The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo.

The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Personal protective effect of wearing surgical face masks in public spaces on self-reported respiratory symptoms in adults: pragmatic randomised superiority trial.

OBJECTIVE: To evaluate the personal protective effects of wearing versus not wearing surgical face masks in public spaces on self-reported respiratory symptoms over a 14 day period. DESIGN: Pragmatic randomised superiority trial. SETTING: Norway. PARTICIPANTS: 4647 adults aged ≥18 years: 2371 were assigned to the intervention arm and 2276 to the control arm. INTERVENTIONS: Participants in the intervention arm were assigned to wear a surgical face mask in public spaces (eg, shopping centres, streets, public transport) over a 14 day period (mask wearing at home or work was not mentioned). Participants in the control arm were assigned to not wear a surgical face mask in public places. MAIN OUTCOME MEASURES: The primary outcome was self-reported respiratory symptoms consistent with a respiratory infection. Secondary outcomes included self-reported and registered covid-19 infection. RESULTS: Between 10 February 2023 and 27 April 2023, 4647 participants were randomised of whom 4575 (2788 women (60.9%); mean age 51.0 (standard deviation 15.0) years) were included in the intention-to-treat analysis: 2313 (50.6%) in the intervention arm and 2262 (49.4%) in the control arm. 163 events (8.9%) of self-reported symptoms consistent with respiratory infection were reported in the intervention arm and 239 (12.2%) in the control arm. The marginal odds ratio was 0.71 (95% confidence interval (CI) 0.58 to 0.87; P=0.001) favouring the face mask intervention. The absolute risk difference was -3.2% (95% CI -5.2% to -1.3%; P<0.001). No statistically significant effect was found on self- reported (marginal odds ratio 1.07, 95% CI 0.58 to 1.98; P=0.82) or registered covid-19 infection (effect estimate and 95% CI not estimable owing to lack of events in the intervention arm). CONCLUSION: Wearing a surgical face mask in public spaces over 14 days reduces the risk of self-reported symptoms consistent with a respiratory infection, compared with not wearing a surgical face mask. TRIAL REGISTRATION: ClinicalTrials.gov NCT05690516.

Potential effects of aerosol generation and transmission during bedside endoscope cleaning.

Airborne transmission is among the most frequent types of nosocomial infection. Recent years have witnessed frequent outbreaks of airborne diseases, such as severe acute respiratory syndrome (SARS) in 2002, Middle East respiratory syndrome (MERS) in 2012, and coronavirus disease 2019 (COVID-19), with the latter being on the rampage since the end of 2019 and bringing the effect of aerosols on health back to the fore (Gralton et al., 2011; Wang et al., 2021). An increasing number of studies have shown that certain highly transmissible pathogens can maintain long-term stability and efficiently spread through aerosols (Leung, 2021; Lv et al., 2021). As reported previously, influenza viruses that can spread efficiently through aerosols remain stable for a longer period compared to those that cannot. The World Health Organization (WHO) has stated that aerosol-generating procedures (AGPs) play an important role in aerosol transmission in hospitals (Calderwood et al., 2021). AGPs, referring to medical procedures that produce aerosols, including dental procedures, endotracheal intubation, sputum aspiration, and laparoscopic surgeries, have been reported to be significantly associated with an increased risk of nosocomial infection among medical personnel (Hamilton, 2021).

Effect of Early pregnancy associated protein-1 on Spike protein and ACE2 interactions: Implications in SARS Cov-2 vertical transmission.

