**7. White light transmission holographic stereograms**

The representational system of the holographic stereogram is characterized by the spatial arrangement of an array of two-dimensional views, which correspond, to the position of the beholder relative to the subject across a horizontal field of view. Typical source image types for holographic stereograms are film footage, photographs and computer graphics all of which use perspective. A batch of any type of two dimensional perspective images is exposed firstly to the H1, which is then transferred as an H2 in order to locate the array of 2D images away from the holographic picture plane. Typically this process introduces many optical aberrations and the output stereograms have distortions. The sequences of 2D images can be of sequential side-to-side viewpoints of a static three-dimensional space or sequential side-to-side viewpoints of a dynamic space over time.

The first type of representation, of a consistent, static space can be seen in James Turrell

Pace Wildenstein 2009 exhibition of "transmission light works". In these works the position of a single shape--a triangle, rectangle, ring or a conjunction of two forms, remains static in the centre of the composition. The stereogram is replayed with monochromatic light lending the form a specific hue almost reminiscent of Bauhaus (Kandinsky) and Russian constructivist (Malevich and Kliun) correspondences between hues and forms. The conditions for stereopsis and motion parallax are satisfied. The lack of occlusion of the subject gives it a less material feeling while holding a stable spatial position (Gallery, 2009).

The second type of imagery, that of a dynamic field of information necessarily deprives the viewer both of motion parallax and stereopsis as side-by-side views now carry information about objects in displaced positions. In order to be able to track the image elements the amount of motion has to be very restricted. Too much movement of the subject in the initial 2D images will result in "time smear" where the parts of the subject do not match up in side-by-side views and consequently cause retinal rivalry. Because the animation of the holographic stereogram is activated by the walking of the viewer side to side, the motion of the subject will be read in forward and reverse.

The fluid motion of floating text in Eduardo Kac's, *Adhuk* , 1991 encourages the viewer to walk right and left to locate the point at which the letters coalesce into a word. At this point the viewer pauses. Instead of the beholder observing the three-dimensional representation of a space, the imagery instead designates that the beholder will be in a specific space in relation to the subject and the hologram plane.

Language plays a fundamental role in the constitution of our experiential world. To question the structure of language is to investigate how realities are constructed. My holograms define a linguistic experience that takes place outside syntax and conceptualise instability as a key signifying agent (Pepper, 1995).

Similar to the rainbow hologram the optimum viewing position within the viewing zone for the beholder of the rainbow stereogram lies along a line, which is at the same height as the centre of the holographic plate. The imagery can appear behind, in front of, or straddling the hologram plane. The viewing zone generally extends to the right or left of the plate or film. The locations of the horizontal boundaries of the viewing zone are variable depending on how the hologram is made.

The confines of this type of viewing zone have been used to great effect in works by Martina Mongrovious. "*Pater Noster"*, 300 X 400 mm stereogram reflection print, was first exhibited at the centre for the Holographic Arts in New York and then in the Stairwell Gallery Melbourne.

The representational system of the holographic stereogram is characterized by the spatial arrangement of an array of two-dimensional views, which correspond, to the position of the beholder relative to the subject across a horizontal field of view. Typical source image types for holographic stereograms are film footage, photographs and computer graphics all of which use perspective. A batch of any type of two dimensional perspective images is exposed firstly to the H1, which is then transferred as an H2 in order to locate the array of 2D images away from the holographic picture plane. Typically this process introduces many optical aberrations and the output stereograms have distortions. The sequences of 2D images can be of sequential side-to-side viewpoints of a static three-dimensional space or

