High Oxygen Flow Research Articles

Impact of c- and m- sapphire plane orientations on the structural and electrical properties of β-Ga2O3 thin films grown by metal-organic chemical vapor deposition

Abstract This work presents a comprehensive investigation into the structural and electrical properties of Ga2O3 thin films grown via metal-organic chemical vapor deposition on both c- and m-plane sapphire substrates. Structural characterization revealed the β-Ga2O3 phase formation in both substrate orientations, with strong epitaxial ( 2 ¯ 01 ) preferential growth on c-plane substrates and polycrystalline films on m-plane substrates. Results show that Ga2O3/m-sapphire exhibits the lower electrical resistivity than its counterpart grown on c-sapphire. Activation energies of acceptor levels were estimated at ~1.4 eV and ~0.7 eV , for Ga2O3 films grown on c- and m-plane, respectively. This result shows that growing Ga2O3 on m-plane sapphire is beneficial to reach a weakly compensated sample. Cathodoluminescence analysis suggests that the additional low activation energy of ~0.18 eV observed in Ga2O3 grown with the highest oxygen flow on m-plane sapphire can be associated to thermally-induced migration of self-trapped hole states.

Determining the optimum high-flow nasal cannula flow rate to achieve the desired fraction of inspired oxygen: A bench study

BackgroundPurpose: High-flow nasal cannula (HFNC) has many benefits in various clinical conditions. The original hypothesis suggests that the high and constant fraction of inspired oxygen (FiO2) is one of the main physiological effects. However, increasing evidence shows that there is a gap between the actual FiO2 and administered FiO2. We aimed to determine the actual FiO2 under different respiratory conditions and develop a regression model using a spontaneous breathing lung model. MethodsA spontaneous breathing simulation model was built using an airway manikin and a model lung. The FiO2 was measured under different respiratory conditions with varying tidal volumes and respiratory and HFNC flow rates. The relationships between the respiratory parameters and actual FiO2 were determined and used to build the predictive model. ResultsThe actual FiO2 was negatively correlated with respiratory rate and tidal volume and positively correlated with HFNC flow. The regression model could not be developed using simple respiratory parameters. Therefore, we introduced a new variable, defined as flow ratio, which equaled the HFNC flow divided by inspiratory flow. Our equation demonstrated that the actual FiO2 was mainly determined by the flow ratio in a non-linear relationship. Accordingly, a flow ratio greater than 1 did not ensure a constant high FiO2, whereas a flow ratio >1.435 could produce FiO2 >0.9. ConclusionThe FiO2 during HFNC was not constant even at sufficiently high oxygen flow compared with inspiratory flow. The predictive model showed that the actual FiO2 was mainly determined by the flow ratio.

The effects of oxygen flow ratio on the properties of Ag x O thin films grown by radio frequency magnetron sputtering.

The Ag x O thin film with various oxygen flow ratios (R[O2]%) deposited by radio frequency magnetron sputtering (RFM-SPT) has been studied. While adjusting R[O2]% from 0% to 30%, the Ag x O thin film transitioned from metal to semiconductor and/or insulator with different transparent appearances on the surface observed using X-ray diffraction (XRD) and transmittance measurement. At high oxygen flow ratios, the Ag x O film is multi-phased as a mixture of Ag(II)O and Ag2 (III)O3. In addition, the work function (ϕ) of those samples changes from 4.7 eV to 5.6 eV as measured by photoelectron yield spectroscopy (PYS). The compositional and chemical state changes that occur at the Ag x O surface during the increments of R[O2]% are evaluated by the relative peak intensities and binding energy shifts in X-ray photoelectron spectroscopy (XPS). With the incorporation of more electrons in chemical bonding, the oxygen-induced band forms. And combining all the results from transmittance (band gap confirmation), PYS (work function confirmation), and XPS (valence band position confirmation), the estimated band diagrams are given for the oxidation state of Ag x O with various oxygen flow ratios.

