*6.1. Pseudocirrhosis*

Alterations in liver blood flow caused by VMs in HHT can lead to either di ffuse or focal hepatocellular regenerative activity, with fibrosis surrounding the abnormal vasculature [12]. On imaging, hepatic nodules and fibrosis mimic the appearance of cirrhosis. However, in HHT this appearance has been termed "pseudocirrhosis," as the normal hepatocellular architecture is preserved (Figure 7) [12,16,36]. Unlike in true cirrhosis, there is not the same increased risk of hepatocellular carcinoma (HCC) in pseudocirrhosis.

**Figure 7.** Chronic liver injury with nodular regenerative hyperplasia, pseudocirrhosis, and peripheral fibrosis in a 54-year-old woman with HHT. (**a**) Axial T1-weighted MR image shows parenchymal nodularity most prominent in the posterior right hepatic lobe (arrow). (**b**) Axial T2-weighted fat-saturated MR image shows a reticular pattern of increased signal in the posterior right hepatic lobe (arrow). (**c**) Delayed enhancement on the axial T1 fat-saturated gadolinium-enhanced MR image (arrow), along with multiple telangiectases (arrowheads).

#### *6.2. Focal Nodular Hyperplasia*

Focal nodular hyperplasia (FNH) is a common benign liver mass and represents a disorganized proliferation of hepatocytes that can occur in response to VMs. FNH has a 100-fold higher incidence in individuals with HHT [37]. Evaluation with multiphase cross-sectional imaging is usually recommended for evaluation of focal liver lesions. FNH has a highly characteristic imaging appearance on MRI, with early arterial enhancement and a T2-hyperintense "central scar" (representing disordered mixture of blood vessels and bile ducts) [29]. It is important for radiologists and clinicians to keep in mind the high incidence of FNH in HHT patients in order to avoid unnecessary biopsies.

Although FNH is benign, the imaging characteristics can pose a diagnostic dilemma, especially on a background of "pseudocirrhosis" (Figure 8). For example, lesions in HHT patients may not have the T2 hyperintense "scar [38]". In such instances, di fferentiating benign FNH from malignant HCC (or other tumors) is challenging. One solution is to obtain further imaging with gadoxetate-enhanced MRI. Gadoxetate disodium is a gadolinium-based contrast agent that is actively taken up by hepatocytes. Because FNH is composed of proliferating hepatocytes, gadoxetate is readily taken up by these cells. Most hepatic malignant tumors (such as HCC or metastases) lack the transporter for gadoxetate, and therefore, gadoxetate remains extracellular. This results in unique imaging appearances with FNH retaining contrast (hyperintense) on the delayed "hepatobiliary phase" of gadoxetate-enhanced MRI (Figure 9), while HCC or other genuine neoplasms are usually hypointense relative to surrounding parenchyma. It is so essential to radiologically di fferentiate FNH from potential HCC due to the di fferences in management. While suspicious lesions require biopsy, a biopsy is not recommended in FNH on a background of hepatic VMs due to the bleeding risk.

**Figure 8.** Focal nodular hyperplasia (FNH) mimicking cholangiocarcinoma in a 41-year-old woman with HHT. (**a**) Pre-contrast axial T1-weighted MR image shows a focal T1 hypointense lesion in segment III of the left hepatic lobe (arrow). (**b**) The lesion shows restricted di ffusion at di ffusion-weighted MR imaging (arrow). (**c**) Axial T1 weighted gadolinium-enhanced MR image with fat saturation shows corresponding peripheral enhancement (arrow) as well as numerous confluent vascular masses (arrowheads). (**d**) The segment III lesion is hyper-enhancing on delayed phase (arrow). The confluent vascular masses are notably isointense to liver parenchyma at this phase. Ultrasound-guided biopsy of the segment III lesion showed features of FNH.

**Figure 9.** Focal nodular hyperplasia (FNH) in a 61-year-old woman with HHT. (**a**) Numerous hepatic lesions (arrows) are essentially imperceptible given signal characteristics similar to that of background parenchyma on pre-contrast-enhanced coronal T1-weighted MR image. (**b**) The lesions (arrows) are hyper-enhancing on the hepatobiliary phase of the gadoxetate-enhanced coronal T1-weighted MR image due to expected retention of contrast, compatible with multifocal FNH.


