs were combined compared to monotherapy.The RDV and AZI synergistic combination led to a marked increase in potency, illustrated by a decrease in LIC100 of a drug has important pharmacological implications, because it is equivalent to increasing the therapeutically active drug exposure in human subjects. For example, the LIC100 of RDV monotherapy in vitro is 1,250 ng/ml. Based on the pharmacokinetic profile of clinically indicated RDV doses [Fig 3B). The scenario changes when RDV is combined with AZI, as the resultant LIC100 of the RDV combination decreases to 360 ng/ml, a concentration of RDV that can be consistently maintained in the plasma for at least one hour.Decreasing the LICDV doses  a 1,250 Table 2, upper portion).For the treatment of all respiratory viruses, including SARS-CoV-2, the drug concentration reached in the lung is the most relevant one. Since RDV is a pro-drug, measuring its PK in the plasma is not sufficient. The active RDV metabolite is its nucleoside triphosphate form (Nuc-TP) that will accumulate intracellularly in the lung at 4–10 μM  followin50 and the IC90 for the Nuc-TP in the lung would be 7.7 μM and 17.6 μM, respectively (that is higher than the IC50 and IC90 for RDV in vitro by a factor of 10). These results explain the inconsistent efficacy of RDV in clinical practice, as hospitalized patients are exposed to a suboptimal Nuc-TP concentration, only able to inhibit 50% of SARS-CoV-2 replication. The LIC100 of RDV monotherapy in vitro was 2.1 μM, corresponding to an estimated concentration of Nuc-TP of 21 μM ( lower portion) that cannot be reached in the lung by RDV monotherapy [100 decreased to 0.6 μM, corresponding to a Nuc-TP concentration of 6 μM, which is reachable intracellularly in the lung after administration of clinically indicated RDV doses. Since the Nuc-TP intracellular half-life is 14–24 hours, it is expected that SARS-CoV-2 would be exposed to therapeutically effective concentrations for the whole day with this combination therapy.It has been estimated that the ICotherapy . In contin vivo. Commonly used antibacterial doses of AZI have not shown anti-SARS-CoV-2 activity in human subjects [100) cannot be achieved in the plasma even by 1 to 4 gr AZI I.V. doses [100 of AZI would decrease to a concentration of 1,500 ng/mL that can be maintained for 4 to 8 hours in the plasma .AZI antiviral activity also benefits from the combination with RDV to an extent that becomes relevant subjects  because V. doses . HoweverFig 3D) and the AZI LIC100 values remain higher than the AZI concentrations, regardless of whether AZI is used as monotherapy or in combination with RDV. However, for the treatment of respiratory viruses what is most relevant is reaching an effective drug concentration in the lung, as complete inhibition of SARS-CoV-2 is expected if the drug concentration in the lung remains higher than the LIC100. While AZI monotherapy has a LIC100 that cannot be reached in the lungs after oral administration of commonly used AZI doses , when used in combination with RDV the resultant LIC100 of AZI drops to a concentration of 1,500 ng/mL that can be maintained in the lungs up to 21 days .When administered orally the AZI exposure in the plasma is lower than after I.V. administration (Table 1) which leads to a marked decrease in LIC100, meaning that a much lower concentration of each drug  was needed to achieve the complete inhibition of virus replication when the drugs were combined compared to monotherapy .The RDV and IVM combination also results in a synergistic increase in anti-SARS-CoV-2 activity  of 21 μM, not reachable in the lung [100 decreased to 0.3 μM, corresponding to a Nuc-TP concentration of 3 μM, attainable intracellularly in the lung (Table 2) and expected to be maintained for 14–24 hrs. The combination of RDV and IVM also enhances the antiviral activity of IVM. When IVM is administered as monotherapy, the LIC100 is not reachable in the plasma and in the lung even with the highest 120 mg dose [100 of IVM decreases to 213 ng/mL, a concentration reachable in the plasma for 12 hours and in the lung for 24 hours .DV doses  to a conthe lung . In comb mg dose . In combIn summary, combining RDV with either AZI or IVM  would result in exposure to therapeutically effective antiviral doses of each drug in the plasma. When RDV, AZI, or IVM would be administered as monotherapy, only RDV would be partially active in the lung. However, when administered in combination, both drugs of the respective combinations would achieve their therapeutically effective antiviral concentrations in the lung with the resultant antiviral activity expected to last for a whole day.Table 3).Finally, combining RDV with either AZI or IVM increases each drug’s activity without increasing cytotoxicity and therefore substantially broadens the TI of each drug, from 14-fold (least good scenario) to 32-fold (best case scenario)  the drug dose could even be decreased while maintaining efficacy against SARS-CoV-2, for example in the case of the onset of reversible side effects, instead of withdrawing treatment.Fig 5. We found strong synergy in each of the conditions tested, however, the continuous treatment resulted in synergy at lower drug concentration compared to the other two conditions. Our results are consistent with the entry/binding and post-entry (RdRp) mechanisms of synergy proposed in the literature and indicate that optimal synergy is obtained by taking advantage of both mechanisms.As RDV, AZI and IVM belong to three different classes of drugs, we asked why these drugs, and not others, would reciprocally synergize among themselves. We postulated the inhibition of common SARS-CoV-2 replication pathways and