Improving Epitaxial Growth of γ‐Al2O3 Films via Sc2O3/Y2O3 Oxide Buffers

Heteroepitaxial growth of γ‐Al2O3 on Sc2O3/Y2O3/Si (111) is achieved with oxygen plasma‐assisted molecular beam epitaxy in order to prevent polycrystalline grain boundary formation caused by lattice mismatch. Substrate temperature as well as oxygen flow are adjusted to optimize epitaxial growth conditions around 715–760 °C and 1.9 sccm, respectively. Epitaxial growth is monitored in situ by reflection high‐energy diffraction, while surface morphology is studied by scanning electron microscopy ex‐situ. X‐ray diffraction indicates epitaxial out‐of‐plane 111 orientation with oxygen flow above 0.6 sccm. However, transmission electron microscopy shows stacking fault formation for high oxygen flows. Finally, nanobeam electron diffraction confirms Smrčok model of a spinel‐like γ‐Al2O3 crystal structure.

Standard vs. targeted oxygen therapy prehospitally for chronic obstructive pulmonary disease (STOP-COPD): study protocol for a randomised controlled trial

BackgroundA high concentration of inspired supplemental oxygen may possibly cause hypercapnia and acidosis and increase mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Even so, patients with AECOPD are being treated with high oxygen flow rates when receiving inhalation drugs in the prehospital setting. A cluster-randomised controlled trial found that reduced oxygen delivery by titrated treatment reduced mortality—a result supported by observational studies—but the results have never been reproduced. In the STOP-COPD trial, we investigate the effect of titrated oxygen delivery compared with usual care consisting of high flow oxygen delivery in patients with AECOPD in the prehospital setting.MethodsIn this randomised controlled trial, patients will be blinded to allocation. Patients with suspected AECOPD (n = 1888) attended by the emergency medical service (EMS) and aged > 40 years will be allocated randomly to either standard treatment or titrated oxygen, targeting a blood oxygen saturation of 88–92% during inhalation therapy. The trial will be conducted in the Central Denmark Region and include all ambulance units. The power to detect a 3% 30-day mortality risk difference is 80%. The trial is approved as an emergency trial. Hence, EMS providers will include patients without prior consent.DiscussionThe results will provide evidence on whether titrated oxygen delivery outperforms standard high flow oxygen when used to nebulise inhaled bronchodilators in AECOPD treatment. The trial is designed to ensure unselected inclusion of patients with AECOPD needing nebulised bronchodilators—a group of patients that receives high oxygen fractions when treated in the prehospital setting where the only compressed gas is generally pure oxygen. Conducting this trial, we aim to improve treatment for people with AECOPD while reducing their 30-day mortality.Trial registrationEuropean Union Clinical Trials (EUCT) number: 2022-502003-30-00 (authorised 06/12/2022), ClinicalTrials.gov number: NCT05703919 (released 02/02/2023), Universal trial number: U1111-1278-2162.

Efficiency of continuous positive airway pressure and high-flow nasal oxygen therapy in critically ill patients with COVID-19.

Critically ill patients with COVID-19 develop acute respiratory distress syndrome characterized by relatively well-preserved pulmonary compliance but severe hypoxemia. The challenge in managing such patients lies in optimizing oxygenation, which can be achieved through either high oxygen flow or noninvasive mechanical ventilation. This study was performed to compare the efficiency of two methods of noninvasive oxygen therapy: continuous positive airway pressure (CPAP) and high-flow nasal oxygen therapy (HFNO). This retrospective cohort study involved 668 patients hospitalized in the intensive care unit (ICU) of the "Sf. Apostol Andrei" Emergency Clinical Hospital, Galati, Romania from 1 April 2020 to 31 March 2021 (CPAP, n = 108; HFNO, n = 108). Mortality was significantly lower in the CPAP and HFNO groups than in the group of patients who underwent intubation and mechanical ventilation after ICU admission. Mortality in the ICU was not significantly different between the CPAP and HFNO groups. HFNO and CPAP represent efficient alternative therapies for patients with severe COVID-19 whose respiratory treatment has failed. Studies involving larger groups of patients are necessary to establish a personalized, more complex management modality for critically ill patients with COVID-19.

Low-temperature homoepitaxial growth of β-Ga2O3 thin films by atmospheric pressure plasma-enhanced chemical vapor deposition technique

Low-temperature homoepitaxial growth of β-Ga2O3(-201) has been successfully demonstrated by the atmospheric pressure plasma-enhanced chemical vapor deposition technique. To search for low-temperature growth, temperature-dependent studies were carried out between 350 and 600 °C. A high N2 gas flow rate, low gallium source concentration, and high oxygen flow rate ratio played key roles in growing independent and homogeneous multiple nuclei of Ga2O3, leading to three-dimensional grain growth mode, single crystallinity, and the highest growth rate of ⁓0.17 µm/h at 350 °C. The highly reactive atmospheric pressure oxygen plasma actively led to epitaxial growth. The low thermal budget homoepitaxial growth is a record reduction reported thus far.

