**6. Regulation of the Transport Activity of Canalicular ABC Transporters**

At the canalicular membrane, ABCB1, ABCB4, ABCB11, ABCC2 and ABCG5 have been proposed to mostly reside within glycosphingolipids-, cholesterol- and caveolin-1 (Cav-1)-enriched raft microdomains [27,79–81]. These domains could provide a favorable environment for the regulation of the activity of canalicular ABC transporters. Indeed, the shift of ABCB1 and ABCB11 from cholesterol-enriched microdomains to low-cholesterol domains lowered their transport activity [82–85]. Moreover, accumulating evidence indicates that phospholipids and cholesterol are required for the proper function of ABCB1, ABCB4, ABCB11 and ABCC2 [86–93]. In purified membrane vesicles, delipidation due to detergent action inactivates ABCB1, whereas phospholipid addition fully restores the ATPase activity of the transporter [94,95]. Phosphoinositides, lipid products from PI3K-mediated activities, are required for ABCB11 and ABCC2 activation because their addition reverses the negative effect of PI3K inhibitors on the activity of these transporters [40,96].

The importance of membrane cholesterol content has been highlighted in Atp8b1 deficient mice [92]. Indeed, in these mice, the normal phospholipid asymmetry of the canalicular membrane is lost, thereby enhancing sensitivity to cholesterol extraction by hydrophobic BA and subsequent loss of ABCB11 and ABCC2 activity [92]. How exactly membrane cholesterol influences the transport activity of these transporters is not known, but this may involve allosteric modulations and/or indirect means such as changes in membrane fluidity. Several studies have proposed that cholesterol directly interacts with the ABCB1 substrate binding site and thereby facilitates the recognition of small drugs (<500 Da) [89,97,98]. Cyclodextrin treatment or Cav-1 overexpression leads to cholesterol depletion from the plasma membrane, which inhibits ABCB1 transport activity by increasing membrane fluidity and loosening lipid packing density [99]. However, Moreno

and colleagues showed that Cav-1 overexpression in mice increases both bile flow and the biliary secretion of phospholipids, BA and cholesterol, suggesting a positive role of Cav-1 in ABCB11 transport activity [100]. Considering the role of Cav-1 in intracellular cholesterol trafficking [101,102], some of the Cav-1 effects may be indirect and mediated through cholesterol homeostasis. Alternatively, Cav-1 may also directly bind ABCB1 and inhibit its transport activity [99,103–105]. It has been reported that the binding capacity of Cav-1 to ABCB1 is negatively modulated by Src kinase-mediated Cav-1 phosphorylation, a process facilitated by RACK1, which interacts with both Src and ABCB1 [105–107].

Several studies suggest a role for phosphorylation in the regulation of canalicular ABC transporters. Phosphorylation sites in the linker domain of ABCB1 have been well documented at Ser661, Ser667, Ser671, Ser675, and Ser683 [108–112]. Likewise, six potential phosphorylation sites have been found in the linker region of ABCC2 at Ser904, Ser912, Ser916, Ser917, Ser922 and Ser926 [113] and in the N-terminal domain of ABCB4 at Thr34, Thr44 and Ser49 [114]. An analysis of ABCB11 amino acid sequence also predicted multiple potential serine/threonine phosphorylation sites [115]. Overwhelming evidence indicates that PKC is a major player in ABC transporter phosphorylation and activity regulation. Phosphorylation within the linker domain of ABCB1 is specific for PKCα in purified vesicles from Sf9 cells [116]. The coexpression of PKCα and ABCB1 increases the ATPase activity of the transporter in insect and ovarian cells [116,117], while PKC inhibitor treatment did not alter ATPase activity in MCF-7 cells [118]. It has been shown that PKCα also mediates ABCB11 phosphorylation [115], as well as ABCC2 phosphorylation, resulting in stimulation of the intrinsic transport activity of ABCC2 [113]. PKC-dependent phosphorylation has also been shown to regulate ABCB4-mediated PC secretion [114]. The variation-induced impairment of ABCB4 N-terminal phosphorylation may also be related to a decrease in ABCB4-mediated PC secretion [114]. The substitution of all conserved serines in the linker domain of ABCC2 by non-phosphorylatable alanines significantly reduces the basal transport activity of ABCC2, while substitution into aspartates (mimicking constitutive phosphorylation of the residues) increases it [113]. Conversely, the role of ABCB1 phosphorylation in the regulation of its transport activity is less obvious because the substitution of potentially phosphorylatable residues by aspartates or non-phosphorylatable residues has no effect [119,120].


**6. CRISPR/Cas9 considerations**

#### **6.1 Fitness impacts**

The fitness load in population modification CRISPR/Cas9 drive lines have been assessed on male and female mosquitoes. An ideal CRISPR/Cas9 drive candidate for population modification would have little-to-no fitness effects resulting from the drive system and its corresponding locus, as it is predicted that the effector components are likely to have some effect on overall fitness [98, 99].

One notable example of a fitness cost was observed in the *An. stephensi* AsMCRkh2 gene drive line following disruption of both copies of the *kh*w gene. As described, the enzyme encoded by this gene is responsible for generating the precursors for the formation of eye-pigments, but interestingly it also plays an important role in tryptophan metabolism in adult females following a blood meal [100, 101]. AsMCRkh2 individuals containing two LOF alleles resulting from homozygous or heteroallelic combinations of gene-drive construct insertions or Non-Homologous End Joining (NHEJ) alleles produce a white-eye phenotype and show a high lethality and reduced fecundity following a blood meal. Follow up experiments showed that after achieving fixation in multi-generation cage trial experiments, the populations experienced extinction due to the significant fertility and fecundity load on homozygous AsMCRkh2 females [100]. The AsMCRkh2 prototype was later modified to include a re-coded version of the *kh* locus (Reckh) to reduce the previously observed fitness load on females by restoring the function of the *kh* gene and thereby reversing the eye phenotype to wild-type [30]. Homozygous Reckh female adults show no significant differences in fertility and fecundity in comparison to the hemizygous Reckh or wild-type females. The improvements of female fitness translated to the success of the drive system in multi-generational cage trials with >95% of individuals carrying a copy of the drive at the termination of the experiments [30].

In contrast, AgNosCd-1 individuals do not have reduced fitness in most of the fitness parameters evaluated (fertility, fecundity, longevity, larval and pupal development), but a mild reduction in male mating competitiveness was observed [29]. AgNosCd-1 males are slightly less likely to contribute to the next generation than wild-type males, ~2% less likely for hemizygote males and ~8% for homozygote males. Despite these observed reductions in fitness, the power of the drive system was sufficient to negate the effects in subsequent generations and the AgNosCd-1 line achieved fixation in all multi-generation cage trial experiments at different release ratios of homozygous AgNosCd-1 to wild type males [29]. However, the AgTP13 homozygous males were ~22% less likely to contribute to the next generation than wild-type males in competition experiments and have a significantly reduced median lifespan than the hemizygous AgTP13 or the wild-type males. Despite the increased fitness burden in AgTP13 males, there was no increased fitness load on AgTP13 females [31]. Theoretical modeling supports the conclusion that given an appropriate drive mechanism, a gene-drive system could have a significant fitness cost and still be driven through the population [102, 103].

Ideally, GEMs should have no or minimal fitness costs to avoid reducing the effectiveness of the genetic drive mechanism that is used to introduce the synthetic construct into field mosquito populations and to maximize the likelihood of successfully introducing refractory genes into a wild population [98]. Several factors can impact the fitness, including the possible negative effect of the transgene products, insertional position effects (chromatin rearrangement and/or new regulatory element interactions/pressure), inbreeding, and to "leaky (low level constitutive) promoter expression". GEMS can have different degrees of fitness cost and estimates of transgene fitness costs are essential for modeling and planning release strategies. However, it is clear that a robust drive system can compensate for reduced fitness.