looked for evidence in the literature. We found that RDV, AZI and IVM might interfere with SARS-CoV-2 by two mechanisms of action (MoA) that are common to all three drugs. One MoA would be at the virus entry/binding level: in fact, RDV has been shown to interact with S protein, ACE2 and TMPRSS2 , 27, AZI100  to levels that are attainable in the human plasma and/or in the lung. In the case of the lung, which is the most relevant target for a respiratory virus like SARS-CoV-2, such levels are likely to be maintained for one or more days after a single administration of RDV combined with either AZI or IVM.To completely suppress viral replication and address the unmet need of hospitalized patients we developed broad-spectrum-antivirals-based cocktails for the treatment of patients with COVID-19. We showed that RDV combined with either AZI or IVM leads to a significant synergy that substantially lowers the concentration of each of the three drugs that is required for complete SARS-CoV-2 suppression, thus overcoming the problem of suboptimal drug exposure. Achieving viral suppression with either RDV, AZI, or IVM as monotherapy would in fact require drug concentrations that are too high to be attainable in humans, however, combining RDV with either AZI or IVM lowers the LIC100 and such concentration cannot be reached in the human plasma or in the organs by using dosages with acceptable toxicity profiles (or can be reached but can be maintained only for a short time), one can adopt different measures such as: a) to increase drug dosage, at risk of toxicity; b) to chemically modify the drug to prolong the time of release (extended-release) or to decrease its catabolism (in both cases a lengthy and expensive procedure that requires a new regulatory pathway), c) to add another boosting drug in order increase its pharmacological exposure by interfering with its metabolism (e.g. slowing down lopinavir metabolism by adding ritonavir as both drugs compete for cytochrome P4503A4). A similar approach has been recently followed by combining ritonavir with PF-07321332, a new protease inhibitor reported being effective to inhibit SARS-CoV-2, decrease viral load and prevent COVID-19 progression [Other approaches have been explored to overcome the problem of suboptimal drug exposure. If a drug has a high LIC100 by combining it with another broad-spectrum antiviral that bears a synergistic activity. This strategy presents several advantages: a) lowering the LIC100 means that the drug will be active at a lower concentration that can be reached in the human plasma or in the lung by using indicated dosages and b) inhibition of virus replication can be maintained for a longer time, without increased toxicity of the drugs, as long as they do not have synergistic cytotoxicity (as it is the case with the combinations described here) and clinicians (who are familiar with these drugs) do not foresee overlapping side effects, c) no requirement of chemical modification or alteration of PK/PD profiles is required, d) no need for dose (and toxicity) increase, on the contrary flexibility to reduce the dose (and toxicity).We followed an alternative approach of lowering a drug’s LICin vitro identify anti-SARS-CoV-2 drugs that have subsequently failed in the clinic [100) as opposed to the less stringent IC50 or IC90 parameters, c) we determined whether the LIC100 could be reached in the plasma and in the lung at clinically indicated doses of the drugs, a key analysis that has not been attempted before and d) we specifically focused only on combinations with no observed increase in cytotoxicity, leading to significant improvements in their respective Therapeutic Indices. Moreover, based on their respective package inserts we are not aware of serious overlapping potential toxicity between RDV and either AZI or IVM that would preclude their combinations in vivo and we have not found any references in the literature that would challenge this assumption. These three drugs have established toxicity profiles and have been extensively used to treat patients with infectious diseases. For example, antibiotics are often administered to hospitalized COVID-19 patients and AZI could become the 1st line antibiotic in this setting. Our results would suggest the possibility of once-a-day (QD) administration may be effective for any of these combinations. A clinical study submitted after our study had been submitted and published while our manuscript was under review found that the coadministration of RDV and AZI was associated with reduced risk of ICU admission, independently of covariates [We recognize that the broad-spectrum antivirals that we have tested here have already been proposed as anti-SARS-CoV-2 drugs and have shown inconsistent results . We belie clinic  for the variates .in vitro looking for synergy and calculating active drug levels that are achievable in vivo, thus predicting which drug combinations might be most effective in the clinics; 4) elucidate the MoA of these combinations.In short, our results 1) explain why add-on of repurposed drugs have mostly failed to induce beneficial clinical effects during SARS-CoV-2 infection when used as monotherapies; 2) suggest that some of these drugs could be selected to generate effective drug combinations; 3) provide a validated model for testing drugs Combining drugs against SARS-CoV-2 would be in line with the treatment of several other viral infections, such as the Human Immunodeficiency Virus (HIV) and Hepatitis C infection, also to prevent the development of resistant mutants . All pro