Supplemental Oxygen Therapy in Interstitial Lung Disease: A Narrative Review.

Patients with interstitial lung diseases (ILD) often have hypoxemia at rest and/or with exertion for which supplemental oxygen is commonly prescribed. The number of patients with ILD who require supplemental oxygen is unknown though estimates suggest it could be as much as 40%, many of whom may require high flow support (>4 L/min). Despite its frequent use, there is limited evidence for supplemental oxygen's impact on clinical outcomes in ILD with recommendations for its use primarily based on older studies in patients with chronic obstructive pulmonary disease (COPD). Oxygen use in ILD is rarely included as an outcome in clinical trials. Available evidence suggests that supplemental oxygen in ILD may improve quality of life and some exercise parameters in patients whose hypoxemia is a limiting factor; however, oxygen therapy also places new burdens and barriers on some patients that may counter its beneficial effects. The cost of supplemental oxygen in ILD is also unknown but likely represents a significant portion of overall healthcare costs in these patients. Current Centers for Medicare and Medicaid (CMS) reimbursement policies provides only modest increase in payment for high oxygen flows which may negatively impact access to oxygen services and equipment for some ILD patients. Future studies should examine clinical and quality of life outcomes for oxygen use in ILD. In the meantime, given the current limited evidence for supplemental oxygen and considering cost factors and other barriers, providers should take a patient-focused approach when considering supplemental oxygen prescriptions in patients with ILD.

On the O2 "Surfactant" Effect during Ag/SiO2 Magnetron Sputtering Deposition: The Point of View of In Situ and Real-Time Measurements.

The use of gaseous species has been proposed in the literature to counteract the three-dimensional growth tendency of noble metals on dielectric substrates and favor an earlier percolation without compromising electrical properties. This "surfactant" effect is rationalized herein in the case of O2 presence during magnetron sputtering deposition of Ag films on SiO2. In situ and real-time techniques (X-ray photoemission, film resistivity, UV-visible optical spectroscopy) and ex situ characterizations (X-ray diffraction and transmission electron microscopy) were combined to scrutinize the impact of O2 addition in the gas flow (%O2), revealing three regimes of evolution of film resistivity, morphology, structure, and chemical composition. At low oxygen flow conditions (%O2 < 4), the observed drastic decrease of the percolation threshold is assigned to a combination of (i) a change in nanoparticle density, wetting, and crystallographic texture and (ii) a delayed coalescence effect. The driving force is ascribed to the presence of specific adsorbed oxygen moieties, the nature of which starts evolving at intermediate oxygen flow conditions (10 ≤ %O2 < 20). At high oxygen flow (20 ≤ %O2 < 40), the found detrimental impact on film resistivity is assigned to an actual oxidation in the form of a Ag2O-like poorly crystallized compound. For all %O2, a composition gradient is observed across the film thickness, with a more metallic Ag at the substrate interface. A correlation between percolation and the nature of the detected O moieties is observed. In parallel to an oxygen spillover mechanism, this gradient can be explained by the competition between different surface processes occurring before percolation, namely, aggregation, metal oxidation, and substrate reactivity. Such findings pave the way to a rational use of O2 as a modifier for Ag growth.

Transnasal Humidified Rapid Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE): a statistical analysis plan for a randomised controlled trial