The first type of representation, of a consistent, static space can be seen in James Turrell Pace Wildenstein 2009 exhibition of "transmission light works". In these works the position of a single shape--a triangle, rectangle, ring or a conjunction of two forms, remains static in the centre of the composition. The stereogram is replayed with monochromatic light lending the form a specific hue almost reminiscent of Bauhaus (Kandinsky) and Russian constructivist (Malevich and Kliun) correspondences between hues and forms. The conditions for stereopsis and motion parallax are satisfied. The lack of occlusion of the subject gives it a less material feeling while holding a stable spatial position (Gallery, 2009). The second type of imagery, that of a dynamic field of information necessarily deprives the viewer both of motion parallax and stereopsis as side-by-side views now carry information about objects in displaced positions. In order to be able to track the image elements the amount of motion has to be very restricted. Too much movement of the subject in the initial 2D images will result in "time smear" where the parts of the subject do not match up in side-by-side views and consequently cause retinal rivalry. Because the animation of the holographic stereogram is activated by the walking of the viewer side to side, the motion of

The fluid motion of floating text in Eduardo Kac's, *Adhuk* , 1991 encourages the viewer to walk right and left to locate the point at which the letters coalesce into a word. At this point the viewer pauses. Instead of the beholder observing the three-dimensional representation of a space, the imagery instead designates that the beholder will be in a specific space in

Language plays a fundamental role in the constitution of our experiential world. To question the structure of language is to investigate how realities are constructed. My holograms define a linguistic experience that takes place outside syntax and conceptualise

Similar to the rainbow hologram the optimum viewing position within the viewing zone for the beholder of the rainbow stereogram lies along a line, which is at the same height as the centre of the holographic plate. The imagery can appear behind, in front of, or straddling the hologram plane. The viewing zone generally extends to the right or left of the plate or film. The locations of the horizontal boundaries of the viewing zone are variable depending on

The confines of this type of viewing zone have been used to great effect in works by Martina Mongrovious. "*Pater Noster"*, 300 X 400 mm stereogram reflection print, was first exhibited at the centre for the Holographic Arts in New York and then in the Stairwell Gallery

**7. White light transmission holographic stereograms**

sequential side-to-side viewpoints of a dynamic space over time.

the subject will be read in forward and reverse.

relation to the subject and the hologram plane.

instability as a key signifying agent (Pepper, 1995).

how the hologram is made.

Melbourne.

Fig. 9. Martina Mrongovius, *Jumping Jellies*, 2007, rainbow stereogram, 30 X 40 and 60 x cm

In both these installations I wanted the viewer to mimic ascending /descending in the image. The subject's (my) holding of the camera links the viewer's proprioception to the subject, establishing an emotional and imaginative connection of shared experience…(Mrongovius, 2009).

In *Figure 8* the beholder is propelled at an increase speed in an office wheelie chair along a horizontal line parallel to the plate at the optimum viewing distance and in *Jelly*, the beholder jumps on a trampoline to fly past the small aperture located on the vertical y-axis. Here there is a deliberate reference to the inability to see the stereogram except from a specific height.

Falling, running, jumping and skipping are descriptions of movements but also come with strong emotive connotations. In the *Jumping Jellies* installations it is the physical mimesis between your own sense of blubber and the jellyfish movement that establishes the image. The intention of this work is both playful and to illustrate how proprioception can create a reading through experience (Mrongovius, 2009).


*1.1.2. Transcription activator-like effector nucleases (TALENs)*

It may seem that ZFN is the most practical method; nevertheless, the challenge lies in the construction as mentioned in addition to less popularity as the success rate for the DNA repair pathway via HDR is still considerably low [7]. Therefore, a more recent genome editing tool known as transcription activator-like effector nucleases (TALENs) had been developed with better modularity [24, 25]. TALENs are quite similar to ZFN in terms of the idea of directing the same nonspecific endonuclease to a specific site with the help of DNA-binding motifs (**Figure 3**).

Unlike ZFN, the DNA-binding domains for TALENs are known as the transcription activatorlike effector (TALE) proteins rather than ZFPs and they are found in pathogenic plant bacteria (specifically of genus *Xanthomonas*) instead of in a eukaryotic cell. TALE protein is comprised of a repetitive sequence of a series of 34 amino acid residues, where each TALE protein has the ability to selectively bind to one nucleotide in the DNA target site [1]. Specifically, the pair residue at the 12th and 13th position is the one that determines the nucleotide specificity of the TALE proteins and they are known as the repeat variable domain (RVD).