#### **6.2 Maternal effects and resistant alleles**

The efficacy of population modification mosquito drive lines may be reduced by the presence of naturally-occurring cleavage-resistant allelic variants of the target site

#### *Mosquito Population Modification for Malaria Control DOI: http://dx.doi.org/10.5772/intechopen.104907*

in wild populations or by such alleles generated through NHEJ during the Cas9/gRNA targeting and DNA repair processes. The latter may result from double-stranded DNA breaks necessary for drive that are occasionally repaired through NHEJ resulting in insertions or deletions at the target site, making them refractory to the drive system. Both the naturally-occurring and induced allelic variants have been called resistance alleles [104–107]. The latter may arise in the germline and be passed on to subsequent generations or may be generated in somatic cells where they give rise to mosaic phenotypes [28–30]. Resistance alleles in the form of naturally-occurring mutations at the target site can be avoided by careful choice of the gene-drive target locus. Resistance alleles occurring because of NHEJ due to undesired Cas9 activity can be controlled by careful choice of the promoter used to induce Cas9 transcription.

Extensive analysis of suitable target loci must be performed prior to the creation of each proof-of-principle modification drive system. Loci must be chosen, in part, based on the minimization of naturally-present single nucleotide polymorphisms (SNPs) and overall conservation of the target site. Several SNPs in the AgNosCd-1 *cardinal* target site were identified after a screening effort of hundreds of diverse *Anopheles gambiae* s.l. sequences [29]. Interestingly, all these major variants still exhibited Cas9/gRNA-mediated cleavage in assays *in vitro*.

The pathways and frequency of resistance allele formation via undesired activity of the drive system was analyzed extensively for the AgNosCd-1 and AsMCRkh2 lines [29, 97]. Exceptional phenotype individuals (mosaics and LOF phenotypes) have been correlated to undesired Cas9 activity and possess indel mutations that would cause LOF in AgNosCd-1 and AsMCRkh2 lines. However, in contrast to the AgNosCd-1 drive system, the mosaic and LOF phenotypes made up the majority of the offspring (>99%) from AsMCRkh2 mothers [28]. The presence of mosaic and LOF phenotypes from female drive parents has been hypothesized to occur due to a maternal effect. The maternal effect is proposed to result from the accumulation of Cas9/gRNA complexes in the cytoplasm of embryos derived from mothers carrying the drive system, which perform cleavage on the paternally-donated allele during embryonic development. The differences in mosaic and LOF phenotypes observed in the progeny from AgNosCd-1 and AsMCRkh2 hemizygote females supports this hypothesis and this affect is higher in females with two copies (homozygous) of the drive system than those with one (hemizygous) [28, 29, 97]. In addition, the frequencies of such events are higher in the AsMCRkh2 line when compared to AgNosCd-1. These differences may result from the difference in the gene promoters used to express the Cas9 nuclease for each drive system, *vasa* for AsMCRkh2 and *nanos* for AgNosCd-1. Follow up studies showed that the transcripts expressed from the *nanos* promoter are more confined to germline cells than those expressed from the *vasa* promoter [108], which likely results in fewer Cas9/gRNA complexes in the cytoplasm of the former embryos.

As described previously, females homozygous for the drive system had a higher rate of resistance allele formation via maternal effect (~57% with mosaic phenotype and ~6% of progeny with LOF phenotype) than hemizygous females (~20% with mosaic phenotype and ~1% of progeny with LOF phenotype) but mosaic individuals were able to bias inheritance of the drive allele and had similar rates of drive efficiency when compared to AgNosCd-1 hemizygotes with wild-type eye phenotypes suggesting that the indels were primary somatic [29].

Suppression gene drive systems are much less flexible to drive-resistant alleles than population modification gene drive systems. Population modification mosquito lines can tolerate higher rates of drive-resistant alleles than population suppression

mosquitoes, however, the former are still susceptible to instability and inability to achieve fixation in a population due to resistance alleles, especially if the drive system and respective cargo are associated with a significant fitness load [109]. Recent work suggests that suppression drive systems that incur a 100% fitness cost (death of females) would require a very low frequency of drive resistant alleles <5 × 10−7 in order to provide a 4–5-year window of protection, as opposed to population modification systems, which would provide a 4–5-year window of protection at a resistance allele frequency of 1%, given that fitness costs of the population modification strain are below 15% [109].

Multiplexed gene drives using additional gRNA target sites are expected to substantially decrease the likelihood of gene-drive resistant allele formation [110]. Practical ways to multiplex Cas9-based gene drives have been demonstrated using post-transcriptional processing of several gRNAs expressed from a single promoter, but these have not yet been applied to mosquitoes [110–113].

#### **6.3 Off-targets**

The utility of CRISPR/Cas9 gene-drive systems may be affected by sequence similarity among gRNAs target and off-target sites in the mosquito genomes. Potential off-target sites can be predicted *in silico* by computational algorithms and then confirmed *in vivo* by deep-sequence screening of indels or SNPs by PCR-based assays. The possible impact of unwanted mutations linked to a drive system are higher since the arising mutations will have the potential to persist within the populations. Off-target mutations also can induce a potential fitness load. Efforts to detect Cas9 off-targets in *An. gambiae* gene drive mosquitoes found very few following sequencing of large number of samples containing putative target variants [29]. The detected indels neither increased in frequency nor were detected through multiple generations in long-term cage trials (indicating that they were not heritable) and did not significantly differ in number from variants observed in wild-type individuals [29]. New approaches to increase Cas9 specificity are being developed in other organisms and include the use of highly-specific Cas9 mutant enzymes together with the constant updating of computational algorithms to better predict the possible off-targets, but their applications for gene drive mosquitoes remain unclear [114–119].

#### **6.4 Deployment challenges**

The discovery, development, and deployment of CRISPR/Cas9 technologies is challenging due to the lack of an accepted pathway to move them from the laboratory to the field. The WHO released in 2014 the Guidance Framework for testing genetically modified (GM) mosquitoes (WHO Guidance Framework) describing a phased testing pathway and best practices to evaluate GEMs proposed as public health tools [120]. The Framework proposes a pathway to move from physically-confined studies in the laboratory/insectary (Phase 1) to a small-scale confined field-testing (Phase 2) that will lead to a staged open release trial (Phase 3). After successful completion of Phase 3, the national authorities in a malaria-endemic country will be responsible for determining if the tested GEMs can be included as part of their malaria control program and further deployment of the technology (Phase 4) [120]. However, pathways for moving gene-drive population modification mosquitoes to the field will be defined simultaneously with the laboratory work progress. As more CRISPR/Cas9 population modification gene-drive systems and strains are developed, new knowledge is being

#### *Mosquito Population Modification for Malaria Control DOI: http://dx.doi.org/10.5772/intechopen.104907*

generated about the impact of introduced anti-parasite genes on the mosquitoes that carry them. Insight into genetic loads and their effects on fitness, generation of driveresistant individuals as well as selection of resistant parasites and long-term stability of the system will emerge from these studies. The new empirical data generated is critical in the development of a phased pathway for further development and deployment. In 2018, James et al. published a series of recommendations that attempt to envision the development pathway for gene drive mosquitoes (from discovery to deployment) and to inform decision-making by regulators and policymakers [121]. They recognized that it is important to examine both the benefits and risks of this approach. Risk assessment will provide guidance on decision-making and information for the regulatory applications as well as for the development of mitigation plans, while cost-benefit analyses will compare the projected or estimated costs and benefits associated to the intervention. It also was recommended that these analyses be done by external third-party organizations or institutions with no interests in the success of the product and the outcomes of these analyses be made publicly available.