INTRODUCTION: Several factors influence transmission of 2019-nCoV from mother to fetus during pregnancy, thus the dynamics of vertical transmission is unclear. The role of cellular protective factors, namely a 90 KDa glycoprotein, Early pregnancy-associated protein (Epap-1), expressed by placental endothelial cells in women during early pregnancy would provide an insight into role of placental factors in virus transmission. Since viral spike protein binding to the ACE2 receptors of the host cells promotes virus invasion in placental tissue, an analysis of effects of Epap-1 on the Spike-ACE2 protein binding was studied. METHODS: Epap-1 was isolated from MTP placental tissue. Molecular interaction of Epap-1 and variants of the spike was analyzed in silco. The interaction of Epap-1 with Spike and RBD were analyzed using ELISA and immunofluorescence studies. RESULTS: The results in silico showed an interaction of Epap-1 with S-protein at RBD region involving K417, Y449, Y453, Y456, Y473, Q474, F486, Q498, N501 residues of spike with Y61, F287, I302, N303, N305, S334, N465, G467, N468 residues of Epap-1 leading to interference of S-protein and ACE2 interaction [1]. Further, the interaction is conserved among the variants. The studies in vitro confirm that Epap-1 affects S protein-ACE2 and RBD- ACE2 binding, thus suggesting that during early pregnancy, SARS CoV-2 infection may be protected by Epap-1 protein present in placental tissue. The results were further confirmed by pseudovirus expressing Spike and RBD in an infection assay. DISCUSSION: Epap-1 interferes with Spike and RBD interaction with ACE2, suggesting a possible mechanism of the antiviral environment during pregnancy.

Aerosol-generating procedures and associated control/mitigation measures: Position paper from the Canadian Dental Hygienists Association and the American Dental Hygienists' Association.

Background: Since the outbreak of COVID-19, how to reduce the risk of spreading viruses and other microorganisms while performing aerosolgenerating procedures (AGPs) has become a challenging question within the dental and dental hygiene communities. The purpose of this position paper is to summarize the evidence of the effectiveness of various mitigation methods used to reduce the risk of infection transmission during AGPs in dentistry. Methods: The authors searched 6 databases-MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Library, and Google Scholar-for relevant scientific evidence published between January 2012 and December 2022 to answer 6 research questions about the risk of transmission, methods, devices, and personal protective equipment (PPE) used to reduce contact with microbial pathogens and limit the spread of aerosols. Results: A total of 78 studies fulfilled the eligibility criteria. The literature on the risk of infection transmission including SARS-CoV-2 between dental hygienists and their patients is limited. Although several mouthrinses are effective in reducing bacterial contaminations in aerosols, their effectiveness against SARS-CoV-2 is also limited. The combined use of eyewear, masks, and face shields is effective in preventing contamination of the facial and nasal region while performing AGPs. High-volume evacuation with or without an intraoral suction, low-volume evacuation, saliva ejector, and rubber dam (when appropriate) have shown effectiveness in reducing aerosol transmission beyond the generation site. Finally, the appropriate combination of ventilation and filtration in dental operatories is effective in limiting the spread of aerosols. Discussion and Conclusion: Aerosols produced during clinical procedures can pose a risk of infection transmission between dental hygienists and their patients. The implementation of practices supported by available evidence will ensure greater patient and provider safety in oral health settings. More studies in oral health clinical environments would shape future practices and protocols, ultimately to ensure the delivery of safe clinical care.