A representative sample of 2520 people was surveyed by completing an online questionnaire using the Tablet Assisted Personal Interviewing (TAPI) method to measure the digital readiness and administrative habits of the population. The data are available in tabular form from an open repository. Some topics were processed by measuring several latent variables and latent class analysis was applied. The database facilitated understanding of the stratification of the population according to digital literacy, preferences with regard to device usage, the purpose of Internet usage, fear of smart systems as well as technophilic and technophobic attitudes. The database revealed the population's administrative practices, particularly their attitudes towards e-government and future development needs. The survey is useful for planning e-government developments. Knowledge of the digital readiness of the population is useful for designing training programs, mapping labor market competencies in the era of Industry 4.0 and developing channels of communication campaigning. Through the regional demographic variables, all of the aforementioned topics can also be used in regional science to measure indices at NUTS 2 or NUTS 3 levels. Specifications Table•The database is representative of society in terms of gender, age, type of settlement and level of education.•It covers a wide range of topics to help understand the spread of digitalization in terms of using smart devices and applications, especially in administration as well as shows the interest in technological openness, Internet usage habits and behavior, e-government developments and demographic characteristics and provides novel insights into the background of digital devices and applications used in terms of e-government developments.•The information extracted from the database can fine-tune the objectives and performance evaluation of future digital development projects.•The database is useful for regional researchers, public administration experts, back offices of ministries, researchers, agencies, think tanks and consultancies to get to know their clients better. as well as smart device and application developers.•The background behind international and regional indicators  can be identified and explanatory factors found by taking regional data into account because NUTS 2 and 3 codes of residence are included in the database.1The rise of digital solutions and devices is bringing a lot of changes and challenges to our everyday lives. Citizens react to these changes in different ways. Public administration is also going digital and should not exclude any citizen. The purpose of this survey was to compile a multi-faceted measurement tool that can capture societal responses to digitization in the context of eGovernment developments. The database will add value to much research on the spread of digitalization knowledge, preparing eGovernment developments, and determining the target and excluded groups to understand their background better.2Systematically surveying stakeholders can assess attitudes towards digital developments and technological systems. The topics investigated are presented in 2520 people participated in our survey. The respondents are representative of the population of Hungary in terms of age, gender, type of settlement and level of education. Respondents were contacted by telephone concerning the COVID-19 pandemic. The questionnaires were completed using the TAPI method. Although a Likert scale was used for the majority of questions, categorical responses were requested in several cases and in some cases multiple choice questions were appropriate when measuring certain topics. In the following three subsections, the topics assessed are described and the distributions of the response categories given.•○Region and subregion ○Classification of settlement ○Gender (D4)○Age (D5)○Level of education (D6)○Family status (D7)○Size of household, number of children under 18 years old ○Employment status, income level ○Commuting characteristics of rural people (D13-D20)Demographic variables•○Technophile - technophobe (part 1 of sample) (T1-T5)○Fear of digital technologies (part 1 of sample) (T6-T15)○Internet usage (T16-T19)○Purpose of Internet usage  (T20-T33)○Preferred and used device when using the Internet (who use the Internet at least every two weeks) (T34-T39)○Use of smart applications (part 1 of sample) (T40-T51)Attitudes towards digital technologies•○Preferred channel for administration (who use the Internet at least every two weeks) (A1-A4), avoid the use of any channels (A5-A8), and preference for a particular channel (A9)○Having (A10) and using (A11) at least one phone number or web page (A12-A13) for public administration○Usage of a customer portal for public administration (A14-A16)○Aspects considered important for maintaining administrative efficiency, channel (A17-A32) and rank (A33-A48) (part 2 of sample)○Openness to trying out some improvements (A49-A52)○Demands for some degree of development in administration (A53-A65)AdministrationThe measured variables can be grouped as follows:The questionnaire was split so part 1 of the sample were asked some questions, while part 2 were asked others to reduce the burden on respondents. Identifying correlations between these question blocks was challenging.The survey data were supplemented with clustered variables , which was beneficial to reduce the information content and smooth out the variance in responses by considering some similar variables. An efficient and powerful statistical method was applied for clustering, namely Latent Class Analysis (LCA), which has been successfully used in other fields of social science research given its many advantages. The technique measures a so-called latent variable by taking categorical indicators into account and