**Figure 3.** Transcription activator-like effector nuclease (TALEN) dimer bound to DNA. Like the ZFN, it has a Fok1 endonuclease domain that can cleave DNA. Indicated by small dotted lines, each TALE protein can specifically detect a single nucleotide base pair and it can be linked with more TALE proteins to detect longer sequences. By coupling the Fok1 endonuclease domain with the TALE proteins, it is now known as TALEN and it can specifically detect and cleave DNA. Adapted from Gupta [73].

TALE proteins have a different method to detect DNA sequences. They recognize a single nucleotide instead of DNA triplets. In fact, TALE proteins can also be assembled in a way to recognize virtually any DNA sequence that is desired by their users [26]. This attribute enables TALENs to have a higher range of target sites to suit user specifications, making them significantly more flexible and generally more straightforward. Like ZFN, the DNA-cleaving domain for TALENs is the nonspecific Fok1 endonuclease domain, which is highly dependent on the DNA-binding domains to achieve higher specificity of DSBs [1]. In a nut shell, both ZFNs and TALENs function as genome editing tools but they are considerably complex, a challenge to be constructed and less efficient compared to newly developed genome editing tool like CRISP/Cas9 system.

## *1.1.3. CRISPR/Cas9*

known that the Fok1 endonuclease domain must dimerize to produce the breaks on DNA [13, 16]. However, the interaction between the dimer ZFN can be weak if it is not optimally designed. Thus, the optimal design for ZFN to achieve DNA cleavage is to direct two sets of fingers to neighboring sequences and join each to a Fok1 DNA-cleaving domain. Once the dimers bind to their respective sequences, adjacent cleavage factors will facilitate the dimerization and cleavage of the DNA strand [9]. Nevertheless, the construction of ZFN has proven to be difficult as there are many complicated interference in the interaction between the ZFPs

**Figure 2.** ZFN dimer binding to DNA at each side of the sequence. Different shaded boxes represent the different zinc fingers and each of them binds to a specific codon. Short dotted lines indicate 3-bp long codons. Shaded ellipses indicate the Fok1 endonuclease domain with the ability to induce DNA double-stranded breaks and they are coupled by the zinc fingers to guide them to their cleavage site. The cleavage site will be between the dimer and it is about 4-bp long.

It may seem that ZFN is the most practical method; nevertheless, the challenge lies in the construction as mentioned in addition to less popularity as the success rate for the DNA repair pathway via HDR is still considerably low [7]. Therefore, a more recent genome editing tool known as transcription activator-like effector nucleases (TALENs) had been developed with better modularity [24, 25]. TALENs are quite similar to ZFN in terms of the idea of directing the same nonspecific endonuclease to a specific site with the help of DNA-binding motifs

Unlike ZFN, the DNA-binding domains for TALENs are known as the transcription activatorlike effector (TALE) proteins rather than ZFPs and they are found in pathogenic plant bacteria (specifically of genus *Xanthomonas*) instead of in a eukaryotic cell. TALE protein is comprised of a repetitive sequence of a series of 34 amino acid residues, where each TALE protein has the ability to selectively bind to one nucleotide in the DNA target site [1]. Specifically, the pair residue at the 12th and 13th position is the one that determines the nucleotide specificity of

the TALE proteins and they are known as the repeat variable domain (RVD).

despite many attempts made in the past to simplify them [17–23].

*1.1.2. Transcription activator-like effector nucleases (TALENs)*

(**Figure 3**).

Adapted from Carroll [9].