Contexte: Depuis l'éclosion de la COVID-19, la façon de réduire le risque de propagation de virus et d'autres microorganismes tout en effectuant des interventions générant des aérosols (IGA) est devenue un enjeu complexe au sein des communautés de la médecine dentaire et de l'hygiène dentaire. L'objectif de cet exposé de position est de résumer les données probantes de l'efficacité des diverses méthodes d'atténuation utilisées pour réduire le risque de transmission des infections pendant les IGA en médecine dentaire. Méthodes: Les auteurs ont effectué des recherches dans MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Library et Google Scholar pour trouver des preuves scientifiques pertinentes publiées entre janvier 2012 et décembre 2022 afin de répondre à 6 questions de recherche sur le risque de transmission, les méthodes, les dispositifs et l'équipement de protection individuelle (EPI) utilisés pour réduire le contact avec les agents pathogènes microbiens et limiter la propagation des aérosols. Résultats: Au total, 78 études ont satisfait aux critères d'admissibilité. La documentation est limitée en ce qui concerne le risque de transmission des infections, y compris le SRAS-CoV-2, entre les hygiénistes dentaires et leurs patients. Bien que plusieurs rince-bouches soient efficaces pour réduire la contamination bactérienne dans les aérosols, leur efficacité contre le SRAS-CoV-2 est limitée. L'utilisation combinée de lunettes, de masques et d'écrans faciaux est efficace pour prévenir la contamination de la région faciale et nasale lors de l'exécution d'IGA. L'évacuation à volume élevé avec ou sans aspiration intraorale, l'évacuation à faible volume, l'aspirateur de salive et la digue dentaire en caoutchouc (le cas échéant) ont démontré une efficacité à réduire la transmission des aérosols au-delà du site de production. Enfin, la combinaison appropriée de ventilation et de filtration dans les salles de traitement dentaire permet de limiter efficacement la propagation des aérosols. Discussion et conclusion: Les aérosols produits lors des interventions cliniques peuvent présenter un risque de transmission des infections entre les hygiénistes dentaires et leurs patients. La mise en oeuvre de pratiques appuyées par les données probantes disponibles assurera une plus grande sécurité des patients et des prestataires dans les milieux de santé buccodentaire. Un plus grand nombre d'études dans les environnements cliniques de santé buccodentaire permettrait de façonner les pratiques et les protocoles futurs dans le but d'assurer la prestation sécuritaire des soins cliniques.

Two novel human coronavirus OC43 genotypes circulating in hospitalized children with pneumonia in China.

HCoV-OC43 is one of the mildly pathogenic coronaviruses with high infection rates in common population. Here, 43 HCoV-OC43 related cases with pneumonia were reported, corresponding genomes of HCoV-OC43 were obtained. Phylogenetic analyses based on complete genome, orf1ab and spike genes revealed that two novel genotypes of HCoV-OC43 have emerged in China. Obvious recombinant events also can be detected in the analysis of the evolutionary dynamics of novel HCoV-OC43 genotypes. Estimated divergence time analysis indicated that the two novel genotypes had apparently independent evolutionary routes. Efforts should be conducted for further investigation of genomic diversity and evolution analysis of mildly pathogenic coronaviruses.

Reasons for SARS-CoV-2 infection in children and their role in the transmission of infection according to age: a case-control study.

BACKGROUND: The locations where children get exposed to SARS-CoV-2 infection and their contribution in spreading the infection are still not fully understood. Aim of the article is to verify the most frequent reasons for SARS-CoV-2 infection in children and their role in the secondary transmission of the infection. METHODS: A case-control study was performed in all SARS-CoV-2 positive children (n = 81) and an equal number of age- and sex- matched controls who were referred to the S. Camillo-Forlanini Pediatric Walk-in Center of Rome. The results of all SARS-CoV-2 nasopharyngeal swabs performed in children aged < 18 years from October 16 to December 19, 2020 were analyzed. RESULTS: School contacts were more frequent in controls than in cases (OR 0.49; 95% CI: 0.3-0.9), while household contacts were higher in cases (OR 5.09; 95% CI: 2.2-12.0). In both cases and controls, school contacts were significantly less frequent, while on the contrary household contacts seemed to be more frequent in nursery school children compared to primary school or middle/high school children. A multivariate logistic regression showed that the probability of being positive to SARS-CoV-2 was significantly lower in children who had school contacts or who had flu symptoms compared to children who had household contacts. Results showed a 30.6% secondary attack rate for household contacts. CONCLUSION: In our study population, the two most frequent reasons for SARS-CoV-2 infection were school and home contacts. The risk of being positive was 5 times lower in children who had school contacts than in children who had household contacts.

