**5. Clinical significance of molecular subtypes of bladder cancer**

Not only do clinical outcomes differ among the molecular subtypes, but also therapeutic response. The gold-standard for management of MIBCs for disease confined to the pelvis includes radical cystectomy preceded by platinum based neoadjuvant chemotherapy. Although a significant minority of patients treated this way achieves durable response and improved cancer specific survival, a sizeable fraction does not respond. In fact, a meta-analysis has suggested that there is only 5% absolute survival benefit at 5 years for patients treated in this manner [34]. In addition, concerns regarding delayed surgery and risk of serious morbidity have limited the usage rates of NACT for cystectomy patients at 25% or less [35, 36]. Biomarker tests

that predict chemo-response could address these problems by identifying patients most likely to benefit. In this regard, data suggests that NAC confers the greatest benefit in basal tumors [11, 29], while the "p53-like subtype" has been reported to confer chemo-resistance [13]. However, current ISUP working group guidelines of 2020 do not recommend routine subtyping to guide NACT [37].

Data published by the TCGA Consortium stated that about 69% of BCs contain potentially actionable therapeutic targets which associate with specific molecular subtypes [11]. Mutations and amplifications of FGFR3 are seen in 50–80% of superficial bladder cancers and up to 20% of MIBCs [19]. Luminal-papillary tumors demonstrate a high rate of these alterations [11]; however, clinical trials have not yet incorporated molecular classification to determine patient eligibility. Similarly PIK3CA is also a frequently mutant gene and therapies targeting PI3K pathway have also shown preclinical BC trials [38]. Other targets such as ERBB2 and TSC1 are also being investigated as therapeutic targets.

Molecular subtyping may also provide a guide to BC immunotherapy. Antiprogrammed death 1 (PD-1) and anti-programmed death-ligand 1(PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) are important second line therapies for MIBC with NAC failure. A few are also approved as first line therapy for cisplatin ineligible cases. Unfortunately, not all patients benefit from immunotherapy [39, 40]. Testing for biomarkers of response involves IHC for PD-1 or PD-L1 or estimation of tumor mutation burden, micro-satellite instability or immunemicroenvironment of the tumor. However, none of these biomarkers have shown overwhelming predictive efficacy over others [41–43]. The luminal infiltrated subtype in the TCGA 2017 subtyping system was found to be enriched in PD-L1, CTLA-4 and other immune signatures. In particular, although this subtype did not respond well to NACT, they showed good response to anti-PD-L1 and anti-PD-1 treatment. The basal subtype has also shown response to immunotherapeutic agents in addition to being sensitive to NACT [11, 29]. Molecular subtypes may thus help define patient selection for immunotherapy.

#### **6. Conclusion**

Compared to traditional classification of BCs, molecular subtypes provide more information regarding tumor biology, prognosis and treatment. In general, BC can be divided into luminal and non-luminal subtypes based on their degree of urothelial differentiation. The luminal subtype is further subdivided into those with papillary features, which are superficial, predominantly non-invasive. Though they carry good prognosis when compared to other treatment-naïve subtypes, they do not respond well to conventional NAC and may benefit from targeted therapies. The luminal infiltrated type has more inflammatory and stromal signatures. They are more invasive than luminal papillary tumors and may respond well to immunotherapies. Basal/squamous tumors express stem cell and squamous differentiation associated gene expression signatures. They are aggressive untreated, but respond well to NACT as well as immunotherapies but are insensitive to radiotherapy. The neural subtype forms a minority of non-luminal tumors with neuronal or neuroendocrine phenotype and usually carry poor prognosis but respond to NACT. There are an increasing number of molecular subtyping systems being constantly updated. While they carry great potential to reform BC prognostication and therapeutics, they are not entirely without limitations. Accessibility is a key issue in the present times. Molecular subtyping is mainly based on "static" research, especially in NMIBC, and enables a one-time detection and analysis of tumor specimens rather than "dynamic" tracking to over the disease course. It has also mainly focused *Molecular Classification of Bladder Cancer DOI: http://dx.doi.org/10.5772/intechopen.97393*

on genome and transcriptome research so far but proteomics and immune status of tumors are also closely related to their development. Therefore, the implementation of multiomics is a key necessity in future studies on molecular subtyping. Intratumor heterogeneity also provides another challenge with patient outcome being dominated by one subtype more than the other. With the rapid development of single-cell high-throughput sequencing, mass spectrometric analysis, immune cell analysis and other technologies, the accuracy of the molecular subtyping prediction system need further improvement. Compared to the existing classification system, molecular subtyping methods offer a more comprehensive analysis, particularly to guide adjuvant chemotherapy, targeted therapy and immunotherapy. In the future, these classifications will become an important complementary approach to traditional pathological classification.