132 Next Generation Plant Breeding

The most recently developed SSN in genome editing technology is known as the CRISPR/ Cas9 system. The CRISPR/Cas9 system was developed based on the bacterial type-II CRISPR/ Cas adaptive immune system that is deployed by the hosts to recognize and eliminate any invading phage or plasmid DNA [27–29]. The three major components of the immune system are the protospacer-containing CRISPR RNA (crRNA), transactivating crRNA (tracrRNA) and the Cas9 endonuclease [27, 30].

During the invasion of foreign DNA, the bacterial type-II CRISPR/Cas system will integrate a short fragment of the foreign DNA, called "spacers," into the CRISPR genomic loci [31]. These spacers act as a form of an acquired immunity memory for the host. Then, the spacers will be transcribed and processed in the form of crRNA. Thus, the CRISPR genome loci act as the library where it can store information to enable the bacteria CRISPR/Cas9 system to retarget any known foreign DNA. In case of another attack by the invader, the crRNAs will then bind to the tracrRNAs that have the ability to trigger the direction of the Cas9 endonuclease to the target site of the foreign DNA. After that, it will induce DSBs on the foreign DNA that carries the same protospacer sequence, which is accompanied by the protospacer adjacent motif (PAM) to disable the virus [7, 30]. As a matter of fact, recent studies have shown that the specificity of Cas9 protein is highly dependent to the PAM sequence as it licenses the landing of the crRNA-tracrRNA-Cas9 complex [32–34].

Conceptually, the spacer acquisition process can be further divided into two steps, which are protospacer selection and integration of the spacer into the CRISPR array to synthesize new repeat [44]. The protospacer selection step of the spacer acquisition stage is guided by a conserved DNA sequence element, namely protospacer adjacent motif (PAM), that is located downstream of the DNA target, which has the sequence of 5'-NGG-3 [44]. Next, the selected protospacer will be integrated into the leader-repeat boundary of CRISPR array as new spacer and is duplicated in order to synthesize new repeats. Each repeat is a 29 nucleotide sequence, and repeats are interspaced by five intervening 32-nucleotide nonrepetitive sequences [30].

The CRISPR/Cas9 System for Crop Improvement: Progress and Prospects

http://dx.doi.org/10.5772/intechopen.75024

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Then, the CRISPR will be transcribed into a long precursor crRNA (pre-crRNA) with the help of Cas proteins (Cas1, Cas2, Cas9 and Cas4/casn2) or simply known as biogenesis. During this process, the tracrRNA will be transcribed from the bacterial genome as it is needed for processing of the pre-crRNA into a mature guide crRNA. Next, the antirepeat sequence of tracrRNA will enable the complementary base pairing with each pre-crRNA repeats, result-

During the target interference stage, the crRNA-tracrRNA duplex recognizes the PAM sequence located downstream of the protospacer in the foreign DNA and triggers the 'non– self-activation,' which prevents self-targeting of CRISPR array. After that, the duplex guides the Cas9 endonuclease to bind and cleave the DNA target, resulting in the formation of DSBs. Additionally, the DNA target specificity duplex is provided by what is called the 'seed sequence,' which is located at approximately 12 bases upstream of the PAM sequence that

The CRISPR/Cas9 system for plant genome editing comprises four steps. First, a gene-specific gRNA is designed and constructed by fusing crRNA and tracrRNA. Many online tools have been developed for computer-based design of gRNA [46]. However, the in silico design of gRNA has not been fully adapted for plants, and large-scale data collection and systematic study of gRNA efficiencies in plant cells are needed to increase the accuracy of computational gRNA selection [46]. Both gRNA and Cas9 expression cassettes are constructed separately. The expression of gRNA is driven by U3 or U6 small nuclear RNA gene promoters with defined initiation and termination site, facilitating the transcription of gRNA by RNA polymerase III. The first nucleotide in the guide sequence is a 'G' if U6 promoter is used or an 'A' if U3 promoter is used [47]. Guide sequence should match the target, except for the first nucleotide (5′ G or A) that does not have to match [47]. In Cas9 expression, nuclear localization of Cas9 requires fusion of a single or dual nuclear localization signal (NLS) to the Cas9 coding sequence, which is 4107-bp in length. Both expression cassettes are then assembled