Clinical characteristics of COVID-19 in family clusters: a systematic review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world and reports of children during early epidemic period showed features of family clusters. The aim of this study is to assess clinical profiles of COVID-19 in family clusters with children. METHODS: We performed a systematic literature review of English database (PubMed, Web of Science) and Chinese database (" www.cnki.net ", " www.cqvip.com " and " www.Wanfangdata.com.cn ") to identify papers on family clusters of COVID-19 with children and their family members. RESULTS: Eighteen studies involving 34 children and 98 adults from 28 families were included. Fever, cough and ground-grass opacity change of chest computed tomography (CT) were the dominant features, whereas proportion of asymptomatic infections for children was higher than adults with statistical significance (32.4% and 13.3%, respectively, P < 0.05). Median time of longer incubation period (10 days) and shorter duration of pharyngeal swab nucleic acid test positive period (11 days) were seen in children than adults (7 and 17 days, respectively) with statistical significance (P < 0.05). There were statistically significant differences in lymphopenia, increased C-reactive protein and abnormal chest CT between children and adult patients (P < 0.05). Twenty-seven families reported adults as first case of COVID-19 in family clusters. CONCLUSIONS: The same virus strain can cause milder disease in children compared with their caregivers. Children of COVID-19 were infected by adults in family during the early epidemic period. Asymptomatic patients can transmit the virus.

COVID-19 Outbreak at an Exercise Facility.

The failure of patchwork infection control.

Association of Tracheostomy With Outcomes in Patients With COVID-19 and SARS-CoV-2 Transmission Among Health Care Professionals: A Systematic Review and Meta-analysis.

Importance: Approximately 5% to 15% of patients with COVID-19 require invasive mechanical ventilation (IMV) and, at times, tracheostomy. Details regarding the safety and use of tracheostomy in treating COVID-19 continue to evolve. Objective: To evaluate the association of tracheostomy with COVID-19 patient outcomes and the risk of SARS-CoV-2 transmission among health care professionals (HCPs). Data Sources: EMBASE (Ovid), Medline (Ovid), and Web of Science from January 1, 2020, to March 4, 2021. Study Selection: English-language studies investigating patients with COVID-19 who were receiving IMV and undergoing tracheostomy. Observational and randomized clinical trials were eligible (no randomized clinical trials were found in the search). All screening was performed by 2 reviewers (P.S. and M.L.). Overall, 156 studies underwent full-text review. Data Extraction and Synthesis: We performed data extraction in accordance with Meta-analysis of Observational Studies in Epidemiology guidelines. We used a random-effects model, and ROBINS-I was used for the risk-of-bias analysis. Main Outcomes and Measures: SARS-CoV-2 transmission between HCPs and levels of personal protective equipment, in addition to complications, time to decannulation, ventilation weaning, and intensive care unit (ICU) discharge in patients with COVID-19 who underwent tracheostomy. Results: Of the 156 studies that underwent full-text review, only 69 were included in the qualitative synthesis, and 14 of these 69 studies (20.3%) were included in the meta-analysis. A total of 4669 patients were included in the 69 studies, and the mean (range) patient age across studies was 60.7 (49.1-68.8) years (43 studies [62.3%] with 1856 patients). We found that in all studies, 1854 patients (73.8%) were men and 658 (26.2%) were women. We found that 28 studies (40.6%) investigated either surgical tracheostomy or percutaneous dilatational tracheostomy. Overall, 3 of 58 studies (5.17%) identified a small subset of HCPs who developed COVID-19 that was associated with tracheostomy. Studies did not consistently report the number of HCPs involved in tracheostomy. Among the patients, early tracheostomy was associated with faster ICU discharge (mean difference, 6.17 days; 95% CI, -11.30 to -1.30), but no change in IMV weaning (mean difference, -2.99 days; 95% CI, -8.32 to 2.33) or decannulation (mean difference, -3.12 days; 95% CI, -7.35 to 1.12). There was no association between mortality or perioperative complications and type of tracheostomy. A risk-of-bias evaluation that used ROBINS-I demonstrated notable bias in the confounder and patient selection domains because of a lack of randomization and cohort matching. There was notable heterogeneity in study reporting. Conclusions and Relevance: The findings of this systematic review and meta-analysis indicate that enhanced personal protective equipment is associated with low rates of SARS-CoV-2 transmission during tracheostomy. Early tracheostomy in patients with COVID-19 may reduce ICU stay, but this finding is limited by the observational nature of the included studies.