**7. References**

202 Current Issues of Water Management

conflicts, creates competition and not necessarily facilitates the participation of the weaker social groups. This paradox is not resolved within the water regulatory framework only, but requires broader political basis for dealing with shared problems. If in the past, public investments were in water infrastructure, the current top-down approaches to water management basically reproduce this engineering-based model of development and management, without questioning the causes of environmental degradation and the main beneficiaries. Under WFD, water is emerging (or re-emerging) as a locus of political disputes involving a myriad of stakeholder groups and spatial relations. The Douro is an emblematic example of how water management should be understood as not only a technical and economic matter, but also directly related to political questions of social exclusion. What is still lacking is a genuinely innovative way of dealing with water problems, one that resolves the uneven balance of power between spatial areas and social groups, as well as incorporates traditional wisdom and the contribution of local people in the development of innovative solutions to old and new water management challenges. Unless social differences and the reproduction of social inequalities are addressed, water

The ultimate result is that, notwithstanding legal and discursive improvements, the longterm causes of water problems – namely, political pressures for maximising the economic outcomes and minimising the investments in social equity and environmental conservation – have been left out of the process of regulatory change. The limited availability of long-term monitoring data and detailed technical studies have contributed to reinforce the two fundamental hindrances of the regulatory regime under WFD (namely, spatial rigidity and monotonic categorisation of problems), leading to an evasion of references about the political origins and the socioeconomic consequences of environmental impacts. In the end, WFD remains a contested experience of environmental regulation that oscillates between attempts to commodify nature (e.g. bulk water charges, valoration of ecosystem services, calculation of disproportionate costs) and the affirmation of techno-bureaucratic mechanisms of law enforcement (i.e. that neglect the demands and needs of large proportion of water stakeholders). The asymmetry of political power also operates in the interstices of the regulation, given that the water reforms promoted through WFD have served to implement a particular worldview and serve specific interests under a universalising discourse and a naturalisation of hegemonic agendas. On the other hand, the imposition of techno-bureaucratic approaches to water management has prompted the emergence of various forms of opposition, either at the local level or in coordination with other national and international forms of contestation (as the criticism of water privatisation and the campaigns against the new dams in the Upper Douro). The success of the next stages of the implementation of WFD will depend on the ability to perceive the broader socionatural complexity of water management, the pursuit of effective forms of social inclusion and a

The author warmly thanks the interviewees in Portugal and Spain, the University of Porto for the logistical assistance and the financial support received from The Carnegie Trust for

management problems will remain unchanged.

more equal balance of negotiation power.

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**10**

*Kenya*

Okeyo Joseph Obosi

*University of Nairobi,*

**Public Private Partnerships in the**

*Department of Political Science & Public Administration*

**Privatization of Water Service Delivery in Kenya**

The paper is divided into four sections. Section I presents background information on the water supply situation including the hydrological situation. Section II presents the privatization of the water supply and the institutional management of the privatisation process globally. International experiences on privatization and water sector reforms including the public-private partnership as a strategy is also discussed. Section III discusses the Water Management, reforms, and governance including monitoring mechanisms in Kenya. Section IV provides a conclusion as it summarises the salient features and challenges

Kenya is mainly an agricultural country with an expanding economy whose basic element for development is water. Water is required for agricultural, commercial, and domestic use Mogaka et al, (2003). However, the climate in Kenya varies by region and season to an extent that whereas some parts of the country would be experiencing floods, others will hardly receive a drop in a year. This makes accessibility to clean water unreliable in Kenya

Kenya's surface water resources are distributed within five drainage basins, namely, the

**Basin Surface Water % Groundwater % Total %**  Lake Basin 11,993 59.2 539 18.7 12532 54.1 Rift Valley 211 1 586 20.3 797 3.4 Athi River 582 2.9 405 14 987 4.3 Tana River 6,789 33.5 685 23.8 7474 32.3 Ewaso Ng'iro 674 3.3 663 23 1337 5.8 **Totals 20249 100 2878 100 23127 100**  Safe yield in '000 cubic metres per day

Lake Basin, Rift Valley, Tana, Athi, and Ewaso Ngiro as shown in the table below.

Source: Mogaka et al., (2006). Climate variability and Water Resources Degradation in Kenya: p.9. Table 1. Showing safe yield from water resources by Major Drainage Basins in Kenya

**1. Introduction**

of the processes discussed in the chapter.

even to the areas where rainfall is abundant.