Any decision made to release gene-drive mosquitoes must be made on a case-bycase basis following a comprehensive environmental risk assessment [122], moreover, gene-drive population modification mosquitoes must meet the established Target Product Profile (TPP) criteria of safety and efficacy. A comprehensive draft TPP for gene-drive population modification mosquitoes was published providing the basis for evaluation of whether gene-drive mosquitoes should be made available for use [37]. Population modification TPPs will need to meet the efficacy and safety standards as well as the demands of different regulatory and social contexts. In addition, viable models for the inclusion of end-user and stakeholder involvement and control are absolutely needed before any such system can be brought to the field. We have favored the relationship-based model (RBM), which gives stakeholders and community key roles at the center of the decision-making processes [123]. It is important that open dialog and relationships with the scientists developing the technologies be established and that appropriate capacity-building take place to empower the communities affected by malaria to make informed decisions about the risk and use of the new technologies.

#### **7. Conclusions**

Population modification genetic control focuses on targeting the mosquito vector to interrupt the malaria transmission by introducing effector genes into the mosquito genome with the purpose of generating parasite-refractory mosquitoes.

Advances in gene-editing technologies using CRISPR/Cas9 gene drives have made available new possibilities for an efficient introduction of the desired genetic traits into mosquito populations. Gene drives represent a powerful tool to achieve genome editing in a species-specific targeted way with minimal infrastructure, are predicted to be self-sustaining and able to spread anti-parasite effectors to fixation.

Gene-drive systems for population modification of anopheline vector species to prevent transmission of parasites may play a future role in the malaria eradication agenda. Future steps will need to consider how to evaluate gene drives at large scale and evaluate their efficacy and robustness under more realistic ecological settings.

Challenges to such technologies are being addressed by scientists and regulators by development of pathways for their deployment and establishing acceptable efficacy and safety criteria. Importantly, the knowledge transfer process is being addressed

in new models for public engagement that will further development, testing and eventual deployment of gene drives for malaria control.


**3. Hemodynamic stabilization and monitoring**

The primary goal of hemodynamic monitoring is to prevent inadequate cardiac filling and the subsequent tissue hypoperfusion, and also to avoid overloading leading to congestion of the lungs and sinusoids and hence allograft dysfunction [8]. The intravascular volume, cardiac output (CO), and systematic vascular resistance (SVR) are important parameters vital in determining the success of a LT. The treatment becomes even more complicated when renal and/or heart failure, portopulmonary hypertension, or hepatopulmonary syndromes are also present [9].

Successful management of patients with end-stage liver disease (ESLD) requires a complete understanding of their hemodynamic profile that is often characterized by high cardiac output (CO) with decreased systemic vascular resistance, depleted intravascular volume, and compensatory tachycardia with concomitant renal vasoconstriction and dilutional hyponatremia, due to excessive production of vasodilators during the development of hepatic failure [10]. Following LT, vasodilation and hyperdynamic circulation remain until the graft begins to function and excretes excess vasodilatory agents that are almost completely restored after 6 months [11].

Upon the arrival of a liver transplant recipient in the ICU, advanced monitoring, which estimates CO and volume status, additionally to standard hemodynamic monitoring, that is electrocardiogram, pulse-oximetry, and invasive blood pressure, are deemed essential [12].

Hemodynamic depression may be the result of hypovolemia, prolonged reperfusion syndrome, cardiac dysfunction, either caused by pre-existing or emerging ischemic cardiomyopathy, and metabolic disorders such as acidosis, hypocalcaemia, hypothermia, vasodilation due to sepsis, or graft dysfunction.

**193**

*Management of Patients with Liver Transplantation in ICU*

The assessment of the intravascular volume is of vital importance given that volume status can be affected by contradictory factors such hypovolemia or hypervolemia, both detrimental for graft and patient survival. Restoring volume status, a continually dynamic parameter, and achieving optimal CO are crucial in order to maintain the delicate balance between preload optimization and avoidance of

Hypovolemia, possibly due to continued bleeding, occult or overt, inadequate fluid replacement and/or loss in the third space, can lead to reduced preload and CO and hence hypoperfusion resulting in additional lesions in the newly transplanted liver [14]. The aim is to replace the intravascular fluid and maintain the circulating blood volume. There is still controversy over the type of fluids administered, with crystalloids gaining ground against the colloids (hydroxyl ethyl starches), which have been associated with renal injury and increased mortality in critically ill patients [15], a conclusion that is not supported by convincing evidence in LT. Nevertheless, the appropriate crystalloid should be carefully selected taking into account its special characteristics and based on its metabolism, electrolyte composition, pH and osmolarity, and considering patients' status [16]*.* Albumin (Alb) administration as a replacement fluid has been a matter of debate. In some centers, a large amount of Alb is exogenously administered following the LT to support circulatory stability. Moreover, a concentration of 25 g/L is considered necessary for the immunosuppressive drugs to be effective [17]. Beneficial properties were attributed to Alb in recent studies; whereas, postoperative hypoalbuminemia has been linked to the development of acute kidney injury (AKI) [18]. It has been found that during LT there is translocation of Alb, probably to the interstitial space, which persists until the third postoperative day and whose role has not been clearly clarified [19]. Certain centers choose to replace two-thirds of the required fluids with crystalloids and one-third of drain losses with albumin [14]. Although, blood and blood products transfusion strategies vary between institutions, it is considered that postoperative hematocrit (Hct) values, ranging between 25 and 30%, are safe for adequately transporting O2 to the new graft [14]. The rational use of blood products depends on the monitoring of the coagulation mechanism. Whole-blood viscoelastic tests, such as thromboelastogram (TEG) and rotational thromboelastometry (ROTEM), that illustrate each step of thrombus formation and fibrinolysis are useful tools to guide transfusions and drug administration (anti-fibrinolytics, coagulation factors) [20, 21] by limiting the number of transfusions, as there has been an association between them and increased morbidity/mortality, prolonged stay in the hospital, postoperative sepsis, increased risk of acute rejection, and hepatic artery thrombosis [22–24]. Hypervolemia occurs either from intraoperative over-resuscitation or coexistence of renal dysfunction. It can result in capillary leak syndrome with loss of fluids in the third space, further congestion and graft edema due to vascular permeability disorder, caused by ischemia/reperfusion injury (I/R) that is more pronounced in grafts with higher preservation injury, greater steatosis, or in older donors [7, 25]. Studies also indicate that massive administration of fluids and blood is a risk factor for complications of the respiratory system postoperatively and is correlated with increased mortality [26]. On the contrary, conservative resuscitation strategy and negative fluid balance during the first three postoperative days, if hemodynamic stability has been achieved, act protectively. Codes et al. [27] concluded that a continuous positive balance in the first 4 days after surgery correlates with the development of ΑΚΙ and the need for renal replacement therapy (RRT). Goal directed therapy (GDT) strategy, which has been successfully applied in major surgical interventions, is proposed. It aims at maintaining an adequate supply of O2 to the end organs by a bundle of measures including fluid titration in conjunction with blood transfusions as well as administration of vasopressors and/or inotropic agents [28]. The hemodynamic

*DOI: http://dx.doi.org/10.5772/intechopen.89435*

pulmonary edema [13].

*Liver Disease and Surgery*

transplantation [7].

ing improved endpoint results.

**2. General principles**

Additionally, recipients are sicker, given that priority of graft allocation is based on higher MELD scores, older and with co-morbidities such as metabolic syndrome, cardiac disease, and diabetes mellitus [5, 6]. Postoperative liver transplant patient care requires careful accounting of the recipient's pre-existing pathophysiology, intraoperative events, and donor's quality. Moreover, the implanted liver represents a unique biological entity that has undergone physiological changes and has to adapt to a new environment. This donor-recipient interaction is the key of a successful

The intensivist's role is essential as a multifaceted approach is critical for optimal

The aim of immediate postoperative support is the adequate O2 supply to tissues

The primary goal of hemodynamic monitoring is to prevent inadequate cardiac

Successful management of patients with end-stage liver disease (ESLD) requires a complete understanding of their hemodynamic profile that is often characterized by high cardiac output (CO) with decreased systemic vascular resistance, depleted intravascular volume, and compensatory tachycardia with concomitant renal vasoconstriction and dilutional hyponatremia, due to excessive production of vasodilators during the development of hepatic failure [10]. Following LT, vasodilation and hyperdynamic circulation remain until the graft begins to function and excretes excess vasodilatory agents that are almost completely restored after 6 months [11]. Upon the arrival of a liver transplant recipient in the ICU, advanced monitoring,

which estimates CO and volume status, additionally to standard hemodynamic monitoring, that is electrocardiogram, pulse-oximetry, and invasive blood pressure,

sion syndrome, cardiac dysfunction, either caused by pre-existing or emerging ischemic cardiomyopathy, and metabolic disorders such as acidosis, hypocalcaemia,

hypothermia, vasodilation due to sepsis, or graft dysfunction.