classifies each set of measurements, in our case, the respondents, into classes according to the latent variable. LCA creates mutually exclusive latent classes, i.e. groups of individuals, based on similar response patterns to the indicator variables.2.1The names of the variables describing demography in the database start with 'D' denoting the word ‘demography’. The variation in the demographic characteristics of respondents by question is shown below.D1: County of residence (NUTS 3)D2: Region of residence (NUTS 2)D3: Administrative classification of the settlementD4: GenderD5: AgeD6: Highest Level of EducationD7: Family statusD8: How many people live in your household?D9: How many in your household are children under 18?D10: Which employment status is most descriptive of you?D11: Level of IncomeD12: Please classify your place of residence.D13: How often do you travel to the county seat?  780 people continuous variable (0–35)99: No answerD14: How often do you travel to the center of the subregion?  780 people continuous variable (0–35)99: No answerD15: How often do you travel to the nearest city?  780 people continuous variable (0–35)99: No answerD16: How often do you travel to the county seat? D17: How often do you travel to the center of the subregion? D18: How often do you travel to the nearest city? D19: Summary variable with regard to the intensity of commuting of rural residents, clustered by LCA using variables D16–18. D20: Summary variable with regard to the intensity of commuting of rural residents, clustered by LCA using variables D16–18.Variable D19 is clustered considering the variables D16–18. Our aim was to determine the frequency of commuting and destination of rural residents to summarize as well as simplify related continuous variables. In our case, the indicator variable was the frequency of travel to a given destination (D16–18) and the latent variable was commuting (D19). The calculations were performed using LCA in R with poLCA 2.2The names of the variables describing demography in the database start with 'T', denoting the word ‘technology’. The distribution of respondents' attitudes towards and characteristics with regard to digital technologies by question are shown below:T1: I like trying new technological tools.T2: I am afraid of using technologies that I am not familiar with.T3: Usually the amount of energy required to learn about technological innovations outweighs their benefits.T4: I don't want to miss out on new smart solutions.T5: Summary variable of technological openness (technophilic or technophobic behavior), clustered by LCA using variables T1–4.Variable T5 is the result of variables T1–4 and is a summary of them. Variable T5 is constructed in the same way as D19, using LCA, which summarizes the respondents' openness to technology, that is, their technophilic or technophobic behavior. The distribution of responses with regard to the respondent clusters is shown in T6: Which of the following factors prevent you from using smart solutions: accessibility/availabilityT7: Which of the following factors prevent you from using smart solutions: difficult to useT8: Which of the following factors prevent you from using smart solutions: no native language menuT9: Which of the following factors prevent you from using smart solutions: data security not guaranteedT10: Which of the following factors prevent you from using smart solutions: personal fears (e.g. making a mistake)T11: Which of the following factors prevent you from using smart solutions: unreliability of the manufacturerT12: Which of the following factors prevent you from using smart solutions: discontinuous operationT13: Which of the following factors prevent you from using smart solutions: aversion to smart solutionsT14: Which of the following factors prevent you from using smart solutions: lack of willpowerT15: Which of the following factors prevent you from using smart solutions: otherT16: How often do you use the Internet?T17: Internet usageat least once every two weeks. .T18: Is your household connected to the Internet (wired or wireless)?T19: Do you use Mobile Internet?T20: How often do you do the following activities online: use search enginesT21: How often do you do the following activities online: view news portalsT22: How often do you do the following activities online: send and receive emailsT23: How often do you do the following activities online: instant message, e.g. Viber, Messenger, etc.T24: How often do you do the following activities online: use social networks, e.g. Facebook, Twitter, etc.T25: How often do you do the following activities online: make online calls, e.g. on SkypeT26: How often do you do the following activities online: do online training coursesT27: How often do you do the following activities online: workT28: How often do you do the following activities online: shop onlineT29: How often do you do the following activities online: trade onlineT30: How often do you do the following activities online: online bankingT31: How often do you do the following activities online: pay utility bills onlineT32: How often do you do the following activities online: online administrationT33: Summary variable with regard to the purpose of Internet usage clustered by LCA using variables T8–20.T8–20 and is a summary of them. Variable T33 is constructed in the same way as T5 and D19 by applying LCA. Variable T33 separates respondents whose habits with regard to Internet usage are different. For different reasons, everyone uses the Internet for different purposes to satisfy various personal needs in their everyday lives. Consumers are referred to as those who only use search engines, read news stories as well as send and