**1.1 Hydrological situation**


**Development of Feline Ileum- and Colon-Derived Organoids and Their Potential Use to Support Feline Coronavirus Infection**

### **Gergely Tekes 1,\*,**†**, Rosina Ehmann 2, Steeve Boulant 3,4 and Megan L. Stanifer 5,\***

Received: 14 August 2020; Accepted: 10 September 2020; Published: 12 September 2020

**Abstract:** Feline coronaviruses (FCoVs) infect both wild and domestic cat populations world-wide. FCoVs present as two main biotypes: the mild feline enteric coronavirus (FECV) and the fatal feline infectious peritonitis virus (FIPV). FIPV develops through mutations from FECV during a persistence infection. So far, the molecular mechanism of FECV-persistence and contributing factors for FIPV development may not be studied, since field FECV isolates do not grow in available cell culture models. In this work, we aimed at establishing feline ileum and colon organoids that allow the propagation of field FECVs. We have determined the best methods to isolate, culture and passage feline ileum and colon organoids. Importantly, we have demonstrated using GFP-expressing recombinant field FECV that colon organoids are able to support infection of FECV, which were unable to infect traditional feline cell culture models. These organoids in combination with recombinant FECVs can now open the door to unravel the molecular mechanisms by which FECV can persist in the gut for a longer period of time and how transition to FIPV is achieved.

**Keywords:** feline coronavirus; feline enteric coronavirus; FECV; feline infectious peritonitis virus; FIPV; feline intestinal organoids


**4. Mechanisms of** *Salvia miltiorrhiza* **in aging-associated CVD and cancer**

#### **4.1 Therapeutic properties of Danshen in aging-associated CVD**

Salvianolic acids, especially SalA and SalB, have potent anti-oxidative capabilities due to their polyphenolic structure. The cardiovascular protection of salvianolic acids include the following mechanisms: ROS scavengers, reduction of leukocyte-endothelial adherence, inhibition of inflammation and metalloproteinases expression from aortic smooth muscle cells, and indirect regulation of immune function, and also competitive binding to target proteins to interrupt protein–protein interactions [77].

SalA inhibits oxidative stress directly by scavenging the free radicals to improve the endothelial dysfunction [78], vascular smooth muscle cell proliferation [79], pulmonary arterial hypertension [80], and cardiac fibrosis. SalA can chelate Cu2+ and inhibit Cu2+-promoted oxidation of low-density lipoprotein to reduce the production of malondialdehyde which is the final product of polyunsaturated fatty acids peroxidation in a cell-free system [81]. Interesting, there is a study showed both Salvianolic acid and tanshinone contribute to the cardioprotective effect of Danshen. Tanshinone mainly inhibits intracellular calcium and cell adhesion pathways at an early stage after ischemic injury whereas Salvianolic acid acts mainly by decreasing apoptosis [82].

#### *Polyphenols of* Salvia miltiorrhiza *in Aging-Associated Cardiovascular Diseases and Cancer DOI: http://dx.doi.org/10.5772/intechopen.98632*

SalB protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways and prevents oxidative-induced endothelial dysfunction via downregulated NADPH oxidase 4 and eNOS expression [18].

Cardiac fibrosis is a chronic harmful result of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9. The inhibition on MMP-9 by SalA was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo [83]. SalA targeted transgelin and had a protective effect on myocardium by stabilizing the transgelin-actin complex, modulating the reorganization of the actin cytoskeleton, facilitating F-actin bundling, further enhancing the contractility and blood flows of coronary arteries, and improving outcomes of myocardial ischemia [84]. SalB facilitates angiogenesis and alleviated cardiac fibrosis and cardiac remodeling in diabetic cardiomyopathy by suppressing insulin-like growth factorbinding protein 3 (IGFBP3) [85]. SalB can alleviate Ang II-induced cardiac fibrosis via suppressing the NF-κB pathway in vitro [86]. It is reported that treatment with 5% water-soluble extract of Danshen which contained SalB for 12 weeks lowers blood cholesterol and reduces atherosclerotic plaque formation in diet-induced hypercholesterolemic rabbits, which is associated with its ROS scavenging capacity (**Table 1**) [87].