Hemodynamic depression may be the result of hypovolemia, prolonged reperfu-

filling and the subsequent tissue hypoperfusion, and also to avoid overloading leading to congestion of the lungs and sinusoids and hence allograft dysfunction [8]. The intravascular volume, cardiac output (CO), and systematic vascular resistance (SVR) are important parameters vital in determining the success of a LT. The treatment becomes even more complicated when renal and/or heart failure, portopulmonary hypertension, or hepatopulmonary syndromes are also

and graft by ensuring hemodynamic stabilization, fluid balance, restoration of diuresis, optimal ventilation, and supporting graft function. It should be noted that graft recovery depends primarily on the intrinsic hepatocyte recovery capacity and

secondly on optimizing liver hemodynamics and preventing venous stasis.

**3. Hemodynamic stabilization and monitoring**

transplantation outcomes. The main hurdles to tackle are early recognition and immediate treatment of the hemodynamic and metabolic disorders, restoration of intravascular volume, avoidance of coagulation disorders, optimization of organs function affected by hepatic failure, prophylaxis and treatment of infections, early enteral nutrition, and evaluation of graft function. Technological advances offer the possibility of continuous cardiovascular and allograft function monitoring facilitat-

**192**

present [9].

are deemed essential [12].

The assessment of the intravascular volume is of vital importance given that volume status can be affected by contradictory factors such hypovolemia or hypervolemia, both detrimental for graft and patient survival. Restoring volume status, a continually dynamic parameter, and achieving optimal CO are crucial in order to maintain the delicate balance between preload optimization and avoidance of pulmonary edema [13].

Hypovolemia, possibly due to continued bleeding, occult or overt, inadequate fluid replacement and/or loss in the third space, can lead to reduced preload and CO and hence hypoperfusion resulting in additional lesions in the newly transplanted liver [14]. The aim is to replace the intravascular fluid and maintain the circulating blood volume. There is still controversy over the type of fluids administered, with crystalloids gaining ground against the colloids (hydroxyl ethyl starches), which have been associated with renal injury and increased mortality in critically ill patients [15], a conclusion that is not supported by convincing evidence in LT. Nevertheless, the appropriate crystalloid should be carefully selected taking into account its special characteristics and based on its metabolism, electrolyte composition, pH and osmolarity, and considering patients' status [16]*.* Albumin (Alb) administration as a replacement fluid has been a matter of debate. In some centers, a large amount of Alb is exogenously administered following the LT to support circulatory stability. Moreover, a concentration of 25 g/L is considered necessary for the immunosuppressive drugs to be effective [17]. Beneficial properties were attributed to Alb in recent studies; whereas, postoperative hypoalbuminemia has been linked to the development of acute kidney injury (AKI) [18]. It has been found that during LT there is translocation of Alb, probably to the interstitial space, which persists until the third postoperative day and whose role has not been clearly clarified [19]. Certain centers choose to replace two-thirds of the required fluids with crystalloids and one-third of drain losses with albumin [14]. Although, blood and blood products transfusion strategies vary between institutions, it is considered that postoperative hematocrit (Hct) values, ranging between 25 and 30%, are safe for adequately transporting O2 to the new graft [14]. The rational use of blood products depends on the monitoring of the coagulation mechanism. Whole-blood viscoelastic tests, such as thromboelastogram (TEG) and rotational thromboelastometry (ROTEM), that illustrate each step of thrombus formation and fibrinolysis are useful tools to guide transfusions and drug administration (anti-fibrinolytics, coagulation factors) [20, 21] by limiting the number of transfusions, as there has been an association between them and increased morbidity/mortality, prolonged stay in the hospital, postoperative sepsis, increased risk of acute rejection, and hepatic artery thrombosis [22–24].

Hypervolemia occurs either from intraoperative over-resuscitation or coexistence of renal dysfunction. It can result in capillary leak syndrome with loss of fluids in the third space, further congestion and graft edema due to vascular permeability disorder, caused by ischemia/reperfusion injury (I/R) that is more pronounced in grafts with higher preservation injury, greater steatosis, or in older donors [7, 25]. Studies also indicate that massive administration of fluids and blood is a risk factor for complications of the respiratory system postoperatively and is correlated with increased mortality [26]. On the contrary, conservative resuscitation strategy and negative fluid balance during the first three postoperative days, if hemodynamic stability has been achieved, act protectively. Codes et al. [27] concluded that a continuous positive balance in the first 4 days after surgery correlates with the development of ΑΚΙ and the need for renal replacement therapy (RRT). Goal directed therapy (GDT) strategy, which has been successfully applied in major surgical interventions, is proposed. It aims at maintaining an adequate supply of O2 to the end organs by a bundle of measures including fluid titration in conjunction with blood transfusions as well as administration of vasopressors and/or inotropic agents [28]. The hemodynamic

targets are predefined and specific variables are used to control fluid adequacy, improvement of CO, and tissue perfusion. GDT has beneficial effects compared to liberal fluid administration, reducing postoperative ileus, mechanical ventilation time, and respiratory system complications, as it has been indicated in relevant, although limited, studies [29]. Jiang et al. [30] suggests the individualization of fluid administration in the perioperative period as an optimal recovery strategy. They estimated that transfusions >100 ml/kg and fluid balance ≤−14 ml/kg during the first postoperative days result in prolonged mechanical ventilation, extubation time, and ICU stay. Prudent use of vasopressor agents is proposed since they increase arterial tone and improve perfusion pressure avoiding overload. Noradrenaline (0.01–1 μg/ kg/min) with mixed α-β-adrenergic effects is most commonly administered to maintain CO and organ perfusion. Vasopressin (0.5–0.6 U/h) and terlipressin (1.5 μg/ kg/h) have also been used in recent years because of their modifying effect on visceral circulation, where approximately 37% of the total blood volume is located in cirrhotic patients, and of their ability to reduce pressure in the portal vein [31, 32].

Since there has been no consensus on hemodynamic monitoring in LT yet, there is a number of invasive and noninvasive CO monitors available in order to evaluate hemodynamic fluctuations (**Table 1**) [13, 36].