The next step involves the transformation of protoplasts with CRISPR in which the activity of gRNA is best validated before being used in genome editing [46]. This step is followed by the selection of active CRISPR using polymerase chain reaction (PCR) or restriction enzyme digestion. Then, the CRISPR/Cas9 system in the form of vector is delivered into the target

ing in the formation of a crRNA-tracrRNA duplex [45].

matches the RNA with the DNA target [29] (**Figure 4**).

**2.2. Engineered CRISPR/Cas9 in plant genome editing**

into a vector.

The CRISPR/Cas9 system has been redesigned to work more efficiently by fusing the Cas9 endonuclease with an artificial crRNA-tracrRNA chimera known as guide RNA (gRNA) [35–37]. The gRNA maintains the function of both crRNA and tracrRNA where just by itself is able to recognize the PAM-containing target sequence to direct the Cas9 protein for DNA cleaving activity. In fact, studies have shown that the gRNA works more efficiently compared to the combination of crRNA and tracrRNA [38, 39].

Compared to ZFNs and TALENs, the CRISPR/Cas9 system is potentially more efficient and effective with three main advantages [40], which are:


The S3 guideline "Recommendations for inpatient therapy of patients with COVID-19" (AWMF registry number 113/001; [16]), which applies in Germany and therefore to the majority of patients in the LEOSS registry, recommends an apparatus-based therapy escalation in acute respiratory failure due to COVID-19. In case of progressive deterioration of gas exchange and increased oxygen demand (PaO2/FiO2 < 150 mmHg and respiratory rate >30/min) accompanied by organ dysfunction, intubation and invasive ventilation should be considered. The implementation of these recommendations is reflected in the study cohort. The majority of patients with severe ARDS and a high degree of organ dysfunction were intubated. However, the data also suggest that not only disease severity, but also age and comorbidity burden may have contributed to the treatment choice. ECMO was limited for patients older than 3 years and younger than 85 years. In contrast, a clustering of individuals older than 76 years was observed in the sub-cohort of nonventilated patients. A shift was also seen in terms of patient comorbidity burden: the more invasive a ventilation option, the lower the comorbidity burden of the patients receiving it. Thus, in the sub-cohort of non-ventilated patients, individuals with a Charlson comorbidity index up to 16 and a total number of documented comorbidities up to 14 were found. In the sub-cohort of ECMO patients, however, the maximum Charlson comorbidity index was nine and the maximum comorbidity count was seven. Apparently, geriatric, multimorbid patients were treated less aggressively without exhausting all treatment options. One can assume that the limited ICU capacities in the first acute COVID-19 pandemic wave added to the reserved usage of invasive ventilation. On the other hand, it is known that about 50% of the elderly population (>60 years) in Germany has composed an advance directive [17]. Therefore, it can be speculated that the limited use of mechanical ventilation in this patient group was primarily in response to patient wishes rather than based on a physician triage system. In fact, a recent study of elderly (≥80 years) ICU patients reported more frequent withholding or withdrawal of life-sustaining measures in COVID-19 patients compared to non-COVID-19 patients [18]. The same study also found an increased 30-day mortality in COVID-19 patients compared to non-COVID-19 patients. However, it remains unclear whether this finding reflects a more active policy of withholding treatment or an inherent increased mortality risk due to COVID-19 [18]. Overall, these findings highlight the need for comprehensive research on LLST. Critical care databases should include advance directives as a mandatory data point. Healthcare professionals' assessment of a patient's risk-benefit profile may be another factor which is worthy of discussion. In the S3 guideline referred to above, it is stated that clinical factors, including age and comorbidities, should be considered when deciding whether to intubate a patient [16]. In addition to the assessment of severity, frailty is often used as a decision-making aid [2,19,20]. This approach raises the question of whether age and multimorbidity are not only risk factors for needing intensive care [1–6,8,21–24], but also influence the success of certain intensive care interventions.