Homocysteine (Hcy), a by-product of methionine metabolism, may lead to hyperhomocysteinemia which is the risk factors responsible for the development of several vascular diseases (thromboembolism, atherosclerosis, stroke, vascular diseases and dementia). The aqueous extracts of Danshen against vascular atherosclerotic lesions though inhibiting Hcy-induced rat smooth muscle cell line(A10) growth via the PKC/MAPK-dependent pathway, attenuated carbonyl-modification of specific cytoskeleton and chaperone proteins leading to cell type transformation, also, scavenging of ROS and subsequent modulation of protein carbonylation to inhibit cell proliferation [88]. Another study demonstrated the protective effect of Danshen extract against the Hcy-induced adverse effect on human umbilical vein endothelial cell and showed different effectiveness in protection according to the following descending order: Danshen aqueous extract, 3-(3,4-dihydroxy-phenyl)-2-hydroxypropionic acid (Danshensu), protocatechuic acid, catechin and protocatechualdehyde [89]. Danshensu decreases foam cell formation by reducing the expression of TNFα, ICAM-1, and ET-1 while increasing NO production, thus protecting the vascular endothelium from injury [90]. SalA markedly attenuated induction of MKP-3(mitogen-activated protein kinase phosphatases 3) and inhibition of eNOS expression and NO formation under endothelial ischemia/reperfusion condition [91].

Some clinical studies reported that the Danshen preparations in combination with Western medicine were more effective for treatment of various CVDs including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases [92]. Our previous series studies showed the most common used single Chinese herbal products which prescribed by TCM Doctors during 2000–2010 in Taiwan is Danshen (16.50% in ischemic stroke; 29.30% in ischemic heart disease; 3.95% in atrill fibrillation; 5.13% in heart failure) [36, 37, 93, 94]*.* There was nearly one-third lower stroke risk in ischemic heart disease patients with combination TCM than patients with non-TCM treatment (95% CI = 0.11–0.84,

↑*: increase;* ↓*: decrease;* ↔*: no change;* ⊝*: inhibit;* ⊕*: promote. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP-response element binding protein; LDL, low-density lipoprotein; MDA, malondialdehyde; MMP-9, Matrix metallopeptidase 9; Akt, protein kinase B; mTOR, mechanistic target of rapamycin; 4EBP1, Eukaryotic translation initiation factor 4E-binding protein 1; p38 MAPK, mitogen-activated protein kinases; ATF2, Activating Transcription Factor 2; ERK1, extracellular signal-regulated kinase 1; Nox4, NADPH oxidase 4; eNOS, Endothelial Nitric Oxide Synthase; ROS, reactive oxygen species; ICAM, intercellular adhesion molecule; IL-6, interleukin-6; sVCAM-1, soluble vascular cell adhesion molecule-1; NF-*κ*B, nuclear factor kappa-light-chain-enhancer of activated B cells; IGFBP3, insulin-like growth factor-binding protein 3.*

#### **Table 1.**

*The main antioxidative mechanisms of* Salvia miltiorrhiza *(Danshen) in CVD.*

P = .02). The higher survival rate (P < .001) and the lower incidence of hemorrhagic stroke (P = .04) in ischemic heart disease patients with TCM treatment was reported [95]. Compared to non-TCM users, the stroke risk was significantly lower in TCM users with atrial fibrillation who were female or younger than 65 years, but not in males, people more than 65 years old, or people with comorbidities [93]. One randomized controlled trial showed *Salvia Miltiorrhiza* Depside Salt combined with aspirin is a clinically effective and safe intervention to treat adults aged 35 and

older with stable angina pectoris without adverse drug reactions such as bleeding tendency occurred [96].

#### **4.2 Therapeutic properties of Danshen in cancer**

SalA and SalB have been reported to owe anti-cancer, anti-inflammatory and cardioprotective activities not only through inducing apoptosis, halting cell cycle and adjourning metastasis by targeting multiple deregulated signaling networks of cancer but also sensitizing cancer cells to chemo-drugs [97].

Acting to protect the organism against these harmful pro-oxidants is a complex system of enzymatic antioxidants (e.g., superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, catalase) and nonenzymatic antioxidants (e.g., glutathione, vitamins C and D) [98].

SalA elevated ROS levels, downregulated P-glycoprotein, and triggered apoptosis by increasing caspase-3 activity and upregulating Bax expression, while downregulating Bcl-2 expression and disrupting the mitochondrial membrane potential in multidrug resistance MCF-7 human breast cancer cells [99]. In lung cancer, SalA could increase the chemotherapeutic efficacy of cisplatin by enhanced sensitivity to cisplatin in A549/DDP cells mainly through suppression of the c-met/AKT/mTOR signaling pathway [100]. In addition, SalA considerably suppressed the migrative and invasive activity of human NPC cells but not presented cytotoxicity. In SalA-treated NPC cells, the activity and expression of matrix metalloproteinase-2 (MMP-2), a key regulator of cancer cell invasion, were reduced. Additionally, the presence of high concentrations of SalA dramatically abolished the activation of focal adhesion kinase (FAK) and moderately inhibited the phosphorylation of Src and ERK in NPC cells [101].