receive emails. Productive respondents work, shop, bank and carry out administrative tasks online on at least a weekly basis. This database offers an opportunity to explore causal effects in terms of behavior and can be used to analyze the consequences of different purposes of Internet usage.Variable T33 is the result of variables T34: Do you use a smartphone?T35: Do you use a smartwatch?T36: Which device do you use to access the Internet: a desktop computer or a laptopT37: Which device do you use to access the Internet: a smartphone or a tabletT38: I prefer to do tasks on a desktop computer or laptop rather than on a smartphone.T39: I do more tasks on a desktop computer or laptop rather than on a smartphone.T40: Do you know about and use the following smart solutions: apps to manage utility bills, e.g. to read metersT41: Do you know about and use the following smart solutions: health monitoring apps, e.g. to monitor sleepT42: Do you know about and use the following smart solutions: receive emergency alerts, make emergency callsT43: Do you know about and use the following smart solutions: to make complaints in public spaces, e.g. to report potholesT44: Do you use online banking?T45: Do you use a digital bank?T46: Do you know about and use the following smart solutions while travelling: online mapsT47: Do you know about and use the following smart solutions while travelling: route plannerT48: Do you know about and use the following smart solutions while travelling: electronic tickets on public transportT49: Do you know about and use the following smart solutions while travelling: carpooling servicesT50: Do you know about and use the following smart solutions while travelling: shared transport T51: Do you know about and use the following smart solutions while travelling: purchase of digital parking tickets2.3A1: To what extent do you agree with the following statement regarding public administration: I prefer to do day-to-day tasks in an office rather than online.A2: To what extent do you agree with the following statement regarding public administration: I prefer to do my day-to-day tasks online rather than over the phone.A3: To what extent do you agree with the following statement regarding public administration: I prefer to do my day-to-day tasks in an office rather than over the phone.A4: Summary variable of people's preferred means of public administration clustered by LCA using variables A1–3.The variable A4 summarizes the variables A1–3 in the same way as D19, T5 and T33 do using LCA. Variable A4 makes a distinction between respondents whose preferred means of public administration differ. The three variables measure the preferred means of public administration by a pairwise comparison, which can be used to rank the three means. The categories of this variable show the differences between the rankings of the three means. A group of respondents (334 people in category 1) prefer to do day-to-day tasks online rather than over the phone and least of all in person in an office.A5: To what extent do you agree with the following statement regarding public administration: If possible, I avoid contacting the customer service team.A6: To what extent do you agree with the following statement regarding public administration: If possible, I avoid handling matters over the phone.A7: To what extent do you agree with the following statement regarding public administration: If possible, I avoid handling matters by post.A8: To what extent do you agree with the following statement regarding public administration: If possible, I avoid handling matters online.A9: I consider it extremely important to be able to choose the means of public administration that is the most convenient for me.A10: Do you know a phone number to call to handle your public administration?A11: Have you ever handled your public administration over the phone? (If A10=1)A12: Do you know a web page to handle your public administration?A13: Have you ever used a webpage to handle your public administration? (If A12=1)A14: Do you have access to a customer portal to handle your public administration?A15: Which of the following statements is characteristic of your access to a customer portal to handle public administration? (If A14 = 1)A16: Private access to a customer portal to handle public administration.Would achieving the following improvement objectives help you to manage your public administrative affairs more efficiently? (multiple-choice question)Which two development goals are most important to you? (ranking-type question)A49: To what extent would you like to try the following improvement with regard to managing your public administrative tasks: using an online chatbot to get informationA50: To what extent would you like to try the following improvement with regard to managing your public administrative tasks: online administration via a video call with an administratorA51: To what extent would you like to try the following improvement with regard to managing your public administrative tasks: use of an administration terminal at a customer service desk instead of face to face with an administratorA52: To what extent would you like to try the following improvement with regard to managing your public administrative tasks: via a video call with an administrator at a customer service deskA53: How important is the following to you in terms of public administration: to book an appointmentA54: How important is the following to you in terms of public administration: to get help from an office when filling in forms and completing paperworkA55: How important is the following to you in terms of public administration: to receive an e-mail or text message when a document is