The placement of an endotracheal tube for children with acute or critical illness is a low-frequency and high-risk procedure, associated with high rates of first-attempt failure and adverse events, including hypoxaemia. To reduce the frequency of these adverse events, the provision of oxygen to the patient during the apnoeic phase of intubation has been proposed as a method to prolong the time available for the operator to insert the endotracheal tube, prior to the onset of hypoxaemia. However, there are limited data from randomised controlled trials to validate the efficacy of this technique in children. The technique known as transnasal humidified rapid insufflation ventilatory exchange (THRIVE) uses high oxygen flow rates (approximately 2 L/kg/min) delivered through nasal cannulae during apnoea. It has been shown to at least double the amount of time available for safe intubation in healthy children undergoing elective surgery. The technique and its application in real time have not previously been studied in acutely ill or injured children presenting to the emergency department or admitted to an intensive care unit. The Kids THRIVE trial is a multicentre, international, randomised controlled trial (RCT) in children less than 16 years old undergoing emergent intubation in either the intensive care unit or emergency department of participating hospitals. Participants will be randomised to receive either the THRIVE intervention or standard care (no apnoeic oxygenation) during their intubation. The primary objective of the trial is to determine if the use of THRIVE reduces the frequency of oxygen desaturation and increases the frequency of first-attempt success without hypoxaemia in emergent intubation of children compared with standard practice. The secondary objectives of the study are to assess the impact of the use of THRIVE on the rate of adverse events, length of mechanical ventilation and length of stay in intensive care. In this paper, we describe the detailed statistical analysis plan as an update of the previously published protocol.

Study of IGZO thin film transistors with Al2O3 gate insulator

In this study focuses on the dielectric layer materials of thin film transistors (TFTs). Gate oxide was deposited using a RF Magnetron Sputtering control system. The first studied the aluminium oxide (Al2O3) dielectric layer material deposited with different oxygen flow and annealed by the furnace tube. The study found that the properties of aluminium oxide (Al2O3) thin film transistors (TFTs) after furnace tube annealing reduced the interface trap density and the roughness of the thin film after annealing. The above dielectric layer is used to make thin film transistors (TFTs) with a bottom gate structure. The characteristics of thin film transistors (TFTs) are significantly improved by higher oxygen flow and additional thermal anneal. By analyzing the structure and electrical measurement of the thin film, the influence of the dielectric layer material on the thin film transistors (TFTs) is analyzed.

High-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy but not to non-invasive mechanical ventilation in reducing intubation rate in hypoxia and dyspnea due to acute heart failure: a systematic review and meta-analysis.

High-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy but not to non-invasive mechanical ventilation in reducing intubation rate in hypoxia and dyspnea due to acute heart failure: a systematic review and meta-analysis.

Descriptive, Prospective Observational Study- Studying Possible Prediction Factors for Disease Severity and Progression among a Sample of COVD 19 Patients in Iraq

Abstract&#x0D; Coronavirus has affected many people around the world and caused an increase in the number of hospitalized patients and deaths. The prediction factor may help the physician to classify whether the patient needs more medical attention to decrease mortality and worsening of symptoms. We aimed to study the possible relationship between C reactive protein level and the severity of symptoms and its effect on the prognosis of the disease. And determine patients who require closer respiratory monitoring and more aggressive supportive therapies to avoid poor prognosis. The data was gathered using medical record data, the patient's medical history, and the onset of symptoms, as well as a blood sample to test the C-reactive protein level. The patients were divided into three groups based on the severity of the disease. A prospective cohort study of 246 patients over the age of 18 years discovered that c-reactive protein levels were significantly higher in more severe cases than in mild cases, and that older patients with high levels of AST, TSB, Urea, Creatinine, and CRP were associated with the need for a high flow of oxygen, an intensive care unit, a longer length of hospitalization, and a have a high mortality rate. The study concluded several predictor factors for the disease (COVID-19) severity, duration of hospitalization, ICU admission and need for oxygen therapy.

On the influence of non equilibrium in the free stream conditions of high enthalpy oxygen flows around a double-cone

This work presents a detailed analysis of the shock wave/boundary layer interaction in hypersonic flows around a double-cone. Numerical simulations have been carried out by solving the axisymmetric Navier–Stokes equations for an oxygen mixture. Thermochemical non-equilibrium is taken into account by employing the multi-temperature model (mT) proposed by Park and the State-to-State model (StS). The occurrence of surface processes is also analyzed considering both non-catalytic and fully-catalytic wall models. It is shown that the evaluation of correct free stream conditions is fundamental for the prediction of the separation extent and the corresponding heat transfer in high enthalpy conditions.