The anti-tumor effect of SalB is via inhibiting the expression of glucosylceramide and GM3 synthases, and then increases the ceramide accumulation and ceramidemediated Triple-negative breast cancer cell apoptosis [102]. One study indicated SalB induced cell death and triggered autophagy in HCT116 and HT29 cells in a dose-dependent manner, and it is as a novel autophagy inducer in colorectal cancer cells through the suppression of AKT/mTOR pathway [103]. Besides, SalB reduced the cytotoxicity of doxorubicin through scavenging ROS generated by doxorubicin in HepG2 cells and enhance the expression of SOD and decrease that of NADPH oxidase, which resulted in the elimination of ROS [104]. Sal-B regulated proliferation, epithelial-mesenchymal transition (EMT) and apoptosis to reduce the resistance to cisplatin via AKT/mTOR pathway in cisplatin-resistant gastric cancer cells [105].

Rosmarinic acid (RA) inhibited non-small cell lung cancer (NSCLC) by inducing G1 phase cell cycle arrest, apoptosis and the sensitivity of cisplatin-resistant cell via activating MAPK, enhancing p21 and p53 expression, and inhibiting the expression of P-gp and MDR1 [106]. RA reverses cisplatin resistance of NSCLS by activating the MAPK signaling pathway.

Most of the currently available chemotherapeutic and radiotherapeutic agents kill cancer cells by increasing ROS stress. Thus, both ROS-elevating and ROS-eliminating strategies have been developed for cancer therapy. As we know either chemotherapy or radiotherapy was usually associate with uncomfortable side-effects which are burdens to clinical physicians. Our previous researches find the aqueous extract of Danshen has shown anticancer as well as antioxidant effects, besides, it could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy (**Table 2**) [108, 109].

↑*: increase;* ↓*: decrease;* ↔*: no change;* ⊝*: inhibit;* ⊕*: promote. ROS, reactive oxygen species; DDP, cisplatin; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; FAK, focal Adhesion Kinase; ERK, extracellular signal regulated kinase; COX-2/PGE-2; SOD; NADPH.*

#### **Table 2.**

*The therapeutic effect mechanism of polyphenols of Salvia miltiorrhiza (Danshen) in common cancers.*


Preface

 It is estimated that one-third of the world's population is anemic, the majority being due to iron deficiency (ID). This great health problem affects approximately to more than 2 billion people worldwide, and IDA remains the main cause of anemia, as confirmed by the analy‐ sis of a large number of reports on the burden of disease in near two hundred countries, performed in the last twenty years and by a survey on the burden of anemia in persons at risk, such as preschool children and young women.

 This situation is applied to the reduction of iron stores that precedes to overt iron deficiency anemia (IDA) or persists without progression. This is a more severe condition, in which low levels of iron are associated with anemia and the presence of microcytic hypochromic red cells. The estimated prevalence of ID worldwide, is twice as high the IDA. The diagnosis and treatment of this condition needs clearly to be improved.

 Iron is a metal compound crucial to biologic functions, including respiration, energy produc‐ tion, DNA synthesis, and cell proliferation. The human body has evolved to conserve iron in several ways, including the recycling of iron after the breakdown of red cells and the retention of iron in the absence of an excretion mechanism. However, since excess levels of iron can be toxic, its absorption is limited to 1 to 2 mg daily, and most of the iron needed daily (about 25 mg per day) is provided through recycling by macrophages that phagocytate senescent eryth‐ rocytes. The latter two mechanisms are controlled by the hormone hepcidin, which maintains total-body iron within normal ranges, avoiding both iron deficiency and excess.

 Prevention programs have decreased rates of IDA globally. The prevalence is now highest in Central and West Africa and South Asia. The reported prevalence of ID in the absence of dietary fortification is approximately 40% in preschool children, 30% in menstruating girls and women, and 38% in pregnant women. These rates reflect the increased physiological need for dietary iron during specific life stages according to sex.