The present study clearly demonstrates that age and comorbidity burden affect the outcome of intensive care treatment of COVID-19 patients. Remarkably, the age at which treatment could be completed with survival in the majority of patients was observed to shift in relation to the invasiveness of the ventilation therapy performed: the more invasive a ventilation option, the earlier the turning point was reached. Apparently, age, therapeutic intervention, and treatment success were interlinked. A critical factor for treatment success is a patient's disease severity. Mechanical ventilation and, even more so, ECMO are used in patients with a serious course of disease, which per se implies an elevated mortality risk. Multiple mechanisms discussed to contribute to more severe disease progression are age-associated. These include pre-existing malfunctions, immune senescence, age-related limitations of lung function, the coagulation system, and the endothelial barrier, as well as imbalances in nutritional status and intestinal dysbiosis, which are more common in the elderly [4,5,7,8]. Another influencing factor is the violence of the therapy performed. With the increasing invasiveness of a treatment, the probability of undesirable side effects rises, which may negatively affect the outcome. It is known that advanced age elevates the risk of such side effects [10]. Therefore, the harm–benefit balance of invasive ventilation strategies becomes rather critical with age.

The group of non-ventilated patients was characterized by a high proportion of very old, multimorbid individuals and also by a substantial mortality rate. The available data do not allow us to conclusively determine whether a more aggressive treatment of these patients would have been associated with better outcomes. Nonetheless, the findings of this study underscore the importance of a holistic approach in decision-making to ensure that treatment is proportionate and meets the patient's wishes. Advanced age is a relative (not an absolute) contraindication to the use of ECMO, although no threshold has been established [25]. In general, the decision to use invasive ventilation therapies, such as mechanical ventilation or ECMO, should be made after careful consideration of potential benefits and harms, especially in patients of advanced age [25,26]. Chronological age is not a good indicator of outcome here. Rather, the patient's health status should also be considered. Accordingly, the frailty of a patient is discussed as a suitable prognostic marker [2,4–7,9,11,27]. Specifically, the use of the clinical frailty scale (CFS) is recommended for priority setting, decision-making, and pandemic triage [2,4,6,9,11]. As a caveat, focusing on CFS (in analogy to the traditional focus on patient age) has the potential to perpetuate established patterns of inequity. This is especially true for older, frail individuals who desire comprehensive intensive care. The extent to which CFS played a role in decision-making in the study population cannot be estimated because CFS data were not available from the patients.

Our analyses based on LEOSS have the advantage of a standardized protocol and data from different regions and sectors. However, the majority of patients included were from Germany, limiting the generalizability of our results. A clear limitation of our study is its retrospective observational nature. The LEOSS registry did not collect data on patients' frailty as assessed by CFS. The lack of knowledge about whether patients were frail and to what extent severely limits the interpretation of the data. Information on the type of non-invasive ventilation used was also not available. It was not possible to determine the prevalence of advance directives among ICU patients because this element was included in LEOSS at a later stage. Our data represent patients recruited during the first pandemic wave. The extent to which the data are different from patients who were in intensive care for SARS-CoV-2 infection later in the pandemic is unknown but may be of interest for investigation.

#### **5. Conclusions**

Our study highlights the impact of age and comorbidity burden on the outcome of COVID-19 patients receiving intensive care. Our data further point toward a relationship between the type and invasiveness of a therapeutic measure, the patient age, and the outcome. The more aggressive an applied procedure, the younger the age in which a majority of patients died in hospital. In addition, our study spotlights that specifically geriatric and multimorbid patients are predominately excluded from invasive ventilation regimens, such as ECMO, thus precluding an assessment of the potential benefit of these therapeutic approaches for that patient population.