Science in 5: la ventilation durante la COVID-19

¿Qué importancia tiene la ventilación y cómo lo mantiene a salvo del COVID-19? La Dra. Maria Neira de la OMS lo explica en este capitulo. Más información: https://www.paho.org/es/temas/coronav...

Congenital and Intrapartum SARS-CoV-2 Infection in Neonates: Hypotheses, Evidence and Perspectives.

INTRODUCTION: Both intrauterine and intrapartum mother-to-child transmission of SARS-CoV-2 have been reported. However, there is still disagreement as to the likelihood and frequency of such vertical transmission. OBJECTIVE: Summarize and analyze the published evidence on forms of SARS-CoV-2 vertical transmission (either intrauterine or intrapartum). EVIDENCE ACQUISITION: We carried out a review of literature published in English and Spanish from January 1, 2020 through October 30, 2020. Search engines included PubMed/MEDLINE, SciELO, LILACS, Cochrane, Google Scholar, ResearchGate and medRxiv. There were no restrictions concerning type of study. The review included 48 original research articles, 11 review articles, a meta-analysis, 2 pre-published articles, 15 systematic reviews, and 10 editorials or comments. DEVELOPMENT: Medical thinking on congenital or intrapartum maternal-fetal/neonatal transmission of SARS-CoV-2 has evolved from preliminary evidence that was divided as to whether these forms of vertical transmission were even possible to current evidence support ing both forms of transmission and hypothesizing as to the mechanisms that guide them. The presence of the SARS-CoV-2 virus in maternal, placental, fetal or neonatal tissues has been demonstrated by RT-PCR, specific immunoglobulin detection tests, immunostaining and in-situ hybridization. It is estimated that infections acquired either congenitally or intrapartum occur in 1.8%-8.0% of newborns born to women who test positive for COVID-19 at the end of their pregnancies. This review found 53 neonates who were diagnosed with COVID-19 in the first 48 hours of life by either RT-PCR or specific IgM tests. According to criteria outlined in this review, the timing of infection corresponded to congenital or intrapartum transmission in 39.6% (21/53) of COVID-19-positive newborns, to postpartum transmission in 15.1% (8/53) and remains unspecified in 45.3% (24/53). CONCLUSIONS: Congenital and intrapartum SARS-CoV-2 infection in the fetus/newborn is possible, but rare. International collaborative studies using common epidemiological surveillance instruments would allow for a more precise specification of the frequency of congenital and intrapartum SARS-CoV-2 infection at the population level.

Learning from the first wave: Lessons about managing patient flow and resource utilization on medical wards at providence health during the COVID-19 pandemic.

We report the successful implementation of a modified Traffic Control Bundling (TCB) protocol called "Red, Yellow and Green" on the inpatient medical units at St. Paul's Hospital in Vancouver, Canada during the first wave of the coronavirus disease 2019 (COVID-19) pandemic. The modified TCB protocol demonstrates an important example on how hospitals can rapidly reorganize operational and clinical processes to reallocate existing capacity to minimize exposure, improve traffic flow and reduce nosocomial transmissions of COVID-19 to health care workers (HCWs) and other patients. Preliminary evidence demonstrates the benefits on how an existing facility can be redesigned for adjustable ward capacity to provide disease containment under a context of uncertainty of disease transmission and varying patient load. Important lessons in preparation for the evolution of the pandemic fall into categories of risk management, capacity and demand management.

Novas variantes do coronavírus

Saiba mais em www.saopaulo.sp.gov.br/coronavirus

Tire suas dúvidas: festas em locais abertos oferecem risco de contaminação?

Saiba mais em www.saopaulo.sp.gov.br/coronavirus

Efficacy of surgical masks or cloth masks in the prevention of viral transmission: Systematic review, meta-analysis, and proposal for future trial.