about to expireA56: How important is the following to you in terms of public administration: to receive an e-mail or text message when the document you have requested is readyA57: How important is the following to you in terms of public administration: to be able to pay by credit card at a customer service deskA58: How important is the following to you in terms of public administration: to be able to pay onlineA59: How important is the following to you in terms of public administration: to receive a confirmation e-mail when a document has been sent electronicallyA60: How important is the following to you in terms of public administration: to be able to save all electronic documents on your own computerA61: How important is the following to you in terms of public administration: to be able to have all your documents printed and posted to youA62: How important is the following to you in terms of public administration: to be able to track the status of your case onlineA63: How important is the following to you in terms of public administration: to communicate with an office in real time via an online interface A64: How important is the following to you in terms of public administration: to manage your affairs online from anywhereA65: Summary variable of the demand for the development of convenience services calculated according to the importance of development and clustered by LCA using variables A53–64.The variable A65 summarizes the variables A53–64 in the same way as D19, T5, T33 and A4 using LCA. Variable A65 separates respondents that demand developments in administration to different extents. The first group does not consider improvements to be necessary in public administration, the second group expresses a medium level of demand and the third group demands improvements in all the options offered.3The presented survey was designed to follow the Social Construction of Technology (SCOT) theory highlighting the social aspects and conditions of technological development Nowadays, the digitalization of public administration is taking place worldwide. Members of an innovative society have different attitudes towards new systems. The challenge is that public administration, as a whole, must be accessible to everyone and digitalization must not exclude any marginalized groups of people. The use of e-government developments, stakeholders and potential users should be continuously monitored. An important question is what factors influence the use of e-government systems, that is, what helps and hinders them? Identifying the pull factors will help to describe the potential customers of e-government developments, moreover, clients who cannot be targeted by e-government developments should also be identified.To the best of our knowledge, by relying on this theoretical basis, no studies have sought and recognized correlations between the proliferation of digital (smart) technologies, changing platforms, channels through which people manage their cases in practice, as well as the relevant demographic and residential factors. The aim of the present survey was to understand the background on the usage of e-government systems in the digital era. In addition, to fill the knowledge gap by applying the overarching measurement methodology, a monitoring system was developed that examines the impacts of e-government-related operational programs supported by the European Union (2014–2020) at the social level. The results of the programs played an important role in implementing the Hungarian Public Administration and Public Service Development Strategy (PAPSDS). The priorities of PAPSDS aim to increase the efficiency of public administration, streamlining its structure and performance as well as reducing administrative burdens, thereby contributing to the creation of a business-friendly economic environment. The program included interventions such as reducing red tape, strengthening e-governance, increasing transparency, reinforcing human resources as well as plans to develop a comprehensive information database for decision-makers in local authorities.According to the three main elements of SCOT, a dual goal was defined, namely to create groups based on the knowledge and use of smart devices as well as solutions, moreover, to show the relationship between the attributes of respondents . The questions were formed by considering suggestions from different disciplines, namely technology studies, public administration, management, urban studies and sociology. Data was collected to explore the attitudes of the population towards public administration and the characteristics of public administration  based on a nationwide census of the Hungarian adult population.The interviewers provided information to respondents with regard to the aims of the survey and how the data would be used. Respondents voluntarily and fully anonymously participated in the research. The authors declare that there are no ethical issues with the data presented. The research was carried out following the procedures outlined by the Declaration of Helsinki. The questionnaire design comply with the personal data protection requirements established in the Hungarian Act CXII of 2011 on the right to information self-determination and freedom of information. All research participants worked according to the protocols declared in Code of Ethics of the University of Public Service, Budapest, Hungary. Ethics approval by the institutional committee is not required specifically for this research.Tamás Kaiser: Conceptualization, Supervision, Writing – original draft. László Gadár: Data curation, Writing – original draft, Visualization, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.