**Author Contributions:** Conceptualization, S.B., D.E. and J.S.; methodology, S.B. and J.S.; validation, M.L.d.H., D.E. and J.S.; formal analysis, M.L.d.H. and J.S.; investigation, M.L.d.H., D.E. and J.S.; data curation, S.B., S.R. (Siegbert Rieg), J.J.V., S.R. (Sebastian Rasch), C.E.M.K., M.H., M.S., F.H. and LEOSS Study Group; writing—original draft preparation, J.S.; writing—review and editing, M.L.d.H., S.B. and D.E.; visualization, M.L.d.H.; supervision, J.S.; project administration, J.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** The LEOSS registry was supported by the German Centre for Infection Research (DZIF) and the Willy Robert Pitzer Foundation.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki. Approval for LEOSS was obtained by the applicable local ethics committees of all participating centers and registered at the German Clinical Trails Register (DRKS, No. S00021145).

**Informed Consent Statement:** Patient consent was waived as the study was based on a scientific use file (SUF) generated from the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) registry. For the LEOSS database, data collection was performed fully anonymized, only once per case, and retrospectively after treatment had finished or the patient had died.

**Data Availability Statement:** Patient data from the LEOSS registry are subject to the LEOSS governance, data use, and access policy (policy text available on https://leoss.net, accessed on 8 March 2023).

**Acknowledgments:** We express our deep gratitude to all study teams supporting the LEOSS study. The LEOSS study group contributed at least 5 per mille to the analyses of this study: University Hospital Regensburg (Frank Hanses), University Hospital Freiburg (Siegbert Rieg), Technical University of Munich (Christoph Spinner), Hospital Ingolstadt (Stefan Borgmann), Klinikum Dortmund gGmbH, Hospital of University Witten/Herdecke (Martin Hower), University Hospital Frankfurt (Maria Vehreschild), University Hospital Wuerzburg (Nora Isberner), University Hospital Tuebingen (Siri Göpel), Hospital Maria Hilf GmbH Moenchengladbach (Juergen vom Dahl), University Hospital Augsburg (Christoph Roemmele), University Hospital Jena (Maria Madeleine Ruethrich), University Hospital Cologne (Norma Jung), University Hospital Erlangen (Richard Strauss), University Hospital Ulm (Beate Gruener), Hospital Bremen-Center (Christian Hohmann), Hospital Ernst von Bergmann (Lukas Tometten), Hospital Passau (Julia Lanznaster), University Hospital Saarland (Robert Bals), Municipal Hospital Karlsruhe (Christian Degenhardt), University Hospital Duesseldorf (Bjoern-Erik Jensen), University Hospital Heidelberg (Uta Merle), Johannes Wesling Hospital Minden Ruhr University Bochum (Kai Wille), University Hospital Dresden (Katja de With), Bundeswehr Hospital Koblenz (Dominic Rauschning), University Hospital of Giessen and Marburg (Janina Trauth), University Hospital Essen (Sebastian Dolff), University Hospital Schleswig-Holstein Kiel (Anette Friedrichs), Elbland Hospital Riesa (Joerg Schubert), Malteser Hospital St. Franziskus Flensburg (Milena Milovanovic), Marien Hospital Herne Ruhr University Bochum (Timm Westhoff), Clinic Munich (Wolfgang Guggemos), Catholic Hospital Bochum (St. Josef Hospital) Ruhr University Bochum (Kerstin Hellwig), Practice for general medicine Elisabeth Schroedter & Gabriele Mueller-Joerger Kuenzelsau (Gabriele Mueller-Joerger), Hospital Universitari Arnau de Vilanova (Juan Antonio Schoenenberger-Arnaiz), Hospital Braunschweig (Jan Kielstein), Hospital Leverkusen (Lukas Eberwein), University Hospital Munich/LMU (Michael von Bergwelt-Baildon), Agaplesion Diakonie Hospital Rotenburg (David Heigener), Thorax University Hospital Heidelberg (Felix Herth), Evangelisches Hospital Saarbruecken (Mark Neufang). The LEOSS study infrastructure group: Jörg Janne Vehreschild (Goethe University Frankfurt), Susana M. Nunes de Miranda (University Hospital of Cologne), Carolin E. M. Koll (University Hospital of Cologne), Melanie Stecher (University Hospital of Cologne), Lisa Pilgram (Goethe University Frankfurt), Nick Schulze (University Hospital of Cologne), Sandra Fuhrmann (University Hospital of Cologne), Annika Claßen (University Hospital of Cologne), and Bernd Franke (University Hospital of Cologne) und Fabian Praßer (Charité, Universitätsmedizin Berlin).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Appendix A**