**2. Systemic lupus erythematosus treatment**

#### **2.1 Antimalarials**

Antimalarials have been used for many years in the treatment of rheumatic diseases [1, 2]. Historically, antimalarials had been observed to ameliorate rheumatic symptoms in soldiers taking these drugs during World War II for the prevention of malaria [3]. Clinical application of hydroxychloroquine and chloroquine in the treatment of rheumatic diseases has been widely reported. The use of hydroxychloroquine in the treatment of SLE has been well established [4, 5]. It has been used in both discoid lupus and SLE [6]. Chloroquine and hydroxychloroquine increase pH within intracellular vacuoles and modify processes such as protein degradation by acidic hydrolases in the lysosome, organization of macromolecules in the

**113**

*Novel Therapeutic Interventions in Systemic Lupus Erythematosus*

reduces glucose levels via multiple mechanisms [18].

Corticosteroids have been used at large bolus doses as induction treatment as well as at small doses as maintenance treatment in patients with SLE [19] (**Figure 1**). They reduce disease activity as well as disease burden accrual on different organ systems [20]. Corticosteroids have potent immunomodulatory properties [21]. They are known to modulate all aspects of immune response and have strong immunosuppressive and anti-inflammatory properties [22, 23]. Their effects on the immune system are known to be mediated mainly by their trans repression mode of action, namely by their ability to reduce the expression of inflammatory transcription factors [24]. As corticosteroids are characterized by many severe and less severe side effects such as propensity to infections [25, 26], blood glucose elevation [27] and osteoporosis [28], different immunomodulating agents have been applied in patients with SLE as

Methylprednisolone pulse therapy is used for the treatment of severe manifestations of SLE. Intravenous pulses of prednisolone rapidly immunosuppress patients with organ and/or life-threatening manifestations of SLE [29, 30]. The gold standard is 1 g/day for 3-5 days [31]. However, this treatment schedule may be associated with significant infectious complications and lower doses may be useful as well. In particular, it has been shown that a lower dose pulse methylprednisolone treatment schedule involving <1500 mg/3 days may have the same beneficial effects

**2.2 Corticosteroids**

corticosteroid sparing agents.

endosomes, and post-translation modification of proteins in the Golgi apparatus. The antirheumatic properties of antimalarials is a consequence of their interference with antigen processing in antigen-presenting cells. For the digestion of antigenic proteins and for the peptides to assemble with the chains of the MHC class II proteins it is necessary to have acidic cytoplasmic compartments. Antimalarials increase the pH thereby diminishing the formation of peptide-MHC protein complexes which are required to stimulate CD4+ T cells and down-regulating the immune response against autoantigenic peptides [7, 8]. It also blocks Toll-like receptors on dendritic cells [9]. A review of controlled trials on the clinical efficacy and safety of antimalarials showed that adequate evidence exist for these drugs, in particular hydroxychloroquine in preventing lupus flares, increasing long term survival of patients and lupus activity in pregnant women without proven teratogenicity [10]. Moderate evidence exists for the prevention of irreversible organ damage, prevention of bone destruction and prevention of thrombosis. Weaker evidence exists for the reduction in severe lupus activity, lipid levels and subclinical atherosclerosis [11]. Hydroxychloroquine has been shown to improve glucose metabolism [12]. The toxicity of antimalarials is mild, infrequent and it is usually reversible. When given attention to dosage hydroxychloroquine has a safer profile. Ruiz-Irastorza et al recommended that hydroxychloroquine should be given to all patients with lupus during the full course of the disease [13]. They have described hydroxychloroquine as being the cornerstone of lupus treatment [13]. There have been very few efforts on discontinuation of the drug due to its proven efficacy and the few and mild side effects. Hydroxychloroquine has multiple beneficial effects in SLE. It reduces lipid levels, thereby inhibiting atherosclerosis [14, 15]. Hydroxychloroquine has multiple effects on cholesterol metabolism, as it inhibits cholesterol biosynthesis, inihibits lysosomal hydrolysis of cholesteryl ester and stimulates the capacity of LDL receptor and the activity of HMG-CoA reductase [16]. Hydroxychloroquine protects lupus patients from thrombosis, as it has known antithrombotic action. It reduces red blood sludging, blood viscosity, platelet aggregation and protects the annexin V "shield" from disruption by antiphospholipid antibodies [17]. Additionally, it