 While anemia is clearly defined according to the World Health Organization as a hemoglo‐ bin (Hb) level less than 12 g/dL in women (< 11 g/dL in pregnant women) and lower than 13 g/dL in men, the situation is ambiguous for for iron deficiency. No single test is diagnostic of ID, unless the serum ferritin is low or the percent transferrin saturation is low with an elevated total iron binding capacity

 Iron deficiency anemia (IDA) is a common complication in routine clinical practice that fre‐ quently originates in the gastrointestinal (GI) tract. Patients with IDA are therefore often re‐ ferred to gastroenterologists for further examination and/or treatment. This finding associated with GI disorders can substantially reduces quality of life, contribute to fatigue, and may even lead to hospitalization.

In contrast to the well-documented inflammatory bowel disease (IBD)-associated IDA prev‐ alence data for associated with other pathological conditions of the GI tract, are sparse. Guidelines for the diagnosis and management of anemia and iron deficiency are available for IBD, but not for other GI conditions. Overall, there are three main pathological contribu‐ tors to IDA, namely chronic bleeding, malabsorption and inflammation.-However, otherfac‐ tors, such as poor or selective diet, as well as iron malabsorption (e.g., due to decreased gastric pH) should not be neglected in patients referred for IDA assessment. This applies particularly to elderly patients.

 Celiac disease (CD) is one of the most common chronic inflammatory conditions of the GI system, affecting about 1% of the population. There is a well established relationship be‐ tween CD and IDA. Anemia is the most common presenting symptom of CD, found in 32%-69% of adult patients. Approximately 80% of anemic patients with CD, are also ID. In 49% of anemic patients with CD, ID was found to be the only detectable abnormality. Con‐ versely, among patients presenting with unexplained IDA, 5% have histologically-con‐ firmed CD. Impaired iron absorption (due to villous atrophy of the intestinal mucosa) and blood loss are important pathological contributors to anemia in CD.

 Occult GI bleeding has been detected in about half of patients with CD adhering to a glutenfree diet (GFD). In some patients, nutritional deficiencies may also be a (contributing) causa‐ tive factor. Inflammation is a major contributor to IDA, with interleukin (IL)-1, IL-6, IL-10, interferon (IFN)-γand tumor necrosis factor (TNF)-αas inducers of hepcidin, the main reg‐ ulator of iron homeostasis .

 Accordingly, CD-related IDA, is refractory to oral iron treatment, and even after switching to a GFD, it takes 6-12 mo until most patients recover from anemia. Notably, half of patients remain iron-deficient even after 1-2 years on a GFD. The slow or lacking recovery from ID, may be due to the low absorption rate of nutritional iron (1-2 mg/d), which hinders the re‐ pletion of severely depleted iron stores, and the potentially low content of iron and other micronutrients in a GFD. Therefore, patients with CD clearly benefit from immediate intra‐ venous iron treatment, instead of switching to intravenous iron only after (foreseeable) nonresponse and/or intolerance to oral iron.

 Oral iron is considered the front line therapy, except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, andhereditary hemorrhagic telangiec‐ tasia. Oral iron has many unpleasant side effects, resulting in low patient adherence. For patients intolerant of or unresponsive to, oral iron, intravenous (IV) administration is the preferred route.

 While early formulations were associated with a high incidence of serious adverse events (SAEs), newer formulations are much safer with SAEs occurring very infrequently. Full re‐ placement doses can be administered in a matter of minutes to a few hours. Nevertheless, there remains a reluctance to use IV iron due to a misunderstanding of the safety of the available formulations. Intrevenous iron is safe and effective in all clinical circumstances in‐ cluding pregnancy. The preponderance of published evidence suggests IV iron therapy is underutilized and IV iron should be moved forward in the treatment of ID and IDA.

> **Prof. Luis Rodrigo MD**  Emeritus Full Professor of Medicine University of Oviedo Oviedo, Spain

### **Chapter 1**


*3.1. Framework*

Figure 3 presents a framework that offers an insight into how the present study applied the research inputs and produced the results.