**Figure A1.** Distribution of age in recovered and deceased COVID-19 patients receiving intensive care. (**A**): Sub-cohort of non-ventilated patients (*n* = 147), (**B**): sub-cohort of non-invasively ventilated patients (*n* = 87), (**C**): sub-cohort of invasively ventilated patients (*n* = 492), (**D**): sub-cohort of ECMO patients (*n* = 114).

**Figure A2.** Distribution of (**A**) the number of comorbidities and (**B**) the Charlson comorbidity index in recovered and deceased COVID-19 patients receiving intensive care (total cohort, *n* = 840).

#### **References**

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**About the Editor**

**Max Cr ¨usemann** is currently a Junior Research Group Leader in the Institute of Pharmaceutical Biology, University of Bonn. He studied Pharmacy at the University of Marburg, and obtained his Ph.D. from the University of Bonn for biosynthetic studies on a complex bacterial natural product (advisor Prof. Jorn Piel). After post-doctoral training on bacterial natural product genomics and ¨ metabolomics in the group of Prof. Bradley Moore at the Scripps Institution of Oceanography, San Diego, he returned to Bonn to Prof. Gabriele Konig's group and started his independent career in ¨ 2017. He and his group are interested in omics-guided discovery and biosynthetic studies of bacterial natural products.


*4.2. Multiple Regression Analysis*

4.2.1. The Effect of Executive's Environmental Protection Background on Green Innovation

Table 4 reports the impact of whether and how corporates on green innovation hire many executives with environmental protection backgrounds. Among them, Columns (1)–(2) show the effect of whether or not a firm employs an executive with environmental protection background on green innovation, and Columns (3)–(4) show the impact of the number of executives with environmental protection background hired by a corporate on green innovation. From the regression results in Column (2), the regression coefficient between whether or not to hire executives with environmental protection backgrounds (hbbjdum) and green innovation is significantly positive, indicating that hiring executives with environmental protection background promotes green innovation. The results in Column (4) show that the regression coefficient between the number of executives with environmental protection backgrounds (lnhbbj) hired by corporates and green innovation is significantly positive at the 5% level, indicating that the more executives with environmental protection backgrounds hired by corporates, the more they can promote green innovation. Therefore, Hypothesis 1 of this study is supported.

**Table 4.** The regression results of environmental protection background on green innovation.

**Table 4.** *Cont.*

Notes: \* *p* < 0.1, \*\* *p* < 0.05, \*\*\* *p* < 0.01.

As pointed out by the upper echelons theory, executives' pre-career experience continuously internalizes the mindset and behavior of executives in their later work, which in turn affects the behavioral decisions and even the strategic layout of the market. Therefore, executives with environmental protection backgrounds are more likely to integrate their environmental experience into corporate strategic decisions and pay more attention to green sustainability performance. Further, to control the fixed effect of the industry is to control the factors that are relatively constant relative to the industry. For example, there are unique differences in different industries that do not change with time, and the food industry is an industry that is less affected by the economic cycle, but the steel industry is cyclical. By controlling the fixed effect of the industry, this study can control the differences between industries, and help to estimate the regression results more reasonably [62].