*DOI: http://dx.doi.org/10.5772/intechopen.97168*

#### *Novel Therapeutic Interventions in Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97168*

*Lupus - Need to Know*

**Figure 1.**

**Figure 2.**

applied in the treatment of severe SLE cases. Recently, the use of belimumab has been introduced in the treatment of SLE and is indicated in patients with nonrenal disease and renal disease not responsive to standard treatment. Although, recent advances in treatment have improved prognosis and life expectancy in lupus patients, much progress remains to be achieved. In the present chapter, the use of various treatment modalities for SLE will be discussed. Additionally, the use of

Antimalarials have been used for many years in the treatment of rheumatic diseases [1, 2]. Historically, antimalarials had been observed to ameliorate rheumatic symptoms in soldiers taking these drugs during World War II for the prevention of malaria [3]. Clinical application of hydroxychloroquine and chloroquine in the treatment of rheumatic diseases has been widely reported. The use of hydroxychloroquine in the treatment of SLE has been well established [4, 5]. It has been used in both discoid lupus and SLE [6]. Chloroquine and hydroxychloroquine increase pH within intracellular vacuoles and modify processes such as protein degradation by acidic hydrolases in the lysosome, organization of macromolecules in the

supplementary drugs will be reviewed.

*Agents contributing to the treatment of lupus nephritis.*

*Agents involved in systemic lupus erythematosus treatment.*

**2.1 Antimalarials**

**2. Systemic lupus erythematosus treatment**

**112**

endosomes, and post-translation modification of proteins in the Golgi apparatus. The antirheumatic properties of antimalarials is a consequence of their interference with antigen processing in antigen-presenting cells. For the digestion of antigenic proteins and for the peptides to assemble with the chains of the MHC class II proteins it is necessary to have acidic cytoplasmic compartments. Antimalarials increase the pH thereby diminishing the formation of peptide-MHC protein complexes which are required to stimulate CD4+ T cells and down-regulating the immune response against autoantigenic peptides [7, 8]. It also blocks Toll-like receptors on dendritic cells [9]. A review of controlled trials on the clinical efficacy and safety of antimalarials showed that adequate evidence exist for these drugs, in particular hydroxychloroquine in preventing lupus flares, increasing long term survival of patients and lupus activity in pregnant women without proven teratogenicity [10]. Moderate evidence exists for the prevention of irreversible organ damage, prevention of bone destruction and prevention of thrombosis. Weaker evidence exists for the reduction in severe lupus activity, lipid levels and subclinical atherosclerosis [11]. Hydroxychloroquine has been shown to improve glucose metabolism [12]. The toxicity of antimalarials is mild, infrequent and it is usually reversible. When given attention to dosage hydroxychloroquine has a safer profile. Ruiz-Irastorza et al recommended that hydroxychloroquine should be given to all patients with lupus during the full course of the disease [13]. They have described hydroxychloroquine as being the cornerstone of lupus treatment [13]. There have been very few efforts on discontinuation of the drug due to its proven efficacy and the few and mild side effects. Hydroxychloroquine has multiple beneficial effects in SLE. It reduces lipid levels, thereby inhibiting atherosclerosis [14, 15]. Hydroxychloroquine has multiple effects on cholesterol metabolism, as it inhibits cholesterol biosynthesis, inihibits lysosomal hydrolysis of cholesteryl ester and stimulates the capacity of LDL receptor and the activity of HMG-CoA reductase [16]. Hydroxychloroquine protects lupus patients from thrombosis, as it has known antithrombotic action. It reduces red blood sludging, blood viscosity, platelet aggregation and protects the annexin V "shield" from disruption by antiphospholipid antibodies [17]. Additionally, it reduces glucose levels via multiple mechanisms [18].