The pulmonary artery (PAC) catheter has traditionally been used for hemodynamic monitoring in LT. It provides the possibility of measuring the CO by the thermodilution method, which is considered the gold standard, but also the cardiac

**195**

*Management of Patients with Liver Transplantation in ICU*

filling pressures, the CVP, and especially the PCWP for assessing the preload [33]. Numerous studies have shown that static preload measurements are indirect markers of the end diastolic volume and have a poor predictive value for fluid management, improvement of hepatic perfusion, and recovery guidance [34]. Although still under debate, current data favor the use of a modified pulmonary artery catheter, with an incorporated heating coil, that provide continuous measurement of CO (CCO) and right ventricular end diastolic volume (RVEDV) as the more reliable preload indicator. Patients with portopulmonary hypertension are highly benefited from PAC, as it is the method of choice for measuring and monitoring pulmonary

In recent years, interest has shifted to the dynamic parameters and expanding data yielded from existing monitoring of blood pressure to assess the CO, the preload and the afterload. There is technology available to accurately analyze pressure waveforms and sufficient knowledge to generate algorithms that are interpreted by

The PiCCO system (Pulsion Medical System, Munich, Germany) uses the method of transpulmonary thermodilution, single indicator technique, and arterial pulse contour analysis which by means of an algorithm can continuously calculate CO and preload markers: global end diastolic volume (GEDVI), extra vascular lung water index (EVLWI), and intrathoracic blood volume index (ITBVI) which is considered a reliable preload indicator in LT. In transplant patients, the CO measurements deriving from the PiCCO system are consistent with those of PAC [38, 39]. Furthermore, this system offers the capability of functional hemodynamic monitoring by detecting the changes in left ventricular pulse volume caused by changes in preload due to mechanical ventilation. Stroke volume variation (SVV) and pulse pressure variation (PPV) have been used successfully to assess the intravascular volume and fluid responsiveness in critically ill patients [12, 13, 40]. Certain LT studies have concluded that the SVV is a better indicator for RVEDVI than CVP, while a SVV greater than 9% is an indicator of low RVEDVI which means fluid responsiveness [41, 42]. However, there are always limitations deriving from

artery pressures intraoperatively and directly postoperatively [13, 35].

the presence of arrhythmia and mechanical ventilation settings.

order to calibrate the arterial waveform analysis algorithm [40].

discrepancy in cases of significantly low SVR [45, 46].

The LiDCO system (LiDCO Plus, Cambridge, United Kingdom) is similar to the PiCCO system, but in its case the lithium indicator dilution technique is applied in

The Flowtrac/Vigileo system (Edwards Lifesciences, Irvine, CA United States) is a special energy converter that links the arterial line with a CO monitor and uses arterial waveform analysis with an algorithm for real-time CO measurement in conjunction with patient demographics without the need for calibration. However, a poor correlation has been found between findings of waveform analysis CO when compared to PAC thermodilution, mainly in patients with cirrhosis B and C according to Child-Pugh classification [43, 44]. Biais et al. came to the same conclusion, using the recent third generation, FloTrac system, pointing out that there was great

In recent years, the use of transesophageal echocardiography (TEE) has been gaining ground not only because it is considered a noninvasive method, but also because it provides the ability to directly visualize the contractility of the left and right heart, preload status, and differential diagnosis of various pathological conditions such as pulmonary embolism, pleural, or pericardial effusion [47]. The CO can be estimated with measurements of flow across the cardiac valve, left ventricular outflow tract, or the flow in the main pulmonary artery. The ability to instantly display real-time preload is considered its biggest advantage. The functional application of TEE is limited by the risk of rupture of the third or fourth grade esophageal varices, but it is considered a reliable hemodynamic monitoring method when used by experienced intensivists [12, 13].

*DOI: http://dx.doi.org/10.5772/intechopen.89435*

the complex pulse wave morphology [36, 37].

**Table 1.** *Hemodynamic monitoring in LT.*

#### *Management of Patients with Liver Transplantation in ICU DOI: http://dx.doi.org/10.5772/intechopen.89435*

*Liver Disease and Surgery*

targets are predefined and specific variables are used to control fluid adequacy, improvement of CO, and tissue perfusion. GDT has beneficial effects compared to liberal fluid administration, reducing postoperative ileus, mechanical ventilation time, and respiratory system complications, as it has been indicated in relevant, although limited, studies [29]. Jiang et al. [30] suggests the individualization of fluid administration in the perioperative period as an optimal recovery strategy. They estimated that transfusions >100 ml/kg and fluid balance ≤−14 ml/kg during the first postoperative days result in prolonged mechanical ventilation, extubation time, and ICU stay. Prudent use of vasopressor agents is proposed since they increase arterial tone and improve perfusion pressure avoiding overload. Noradrenaline (0.01–1 μg/ kg/min) with mixed α-β-adrenergic effects is most commonly administered to maintain CO and organ perfusion. Vasopressin (0.5–0.6 U/h) and terlipressin (1.5 μg/ kg/h) have also been used in recent years because of their modifying effect on visceral circulation, where approximately 37% of the total blood volume is located in cirrhotic

patients, and of their ability to reduce pressure in the portal vein [31, 32].

hemodynamic fluctuations (**Table 1**) [13, 36].

PiCCO Pulse contour

LiDCO Pulse contour

FlowTrac/Vigileo Pulse contour

TEE Ultrasound,

*Hemodynamic monitoring in LT.*

analysis

analysis

analysis

Doppler

Since there has been no consensus on hemodynamic monitoring in LT yet, there is a number of invasive and noninvasive CO monitors available in order to evaluate

> measures of CO Direct measures of PAP and RVEDVI Gold standard in POPH

Less invasive Continuous CO, SV measures

SVV

status

ITBVI, EVLWI, PPV,

Reliable indicators of fluid responsiveness

Continuous CO, SV measures comparable to PAC measures PPV, SVV

Indicative of volume

No need for calibration Continuous CO, SV measures

PPV, SVV, indicative of volume status

Less invasive Direct visualization of cardiac function and volume status

Invasive CVP, PCWP static pressures measurement Unreliable indicators of volume status, SV and fluid responsiveness

in cirrhosis

in cirrhosis

Not reliable in

Need for recalibration in marked changes of SVR Inaccurate CO measures in Child-Pugh Band C stages

Requires sinus rhythm and certain ventilator setting

Calibration with lithium Inaccurate CO measures in Child-Pugh Band C stages

hyperdynamic circulation with very low SVR

Advanced training is

Risk of rupture in 3rd or 4th grade of esophageal

required

varices

The pulmonary artery (PAC) catheter has traditionally been used for hemodynamic monitoring in LT. It provides the possibility of measuring the CO by the thermodilution method, which is considered the gold standard, but also the cardiac

**Monitors Principle Advantages Limitations**

PAC Thermodilution Accurate continuous

**194**

**Table 1.**

filling pressures, the CVP, and especially the PCWP for assessing the preload [33]. Numerous studies have shown that static preload measurements are indirect markers of the end diastolic volume and have a poor predictive value for fluid management, improvement of hepatic perfusion, and recovery guidance [34]. Although still under debate, current data favor the use of a modified pulmonary artery catheter, with an incorporated heating coil, that provide continuous measurement of CO (CCO) and right ventricular end diastolic volume (RVEDV) as the more reliable preload indicator. Patients with portopulmonary hypertension are highly benefited from PAC, as it is the method of choice for measuring and monitoring pulmonary artery pressures intraoperatively and directly postoperatively [13, 35].

In recent years, interest has shifted to the dynamic parameters and expanding data yielded from existing monitoring of blood pressure to assess the CO, the preload and the afterload. There is technology available to accurately analyze pressure waveforms and sufficient knowledge to generate algorithms that are interpreted by the complex pulse wave morphology [36, 37].

The PiCCO system (Pulsion Medical System, Munich, Germany) uses the method of transpulmonary thermodilution, single indicator technique, and arterial pulse contour analysis which by means of an algorithm can continuously calculate CO and preload markers: global end diastolic volume (GEDVI), extra vascular lung water index (EVLWI), and intrathoracic blood volume index (ITBVI) which is considered a reliable preload indicator in LT. In transplant patients, the CO measurements deriving from the PiCCO system are consistent with those of PAC [38, 39].

Furthermore, this system offers the capability of functional hemodynamic monitoring by detecting the changes in left ventricular pulse volume caused by changes in preload due to mechanical ventilation. Stroke volume variation (SVV) and pulse pressure variation (PPV) have been used successfully to assess the intravascular volume and fluid responsiveness in critically ill patients [12, 13, 40]. Certain LT studies have concluded that the SVV is a better indicator for RVEDVI than CVP, while a SVV greater than 9% is an indicator of low RVEDVI which means fluid responsiveness [41, 42]. However, there are always limitations deriving from the presence of arrhythmia and mechanical ventilation settings.

The LiDCO system (LiDCO Plus, Cambridge, United Kingdom) is similar to the PiCCO system, but in its case the lithium indicator dilution technique is applied in order to calibrate the arterial waveform analysis algorithm [40].