OBJECTIVE: Recommendations for widespread use of face mask, including suggested type, should reflect the current published evidence and concurrently be studied. This review evaluates the preclinical and clinical evidence on use of cloth and surgical face masks in SARS-CoV-2 transmission and proposes a trial to gather further evidence. METHODS: PubMed, EMbase, and the Cochrane Library were searched. Studies of SARS-CoV-2 and face masks and randomized controlled trials (RCTs) of n ≥ 50 for other respiratory illnesses were included. RESULTS: Fourteen studies were included in this study. One preclinical and 1 observational cohort clinical study found significant benefit of masks in limiting SARS-CoV-2 transmission. Eleven RCTs in a meta-analysis studying other respiratory illnesses found no significant benefit of masks (±hand hygiene) for influenza-like-illness symptoms nor laboratory confirmed viruses. One RCT found a significant benefit of surgical masks compared with cloth masks. CONCLUSION: There is limited available preclinical and clinical evidence for face mask benefit in SARS-CoV-2. RCT evidence for other respiratory viral illnesses shows no significant benefit of masks in limiting transmission but is of poor quality and not SARS-CoV-2 specific. There is an urgent need for evidence from randomized controlled trials to investigate the efficacy of surgical and cloth masks on transmission of SARS-CoV-2 and user reported outcomes such as comfort and compliance.

A SARS-CoV-2 Cluster in an Acute Care Hospital.

BACKGROUND: Little is known about clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in acute care hospitals. OBJECTIVE: To describe the detection, mitigation, and analysis of a large cluster of SARS-CoV-2 infections in an acute care hospital with mature infection control policies. DESIGN: Descriptive study. SETTING: Brigham and Women's Hospital, Boston, Massachusetts. PARTICIPANTS: Patients and staff with cluster-related SARS-CoV-2 infections. INTERVENTION: Close contacts of infected patients and staff were identified and tested every 3 days, patients on affected units were preemptively isolated and repeatedly tested, affected units were cleaned, room ventilation was measured, and specimens were sent for whole-genome sequencing. A case-control study was done to compare clinical interactions, personal protective equipment use, and breakroom and workroom practices in SARS-CoV-2-positive versus negative staff. MEASUREMENTS: Description of the cluster, mitigation activities, and risk factor analysis. RESULTS: Fourteen patients and 38 staff members were included in the cluster per whole-genome sequencing and epidemiologic associations. The index case was a symptomatic patient in whom isolation was discontinued after 2 negative results on nasopharyngeal polymerase chain reaction testing. The patient subsequently infected multiple roommates and staff, who then infected others. Seven of 52 (13%) secondary infections were detected only on second or subsequent tests. Eight of 9 (89%) patients who shared rooms with potentially contagious patients became infected. Potential contributing factors included high viral loads, nebulization, and positive pressure in the index patient's room. Risk factors for transmission to staff included presence during nebulization, caring for patients with dyspnea or cough, lack of eye protection, at least 15 minutes of exposure to case patients, and interactions with SARS-CoV-2-positive staff in clinical areas. Whole-genome sequencing confirmed that 2 staff members were infected despite wearing surgical masks and eye protection. LIMITATION: Findings may not be generalizable. CONCLUSION: SARS-CoV-2 clusters can occur in hospitals despite robust infection control policies. Insights from this cluster may inform additional measures to protect patients and staff. PRIMARY FUNDING SOURCE: None.

Commentary: Lessons from the COVID-19 global health response to inform TB case finding.

The coronavirus disease 2019 (COVID-19) has emerged as a serious threat to global public health, demanding urgent action and causing unprecedented worldwide change in a short space of time. This disease has devastated economies, infringed on individual freedoms, and taken an unprecedented toll on healthcare systems worldwide. As of 1 April 2020, over a million cases of COVID-19 have been reported in 204 countries and territories, resulting in more than 51,000 deaths. Yet, against the backdrop of the COVID-19 pandemic, lies an older, insidious disease with a much greater mortality. Tuberculosis (TB) is the leading cause of death by a single infectious agent and remains a potent threat to millions of people around the world. We discuss the differences between the two pandemics at present, consider the potential impact of COVID-19 on TB case management, and explore the opportunities that the COVID-19 response presents for advancing TB prevention and control now and in future.