**Figure 3.** Research study framework.

The top layer reflects the five themes that formed the basis for the data gathering template. These themes were developed through an iterative process of conducting focus group sessions with two themes emerging, i.e., root cause and reporting. Concurrently, a systematic literature review was performed using NVivo software to assist the researchers manage over 1000 screened publications. Following a thematic analysis of the data, three main themes (Appendix B) emerged from a final cache of 18 publications, i.e., learning from incidents, precursors and just culture. The five themes informed the structure of a data gathering instrument that supported 34 semi-structured interviews in the continuing airworthiness segment of the industry. Following transcription, the data were uploaded to NVivo where they were thematically analyzed using the Braun and Clarke [47] framework. The outputs from the thematic analysis distilled the interview analysis into three main outputs, i.e., learning from incidents, learning process and learning product. The lower tier represents the elements the themes were comprised of and the findings are presented under these headings (Table 5).

> **Table 5.** Summary of results. 1 Learning from incidents (LFI) is a safety management activity with a desired outcome of preventing unwelcome event recurrence.2 A learning process facilitates a change in knowledge and behavior intended to support LFI.3 Safety related information arising from the LFI process.

### 3.1.1. Learning form incidents—Acquiring, Processing and Storing Data

Incident reporting is accepted as a worthwhile activity amongst those participating in the study. This is based on the collective notion that the initiative raises awareness of incidents and potential hazards and can therefore help prevent event recurrence. The authors recognize that awareness is an important component of learning from incidents. Situations do arise where due to lack of report data, it is questionable if all the necessary reports are being submitted as required. Amongst the constraints to making a report are perceived production pressures and the potential embarrassment that could arise from making a mistake and highlighting it [5]. There are just culture concerns amongst some sta ff because they do not always know what the impact for them personally will be if they submit an incident report [44].

A dedicated focal point in organizations is essential for the systematic management of reported incidents. Where this discipline is applied, the process owner is responsible for highlighting reported issues and raising the necessary awareness amongst operational sta ff. Once an incident is acquired through the e fforts of a reporting system, some form of processing and analysis is necessary. The availability of adequate resources for determining causation and implementing measures to prevent recurrence was identified as a primary point of concern. Perceived premature closure of reports was also highlighted amongst participants. There was a call for improved accountability and transparency on decisions relating to some closure actions. Respondents associate the practice of applying commercial key performance indicators to safety management as shallow e fforts are sometimes made by organizations to expeditiously and prematurely close reports on occasion. Incident reporting and safety management initiatives have been in existence for some time. Large repositories of associated safety data are stored in many organizations. Although entities are mandated to inform key stakeholders, there is a strong opinion amongst some participants that the data repositories could be aggregated and put to better use in support of learning amongst all operators.

### 3.1.2. Learning Process—Single-Loop, Double-Loop and Deutero Learning

The interview data confirms that safety is a primary underpinning value in the organizations that participated in the study. The release of a safe product, i.e., an aircraft or component, is a formative pursuit and measure of learning. In organizational environments where a "find and fix" ethos may prevail, single-loop learning [11] is evident in the examples presented.

A desired outcome of double-loop learning [11] is often witnessed for example through the adjustment of environmental, behavioral and procedural norms. Instances of double-loop learning can be evident following unsuccessful attempts through single-loop learning where causation is then adequately understood and actioned. Continuation (mandatory in-service) training was considered by study participants as an e ffective mechanism that enables double-loop learning. During the study, it was apparent that single and double learning loops are recognized amongst many participants as having di ffering capabilities in terms of delivering an e ffective learning product. However, there was no evidence of formal reviews of single and double-loop learning being performed within the participants' organizations. Although deutero-learning [11,55] may be considered as a natural extension of other levels of learning, the concept did not feature strongly amongst the participants. A review of the EU1321/2014 [6] implementing requirements confirms an absence of any mandatory requirement to review learning processes.

### 3.1.3. Learning Product—E ffectiveness and Types of Knowledge

Continuation training is a mandated European requirement [6] for all aircraft maintenance and continuing airworthiness management organizations. It is a product as well as a medium for imparting learning from incidents and safety related hazards. It was identified during the study that the learning product is shared amongst sta ff through three primary means of distribution: formally delivered

continuation training, tool-box talks and safety briefings and electronic, paper, notice board and "read and sign" safety publications. The study suggests a learning product can arise as a result of an output from an incident lifecycle. Feedback from submitted occurrences to stakeholders varies from very good to poor. Cost is seen as a major consideration in some of the participating organizations when planning continuation training delivery. Although computer-based training is being considered in some companies as a viable option to class-room delivery, concerns are evident in respect of e ffectiveness of this medium in its current form. Bedwell and Salas [56] suggest computer-based training (CBT) can be used as a methodology for providing, "*systematic, structured learning; a useful tool when properly designed*".