The Flowtrac/Vigileo system (Edwards Lifesciences, Irvine, CA United States) is a special energy converter that links the arterial line with a CO monitor and uses arterial waveform analysis with an algorithm for real-time CO measurement in conjunction with patient demographics without the need for calibration. However, a poor correlation has been found between findings of waveform analysis CO when compared to PAC thermodilution, mainly in patients with cirrhosis B and C according to Child-Pugh classification [43, 44]. Biais et al. came to the same conclusion, using the recent third generation, FloTrac system, pointing out that there was great discrepancy in cases of significantly low SVR [45, 46].

In recent years, the use of transesophageal echocardiography (TEE) has been gaining ground not only because it is considered a noninvasive method, but also because it provides the ability to directly visualize the contractility of the left and right heart, preload status, and differential diagnosis of various pathological conditions such as pulmonary embolism, pleural, or pericardial effusion [47]. The CO can be estimated with measurements of flow across the cardiac valve, left ventricular outflow tract, or the flow in the main pulmonary artery. The ability to instantly display real-time preload is considered its biggest advantage. The functional application of TEE is limited by the risk of rupture of the third or fourth grade esophageal varices, but it is considered a reliable hemodynamic monitoring method when used by experienced intensivists [12, 13].


**Congenital Fetal Anomalies and the Role of Prenatal Ultrasound Ultrasound**

**Congenital Fetal Anomalies and the Role of Prenatal**

DOI: 10.5772/intechopen.71907

Fanni Rebeka Erős and Artúr Beke

Fanni Rebeka Erős and Artúr Beke Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71907

#### **Abstract**

The ultrasound is the most widely used diagnostic tool in obstetrics nowadays, in particular in the detection of developmental disorders. However, it is important to know which are those disorders that can be detected prenatally with great certainty, and which ones can be detected only partially or not at all prior to giving birth. Pregnant women have high expectations, that any abnormalities should be fully recognizable and detected early during pregnancy, and this often leads to damages lawsuits. Thus, the right information is essential, so the doctors providing information also must have up to date knowledge about the effectiveness of ultrasound diagnostics. Prenatal diagnostics also entails enormous medical professional responsibility, since the consequences of an accidental inaccurate diagnosis can have significant consequences for both the fetus and the family. Thus, it is important to determine that how early and in what proportion the ultrasound protocol of the current Hungarian pregnancy care system is able to detect the individual disorder groups.

**Keywords:** congenital malformations, prenatal ultrasound, ultrasound detection


**Appendix A**

**Text preprocessing details:** We decompose tags such as 'p-value' as 'p' and 'value' and split latex equations into command words, as they would otherwise create many long, unique tokens. In the future, character encodings may be better for this specific dataset, but that is out of our current research scope. Words embedding are pretrained via fastText on the training corpus text. 10 tag words are not in the input vocabulary and thus we randomly initialize their embeddings. Though we never explicitly used this information, we parsed the text and title and annotated them with 'Html-like' title, paragraph, and sentence delimiters, i.e. *</title>, </p>, and </s>*.


2. Introduction on intelligence material design

### 2.1. Experimental data

production around the world. Although the research and development of CIGS are still in crucial phase due to low production yields, non-reproducibility, and non-uniformity over large area confronted during the industrialization and commercialization. Governing such issues, we published our first research paper in the year 2003 on "Steps toward industrialization of Cu-III-VI2 thin film solar cells: A novel in-line concept" [1]. After that, the concept of in-line sputtering and selenization become international standard globally. From that time, dozens of CIGS manufacturing units established worldwide but rare claim successful in production due to difficulty in controlling the local chemical composition distribution of the film. Moreover, the production efficiency of large-area photovoltaic (PV) cells and panels varies in the wide range from 6 to 13%. During the decades of fast development of Cu-III-VI2 thin film solar cells, much more research and industrial method were proposed. In this chapter, we will depict the principles and development of some essential issues for industrialization of Cu-III-VI2 thin film solar cells.

In the year 2003, we published another research "Preliminary steps toward industrialization of Cu-III-VI2 thin film solar cells: development of an intelligent design tool for non-stoichiometric photovoltaic materials" [1] pointing on the problem encountered during the commercialization. Over the years, many experimental and theoretical research works published in many journals focused on various subjects of problems and its solutions for CIGS TFSCs [2–9].

In 2013, we published one more research article "Steps toward removing some obstacles of industrialization of CIGS solar cells" [10]. This article pointing to the new concept of metal organic sputtering was used to tune and tailor the film compositions based on the programme material and device design. What shown in Figure 1 is the method of our intelligence material and device design, describing the detailed calculation of the neutral defect concentrations of non-stoichiometric CuInSe2, CuGaSe2, and ZnO in specific atomic chemical potential condi-

Figure 1. The scheme of our materials design and device design in which the electrical and device properties are

optimized, and related to the process parameters such as, chemical potential and non-stoichiometry.

tions (μx = 0, X = Cu, In/Ga, Zn).

130 Emerging Solar Energy Materials

We all know that Cu-III-VI2 typically have a wide phase stability range, which extends a few atomic percents of the chemical composition of the thin-film, contract to III-V, and II-VI compounds. Shown in Figure 2 is the chemical composition for a near-stoichiometric CuInSe2. The variations in the CuInSe2 film was detected using a transmission electron microscope (TEM) equipped with a field emission gun [10]. A similar result had also been reported for CIGS thin-film [11].

#### 2.2. Theoretical data

In 2003, we published an example of the design tool for the non-stoichiometric compound using the concept of minimization of total free energy [1, 12, 13], which includes the configurational entropy, that defined as;

Figure 2. Chemical composition of a near-stoichiometric CuInSe2 film measured consecutively by using an electron beam with a 3 nm probe size along a line marked on a TEM micrograph (left) and the plotted data (right) (corresponding to the data in Table 1).

Table 1. Chemical composition of a near-stoichiometric CuInSe2 films.

$$\text{G(T, Crystal\ size)} = \Sigma n\_i E\_{\text{ft}} - T S\_{\text{config}}, \\ \text{S}\_{\text{config}} = K \ln \frac{N\_{\text{total}}!}{\pi\_i N\_{\text{j}}!} \tag{1}$$

Figure 3. The calculated carrier concentration and electrical conductivity of CuInSe2 (left) and CuGaSe2 (right) at 300 K.

Some Essential Issues and Outlook for Industrialization of Cu-III-VI2 Thin-Film Solar Cells

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133

Figure 4. The measured conductivity of the CuInSe2 thin-film along the Cu2Se-In2Se3on-tie line with composition (Cu2Se)

1x(In2Se3)x(line 1) and the calculated range (between line 2 and 3) near the Cu2Se-In2Se3 tie line at 300 K.

where ni is the number of the ith defect, Efi is the formation energy, Sconfig is the configurational entropy, T is the temperature, K is the Boltzmann constant, N is the total number of lattice sites, and Ni is the total number of defect sites of the ith defect. We find the possible results for the coexistence of donors and acceptors in CuMSe2 (M = In, Ga), which includes either the new defects produced through interaction or donor-acceptor pair/cluster formation.

Table 2 shows the defect formation energies and the defect transition levels. We also find the possible phases of CuMSe2 resulted due to the compensated donor-acceptor pairs in different Cu concentration, for example, Cu1M3Se5 phase is observed by 80% Cu1M5Se8 and 20% CuMSe2.

Table 2. The defect formation energies and defect transition levels used in our calculations [14].

Some Essential Issues and Outlook for Industrialization of Cu-III-VI2 Thin-Film Solar Cells http://dx.doi.org/10.5772/intechopen.77023 133

G T; Crystal size ¼ ΣniEfi � TSconfig, Sconfig ¼ Kln Ntotal!