Mutations in the nonstructural proteins of SARS-CoV-2 may contribute to adverse clinical outcome in patients with COVID-19

BackgroundFrom late March through April 2021, we experienced a cluster of patients with COVID-19, named “Cluster K”, with rapid severe illness compared with those who were infected before. MethodsPatients with COVID-19 who were enrolled in this study were divided into two groups: 66 patients from November 2020 to March 2021 (group A) and 37 patients whose infection links were traced from Cluster K (group B). The primary outcome was mortality rate, and the secondary outcome was maximal oxygen flow rate as the severity of the disease. Viral genome sequences were compared between the two groups. ResultsMortality rates were 6.1% in group A and 16.2% in group B (odds ratio: 2.97, 95% confidence interval: 0.65–15.38). The patients in group B required high oxygen flow rate (O2 ≥10 l/min) in the earlier clinical course (P = 0.029). Viral genome sequences revealed five amino acid mutations; of these, four were found on three nonstructural proteins (NSPs): one in nsp3 and nsp15, two in nsp6 (one of them is near the potential sites under positive selective pressure). Another one was on the S protein. ConclusionThis study suggests that mutations in NSPs, especially nsp6, are associated with adverse clinical outcome in patients with COVID-19.

Association between the fatty liver index and the risk of severe complications in COVID-19 patients: a nationwide retrospective cohort study

BackgroundResearch on the association of non-alcoholic fatty liver disease (NAFLD) with prognosis in COVID-19 has been limited. We investigated the association between the fatty liver index (FLI), a non-invasive and simple marker of NAFLD, and the severe complications of COVID-19 patients in South Korea.MethodsWe included 3122 COVID-19-positive patients from the nationwide COVID-19 cohort dataset in South Korea between January and June 2020. The FLI was calculated using triglyceride, body mass index, glutamyl transpeptidase, and waist circumference, which were obtained from the national health screening program data. Severe complications related to COVID-19 were defined as the composite of mechanical ventilation, intensive care unit treatment, high-oxygen flow therapy, and death within 2 months after a COVID-19 infection. We performed a multivariate logistic regression analysis for the development of severe complications in COVID-19 patients.ResultsThe mean ± standard deviation of FLI were 25.01 ± 22.64. Severe complications from COVID-19 occurred in 223 (7.14%) patients, including mechanical ventilation in 82 (2.63%) patients, ICU admission in 126 (4.04%), high-flow oxygen therapy in 75 (2.40%), and death in 94 (3.01%) patients, respectively. The multivariate analysis indicated that the highest tertile (T3) of FLI was positively associated with severe complications from COVID-19 (adjusted odds ratio (OR): 1.77, 95% confidence interval (CI) (1.11–2.82), P = 0.017) compared with the lowest tertile (T1).ConclusionsOur study demonstrated that FLI, which represents NAFLD, was positively associated with an increased risk of severe complications from COVID-19. FLI might be used as a prognostic marker for the severity of COVID-19.

Excessive Oxygen Peroxide Model‐Based Analysis of Positive‐Bias‐Stress and Negative‐Bias‐Illumination‐Stress Instabilities in Self‐Aligned Top‐Gate Coplanar In–Ga–Zn–O Thin‐Film Transistors

AbstractAn excess oxygen‐peroxide‐based model that can simultaneously analyze the positive‐bias‐stress (PBS) and negative‐bias‐illumination‐stress (NBIS) instabilities in commercial self‐aligned top‐gate (SA‐TG) coplanar indium–gallium–zinc oxide (IGZO) thin‐film transistors (TFTs) is proposed herein. Existing studies have reported that the transition of oxygen vacancy (VO) charge states from VO0 to VO2+ is the dominant physical mechanism responsible for the negative shift of threshold voltage (VTH) under NBIS. However, in this study, it is observed that both the PBS and the NBIS stabilities of IGZO TFTs deteriorate at a faster rate as the amount of oxygen increases within the channel layer, implying that the conventional VO‐related defect model is inappropriate in elucidating the PBS and NBIS instabilities of commercial SA‐TG coplanar IGZO TFTs, where the channel layers are formed under high oxygen flow rates (OFRs) to make VTH positive. On the basis of the full‐energy range subgap density of states extracted before and after each stress from IGZO TFTs with different OFRs, it is determined that the generation and annihilation of the subgap states in the excess oxygen peroxide configuration are the dominant physical mechanisms for PBS and NBIS instabilities in commercial SA‐TG coplanar IGZO TFTs, respectively.