The perceived overburdening of operational sta ff with complex learning products and excessive cognitive loads was recorded as an impediment to learning during the study. Participants suggested this can arise from poorly designed training syllabi delivered during periods of high operational activity.

Four knowledge types were identified and relate to: conceptual, dispositional, procedural and locative knowledge forms [57]. One of the key objectives of learning from incidents is to identify the type of knowledge needed to prevent an issue recurring. When a reportable issue, for example, is discovered, the submitted report will identify "what" happened. Subsequent follow up will set out to determine "why" the issue occurred. The guiding principles of "how" to perform the task or operation are often contained in procedures or data particular to the task. The information contained in procedures will enable a person to utilize other forms of knowledge. Prevailing safety culture within an organization will have an impact on learning from incidents. If a strong commercial/production culture exists, this may have an impact on, for example, the depth and breadth of learning from incidents within the company. Induction and initial training are important when accessing information for new sta ff. Accident data repositories contain well-documented human factor-related examples often relating to access to approved data and consequently resulting in potentially preventable incidents. Examining the limitations of each type of knowledge when continuation training programs are being developed was flagged as important by some participants. During the study, no discernible di fferences were recorded in how the types of knowledge were di fferentiated in participant organizations. A review of the EU 1321/2014 [6] human factors syllabus requirements did not highlight a need to appreciate or account for these human centered limitations when designing and delivering training lessons. Improved regulatory guidance on the design of e ffective human factor related material should therefore be developed. Information on how training should be structured in order to appreciate types of knowledge and capitalize on it as a minimum are required to ensure the most e fficacious outcome from incident-related training.


*3.5. Sorption Thermodynamics*

To estimate the thermodynamic action of the CIP and LEV adsorbed onto the Fe– Cu/Alg–LS nanocomposite, the thermodynamic factors were assessed in order to determine the thermodynamic viability and spontaneous nature of the process of adsorption. At varied temperatures (30, 40, and 60 ◦C), the findings were recorded. The formulae listed below were used to calculate the thermodynamic factors [56,57]:

$$
\Delta \mathbf{G}^{\odot} = -\mathbf{R} \mathbf{T} \ln \mathbf{K}\_{\mathbf{d}} \tag{11}
$$

$$
\Delta \mathbf{G}^{\diamond} = \Delta \mathbf{H}^{\diamond} - \mathbf{T} \Delta \mathbf{S}^{\diamond} \tag{12}
$$

$$
\ln \mathbf{K\_d} = -\Delta \mathbf{H^\diamond} / \mathbf{RT} + \Delta \mathbf{S^\diamond} / \mathbf{R} \tag{13}
$$

where T is the absolute temperature (K), Kd is the distribution coefficient, and R is the gas constant (8.314 J mol−1 K−1). Using Equation (11), the Gibbs free energy was calculated. Furthermore, using Equation (12), G◦ might be calculated from H. Using Equation (13), the thermodynamic variables S◦ and H◦ were calculated (from the intercept and slope). The data showed that the amount of CIP and LEV ions taken up by nanocomposites slightly decreased in direct proportion to the temperature increase. In contrast to the adsorbent particles, the rise in degree of temperature increased the pollutants' solubility in a bulk solution to a larger extent [58]. Table 5 illustrates the Fe–Cu/Alg–LS nanocomposite components' thermodynamic sorption response to CIP and LEV ions.

**Table 5.** Thermodynamic conditions using 0.2 g/25 mL of the nanocomposite at pH 6 for CIP (10 ppm) and 7 for LEV (20 ppm), with contact times of 40 min and 45 min for CIP and LEV, respectively.

Negative G◦ show that the adsorption process is feasible and spontaneous. Additionally, negative findings of H◦ also suggest that LEV was adsorbed onto the Fe–Cu/Alg–LS nanocomposite in an exothermic manner. Positive readings of H◦ show that CIP was adsorbed endothermically. Given how CIP and LEV adsorbed onto the surfaces of the adsorbents, negative S◦ for the Fe–Cu/Alg–LS adsorbent demonstrated that randomness declined at the solid–liquid interfaces, demonstrating that the adsorption was energetically stable [59]. For G◦ values under 80 kJ mol−1, the sorption was of a physical origin. However, if G◦ was between 80 and 400 kJ mol−1, it might have been chemical [60]. Table 4 shows the "G" values, which show that CIP and LEV sorption were of a physical origin. These results support the D-R isotherm.