Maximum 28.2 28.1 57.1 1.18 Minimum 17.2 22.6 47.9 0.62 Average 20.9 25.9 53.3 0.81 Standard deviation 2.73 1.37 2.80 0.12

Cu(at%) In(at%) Se(at%) Cu/In

where ni is the number of the ith defect, Efi is the formation energy, Sconfig is the configurational entropy, T is the temperature, K is the Boltzmann constant, N is the total number of lattice sites, and Ni is the total number of defect sites of the ith defect. We find the possible results for the coexistence of donors and acceptors in CuMSe2 (M = In, Ga), which includes either the new

Table 2 shows the defect formation energies and the defect transition levels. We also find the possible phases of CuMSe2 resulted due to the compensated donor-acceptor pairs in different Cu concentration, for example, Cu1M3Se5 phase is observed by 80% Cu1M5Se8 and 20%

defects produced through interaction or donor-acceptor pair/cluster formation.

Table 2. The defect formation energies and defect transition levels used in our calculations [14].

Table 1. Chemical composition of a near-stoichiometric CuInSe2 films.

CuMSe2.

132 Emerging Solar Energy Materials

πjNj! (1)

Figure 3. The calculated carrier concentration and electrical conductivity of CuInSe2 (left) and CuGaSe2 (right) at 300 K.

Figure 4. The measured conductivity of the CuInSe2 thin-film along the Cu2Se-In2Se3on-tie line with composition (Cu2Se) 1x(In2Se3)x(line 1) and the calculated range (between line 2 and 3) near the Cu2Se-In2Se3 tie line at 300 K.

To solve the charge neutrality equation, we require several parameters, such as the carrier concentrations, Femi level at a certain temperature and ionized/neutral defect concentrations. In Figure 3, the calculated carrier concentration and electrical conductivity of CuInSe2 and CuGaSe2 at 300 K are shown. Note that in Figure 4, the conductivity will increase first and then decrease down to the film composition from stoichiometry to Cu-poor, after that the conductivity is even lower than that of the stoichiometry.

#### 3. Brief on the device design

The simulator SCADS 3.2 [15] has been widely accepted for numerical analysis of CIGS solar cell devices. In 2014, the 19% efficiency of the solar cell was simulated by Naoki Ashida et al. [16]. In this report, the 2 μm thick CIGS absorber layer was divided into two regions, such as low defect density region (front side) and high defect density region (back side).

We also developed an alternate full function (indoor, outdoor, and I-V, C-V) analytic solar cell simulator, in which the following (time-independent) device equations are considered.

a. The continuity equation

$$\mathbf{O} = -\frac{1}{\mathbf{q}} \frac{\mathbf{d}}{\mathbf{dx}} \boldsymbol{\tau}\_p + \mathbf{G}\_p - \mathbf{R}\_p,\\ \mathbf{R}\_p = \frac{\Delta p}{\mathbf{\tau}\_h},\\ \Delta p = p\_n - p\_{no} \tag{2}$$

$$\mathbf{O} = -\frac{1}{\mathbf{q}} \frac{\mathbf{d}}{\mathbf{dx}} \boldsymbol{\tau}\_n + \mathbf{G}\_n - \mathbf{R}\_n \boldsymbol{R}\_n = \frac{\Delta n}{\mathbf{\tau}\_\varepsilon}, \Delta n = n\_p - n\_{po} \tag{3}$$

b. Transport equations

$$
\tau\_p = \mathbf{p} \mathbf{q} \mu\_p \to -\mathbf{q} D\_p \frac{\mathbf{dp}}{\mathbf{dx}} \tag{4}
$$

$$
\pi\_n = \mathbf{n} \mathbf{q} \mu\_n \to + \mathbf{q} D\_n \frac{\mathbf{dn}}{\mathbf{dx}} \tag{5}
$$

In the last decades, many studies on interface and surface compositional profile have been dealt with the advanced characterizations for the high-efficiency CIGS solar cells. A few

Figure 5. The comparison of the computed efficiencies as compared with NREL's database of ZnO/CdS/CuInSe2 solar

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135

2. Ordered defect compounds (ODC: CuInSe2, CuIn3Se5, CuIn5Se8, etc.) resulted from CuInSe2/CIGS solar cell studies, in which the X-ray photoelectron Spectroscopy (XPS) investigations depicted the depletion of Cu near the surface, and the theory as well

3. Shown in Figure 6, defect pairs (2Vcu and Incu) stabilizes the CuInSe2 surface and band alignment gives hole barrier at the interface via the investigations by low energy electron

1. Conduction band profiles are changed by the three stage selenization [17].

experiments predicted ordered defect compound structured [18].

examples are:

cells: (upper) 3D view, (lower) 2D view.

We have considered all the boundary conditions (n-QNR/SCR interface, front contact, p-QNR/ SCR interface, and back contact), in which QNR stands for the quasi-neutral region and SCR stands for space charge region for a typical n-CdS/p-CIGS device structure. In results of our simulation, we show that the higher efficiency cells are distributed along the line from Cu: Se = 0.3:0.5 to the stoichiometric point and the line from Cu:Se = 0.21:0.52 to the stoichiometric point. What is shown in Figure 5 is the comparison of the computed efficiencies with the national renewable energy laboratory (NREL) experimental data, where the device structures of these cells are ZnO/CdS/CuInSe2. As to the higher efficiency cells, the atomic compositions are especially concentrated near Cu:Se = 0.22:0.51 or along the line from Cu:Se = 0.22:0.51 to the stoichiometric point.

To solve the charge neutrality equation, we require several parameters, such as the carrier concentrations, Femi level at a certain temperature and ionized/neutral defect concentrations. In Figure 3, the calculated carrier concentration and electrical conductivity of CuInSe2 and CuGaSe2 at 300 K are shown. Note that in Figure 4, the conductivity will increase first and then decrease down to the film composition from stoichiometry to Cu-poor, after that the conduc-

The simulator SCADS 3.2 [15] has been widely accepted for numerical analysis of CIGS solar cell devices. In 2014, the 19% efficiency of the solar cell was simulated by Naoki Ashida et al. [16]. In this report, the 2 μm thick CIGS absorber layer was divided into two regions, such as low defect density region (front side) and high defect density region

We also developed an alternate full function (indoor, outdoor, and I-V, C-V) analytic solar cell

τh

τe

dp

dn

, Δp ¼ pn � pno (2)

, Δn ¼ np � npo (3)

dx (4)

dx (5)

simulator, in which the following (time-independent) device equations are considered.

dx τp þ Gp � Rp, Rp ¼ Δp

dx τn þ Gn � Rn, Rn ¼ Δn

τp ¼ pqμp E � qDp

τn ¼ nqμn E þ qDn

We have considered all the boundary conditions (n-QNR/SCR interface, front contact, p-QNR/ SCR interface, and back contact), in which QNR stands for the quasi-neutral region and SCR stands for space charge region for a typical n-CdS/p-CIGS device structure. In results of our simulation, we show that the higher efficiency cells are distributed along the line from Cu: Se = 0.3:0.5 to the stoichiometric point and the line from Cu:Se = 0.21:0.52 to the stoichiometric point. What is shown in Figure 5 is the comparison of the computed efficiencies with the national renewable energy laboratory (NREL) experimental data, where the device structures of these cells are ZnO/CdS/CuInSe2. As to the higher efficiency cells, the atomic compositions are especially concentrated near Cu:Se = 0.22:0.51 or along the line from Cu:Se = 0.22:0.51 to the stoichio-

tivity is even lower than that of the stoichiometry.

O ¼ � 1 q d

O ¼ � 1 q d

3. Brief on the device design

134 Emerging Solar Energy Materials

(back side).

a. The continuity equation

b. Transport equations

metric point.

Figure 5. The comparison of the computed efficiencies as compared with NREL's database of ZnO/CdS/CuInSe2 solar cells: (upper) 3D view, (lower) 2D view.