Role of oxygen flow rate on the structure and stoichiometry of cobalt oxide films deposited by reactive sputtering

The influence of the oxygen gas supply on the stoichiometry, structure, and orientation texture of polycrystalline cobalt oxide films was investigated in this study. The films were grown by direct current reactive magnetron sputtering using a metallic Co target and different O2 inlet flow rates (0.5–5.0 SCCM). The deposition power (80 W), the argon gas flow (40 SCCM), and the total working pressure (0.67 Pa) were kept constant during depositions. The results evidence a strong influence of the oxygen flow over the film’s stoichiometry and structure, where low oxygen flows (&amp;lt;2.0 SCCM) favor the formation of the rock salt CoO phase while higher oxygen flows (&amp;gt;2.5 SCCM) favor the spinel Co3O4 phase formation. The coexistence of monoxide and tetraoxide phases is only observed for the 2.5 SCCM oxygen flow condition. Strain effects related to the oxygen partial pressure are also observed and discussed. Computer simulations of the reactive sputtering growth supported the analysis of the film properties and its correlation to the oxygen partial pressure.

Anakinra versus Baricitinib: Different Strategies for Patients Hospitalized with COVID-19.

Background: Immunomodulatory drugs have been used in patients with severe COVID-19. The objective of this study was to evaluate the effects of two different strategies, based either on an interleukin-1 inhibitor, anakinra, or on a JAK inhibitor, such as baricitinib, on the survival of patients hospitalized with COVID-19 pneumonia. Methods: Individuals admitted to two hospitals because of COVID-19 were included if they fulfilled the clinical, radiological, and laboratory criteria for moderate-to-severe disease. Patients were classified according to the first immunomodulatory drug prescribed: anakinra or baricitinib. All subjects were concomitantly treated with corticosteroids, in addition to standard care. The main outcomes were the need for invasive mechanical ventilation (IMV) and in-hospital death. Statistical analysis included propensity score matching and Cox regression model. Results: The study subjects included 125 and 217 individuals in the anakinra and baricitinib groups, respectively. IMV was required in 13 (10.4%) and 10 (4.6%) patients, respectively (p = 0.039). During this period, 22 (17.6%) and 36 (16.6%) individuals died in both groups (p = 0.811). Older age, low functional status, high comorbidity, need for IMV, elevated lactate dehydrogenase, and use of a high flow of oxygen at initially were found to be associated with worse clinical outcomes. No differences according to the immunomodulatory therapy used were observed. For most of the deceased individuals, early interruption of anakinra or baricitinib had occurred at the time of their admission to the intensive care unit. Conclusions: Similar mortality is observed in patients treated with anakinra or baricitinib plus corticosteroids.

Case Report: An immunocompromised, vaccine breakthrough COVID-19 patient with pneumonia

Background: The novel SARS-CoV-2 pandemic has inflicted a major blow on public health worldwide accounting for millions of deaths and subsequent socio-economic consequences. The main challenge for scientists and researchers has been to restrain transmission of the virus and prevent severe respiratory disease. Novel promising vaccines aim to fulfil these expectations, although new variants of the coronavirus have emerged. The present manuscript aims to add to the knowledge, through a case of an immunodeficient patient, who developed remarkably favorable recovery from SARS-CoV-2 pneumonia after having been fully vaccinated against the novel coronavirus. Case presentation: An 82-year-old Caucasian male with a history of metastatic pancreatic cancer was admitted with signs and symptoms of pneumonia. Workup revealed a positive SARS-CoV-2 real time – polymerase chain reaction (RT-PCR) and further investigation identified a B.1.1.7 variant. The imaging essays showed extensive lung disease. Interestingly, the patient had already received the second dose of the BNT162b2 (Pfizer) vaccine against the new coronavirus 16 days prior. After having been treated with appropriate antiviral and antibiotical agents the patient showed significantly favorable recovery and no need for high oxygen flows and no complications presented. The patient was discharged after six days of hospitalization in good condition, with no need for supplementary oxygen at home. Conclusions: Despite breakthrough cases, vaccination against COVID-19 is crucial for restraining the novel coronavirus. Further studies should be carried out in order to determine the optimal strategies for large-scale vaccination while minimizing the risk of further and faster evolution of the virus.