In the last decades, many studies on interface and surface compositional profile have been dealt with the advanced characterizations for the high-efficiency CIGS solar cells. A few examples are:

The properties of the interfaces in semiconductor devices are critically dependent on the detailed atomic structure of the contact plane. Therefore, the model of the junction in chalcopyrite thin-films was simulated by the well-defined interface to classify the influence of grain boundaries, lateral inhomogeneity and chemical variations in compositions and their distributions across and aside from the contact planes. By X-ray photoelectron spectroscopy (XPS), ultra-violet photoelectron spectroscopy (UPS), Low energy electron diffraction (LEED), scanning tunneling microscopy (STM), and X-ray photoemission electron microscope (XPEEM), we can be obtain all these information using the modern analytic tools such as in-situ band alignment, band broadening, and chemical reacted interfaces. After that by experiments and incorporated with our material analysis we could determine their crystalline structure with high resolution for better accuracy and reproducibility obtained in the device design for the

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137

In sections above, the opto-electrical properties of the polycrystalline semiconductors are

In this section, the way of the poly-structure generation is better described through careful observation of the transfer procedures during the manufacturing process, which would be beneficial to know the deposited atoms final positions and the microstructures of the materials. The composition and the structures could be tuned based on controlling and modifying the process by adjusting the process parameters in order to obtain the desired opto-electrical properties.

We describe the better understanding of the way to generate poly-structure through careful observation of the particle transfer procedures during the manufacturing processes after knowing the final positions of the deposited atoms and the materials microstructures. On controlling and modifying the process, the composition as well structure can be tuned directly

The metallic grain structures are described by the original Thornton's zone model [21] according to the sputtering gas pressure and the substrate temperature. Since the high deposition rate, the magnetron sputtering process is most preferred for the industrial application. Also, the energy-dependent sputter yield is noted. Ellmer illustrates the inter-relationships between the process parameters (like substrate temperature and deposition rate) and the structural/optoelectrical properties in a new model [22]. However, the pressure (particles

The Berg's model is particularly utilized in the ZnO reactive sputtering. Basically, the surface coverage on the deposited film is just the composition of the film, but the composition is not easy to control since the system is unstable, where it requires the plasma diagnose sensor for feedback control. About the basic idea of the Berg's model [23, 24], the changes of the number

of absorbed oxygen atoms per unit area Nx at the surfaces of the target is:

by varying the process parameters to acquire the desired opto-electrical properties.

future industrial applications.

4. Brief on the process design

affected by structure and composition greatly.

momentum) effect is not considered in this model.

4.1. Berg's model

Figure 6. The complete band alignment includes the copper depletion at the interface.

diffraction (LEED), angular resolved ultraviolet photoelectron spectroscopy (ARUPS) and auger electron spectroscopy (AES) [14].

4. Secondary ion mass spectrometry (SIMS) depth profile of Cu, In, Ga, Se, Cd, and Na revealed the CdS/CIGS/ZnO diffusion phenomena as shown in Figure 7 [19].

Sample Figure 7(a) and (b) were obtained from the different origins, note that the difference in the Ga profile in the SIMS depth profiles are due to the different processes.

5. Defect in grains and grain boundaries [20].

Figure 7. SIMS depth profile of Cu, In, Ga, Se, Cd, and Na. (1) CdS/CIGS and ZnO diffusion. (2) Cu, In, Ga, and Se depth profile. (3) Quantitative analysis of Na in CIGS.

The properties of the interfaces in semiconductor devices are critically dependent on the detailed atomic structure of the contact plane. Therefore, the model of the junction in chalcopyrite thin-films was simulated by the well-defined interface to classify the influence of grain boundaries, lateral inhomogeneity and chemical variations in compositions and their distributions across and aside from the contact planes. By X-ray photoelectron spectroscopy (XPS), ultra-violet photoelectron spectroscopy (UPS), Low energy electron diffraction (LEED), scanning tunneling microscopy (STM), and X-ray photoemission electron microscope (XPEEM), we can be obtain all these information using the modern analytic tools such as in-situ band alignment, band broadening, and chemical reacted interfaces. After that by experiments and incorporated with our material analysis we could determine their crystalline structure with high resolution for better accuracy and reproducibility obtained in the device design for the future industrial applications.


*2.3. Data Analysis*

Pearson's correlations were calculated to examine the relationships among the variables. Then, structural equation modelling (SEM) was used to estimate the statistical models (Amos 21 SPSS, an IBM Company: Chicago, IL, USA) [47]. In accordance with the rules of SEM, we first validated the measurement model by confirmatory factor analyses (CFA) and then we tested the structural relationship between measured variables and latent constructs. The goodness of fit of the model was evaluated by applying different indices: χ2 statistic, the standardized root-mean-square residual (SRMR), root-mean-square error of approximation (RMSEA), and three modification indices—goodness of fit index (GFI), Tucker Lewis index (TLI), and comparative fit index (CFI). We were removing non-significant parameters and non-significant paths of the original model one at a time in relation to the modification indices to improve the model fit (Table S1, Supplementary Material) [48]. In addition, the modifications were to improve the model fit as long as they were corroborated by the theory. Bootstrapping was used to estimate direct and indirect effects (samples = 5000; 95% bias-corrected confidence intervals; standardized coefficients were presented). This approach enabled us to examine the relationship between risk perception of COVID-19 and psychological well-being as well as the relationship between meaning-based resources and psychological well-being.


**5. Aptamer-based targeting**

Nanoconjugates functionalized with disease cell-specific aptamers have been reported to enhance specificity for microbial pathogens. Aptamers are single strands of intact sequences of nucleic or xeno nucleic acids. Because of their high affinity, selectivity, and specificity for specific microorganism targets, aptamers are selected and prepared, typically using the SELEX procedure [67] and used for NP functionalization [68]. The use of aptamers for the targeted delivery of anticancer drugs and PSs has been ubiquitously studied [69]. However, the use of aptamers for the targeted delivery of antibacterial drugs and PSs in aPDT has recently attracted attention [70]. Disease cell targeting aPDT applications may be illustrated with the studies of a DNAaptamer-functionalized nanographene oxide as a targeted nanomaterial-mediated bio-theragnostic approach against *Porphyromonas gingivalis*, a pathogenic periodontitis constituent of the periopathogenic complex [71]. Following synthesis and characterization, the nanographene oxide was functionalized with an aptamer [72], which was selected using the SELEX procedure [73, 74]. Using fluorescence flow cytometry, this study showed that graphene oxide NPs, functionalized with the DNA aptamer, enhanced target specificity of the nanoconjugate for *P. gingivalis* disease cells. In a similar study, aptamer-functionalized emodin NPs showed binding specificity and enhanced antibacterial activity against *Enterococcus faecalis* [75]. Regarding the applications of aptamers in aPDT, literature reviews have indicated that the effect of aptamers goes beyond disease cell targeting to include bactericidal and biofilm disruptive effects [76], suggesting that in addition to targeting specific bacterial pathogens, the aptamer-functionalized nanoconjugates could also exhibit bactericidal and biofilm disruptive effects.

### **6. Glycan-based targeting**

Evidence that the carbohydrate-based polysaccharide polymers found on bacterial cells, also known as glycans, can form the basis for bacterial targeting has been presented [77]. There are glycan-recognizing and binding proteins on bacterial target host cell surfaces, known as lectins. These protein molecules are recognized by the glycan structures on bacterial target host cell surfaces where the bacteria attach for host cell invasion [78]. The antibacterial macrophage strategy involves the initial attachment to the bacterial cell surface, followed by the delivery of depolymerases and lysins to degrade the bacterial cell wall-based glycans [79]. Similarly, the bacterial glycan cell targeting technology is based on extensively lectin-functionalized nanoconjugate systems that attract and selectively bind to bacteria with high binding affinity, delivering their antibacterial cargo, such as antibiotic chemotherapy drugs and PDT PSs, yet maintaining host microenvironment biocompatibility [80, 81].