### **2.2 Corticosteroids**

Corticosteroids have been used at large bolus doses as induction treatment as well as at small doses as maintenance treatment in patients with SLE [19] (**Figure 1**). They reduce disease activity as well as disease burden accrual on different organ systems [20]. Corticosteroids have potent immunomodulatory properties [21]. They are known to modulate all aspects of immune response and have strong immunosuppressive and anti-inflammatory properties [22, 23]. Their effects on the immune system are known to be mediated mainly by their trans repression mode of action, namely by their ability to reduce the expression of inflammatory transcription factors [24]. As corticosteroids are characterized by many severe and less severe side effects such as propensity to infections [25, 26], blood glucose elevation [27] and osteoporosis [28], different immunomodulating agents have been applied in patients with SLE as corticosteroid sparing agents.

Methylprednisolone pulse therapy is used for the treatment of severe manifestations of SLE. Intravenous pulses of prednisolone rapidly immunosuppress patients with organ and/or life-threatening manifestations of SLE [29, 30]. The gold standard is 1 g/day for 3-5 days [31]. However, this treatment schedule may be associated with significant infectious complications and lower doses may be useful as well. In particular, it has been shown that a lower dose pulse methylprednisolone treatment schedule involving <1500 mg/3 days may have the same beneficial effects and fewer adverse effects, in particular severe infections [32]. An intensive treatment schedule of rituximab, cyclophosphamide and intravenous pulses of methylprednisolone has been applied with excellent results in patients with SLE and severe organ manifestations including nephritis [33]. Patients improved significantly and long-term immunosuppression other than prednisone 5 mg/day was avoided.

Corticosteroids in the form of prednisone daily as maintenance treatment for SLE patients has been applied for years. New data show that introducing lower initial doses of prednisone (<15 mg/day) and thereafter tapering to low doses of prednisone (5 mg/day or even lower) has been shown to be effective in SLE [34–36]. Mild flares can be managed with transient increases of prednisone up to 15 mg/day with rapid reduction. In moderate severe flares the use of pulse methylprednisolone 125 mg, 250 mg or 500 mg/day for three consecutive days is much more effective and less toxic than increasing oral prednisone to 0.5-1 mg/kg/day [32]. Rapid reduction from doses up to 30 mg/day prednisone should be performed to 5-2.5 mg/ day within few weeks. Immunosuppressive therapy should be started early in severe forms of the disease and when prednisone cannot be reduced to 5 mg/day or less.


**3.4 The signal's "scale of preference"**

In a bid to approve the genuineness of a sign, it was essential to take note of the effect of the unfavorable occasion on general wellbeing, as prior expressed. It is important to speedily distinguish the signs with significant general well-being effects or that might influence the advantage risk balance of the clinical items in the treated patients. To organize the size of inclination, the strength and consistency of proof ought to be thought of.

## *3.4.1 Methods of getting the scale of preference*


*Article* **Multilayer Detection of Network Steganography**

#### **Milosz Smolarczyk 1, Krzysztof Szczypiorski 1,2,\* and Jakub Pawluk 1**

Received: 19 November 2020; Accepted: 10 December 2020; Published: 12 December 2020

**Abstract:** This paper presents a new method for steganography detection in network protocols. The method is based on a multilayer approach for the selective analysis of derived and aggregated metrics utilizing machine learning algorithms. The main objective is to provide steganalysis capability for networks with large numbers of devices and connections. We discuss considerations for performance analysis and present results. We also describe a means of applying our method for multilayer detection of a popular RSTEG (Retransmission Steganography) technique.

**Keywords:** steganography; network security; steganography detection; steganalysis; machine learning; big data; IoT; pattern mining


**4. Endogenous salicylic acid**

#### **4.1 Background**

There were clear suggestions in the literature that SA and SU in urine might not all derive from diet, given their presence in the urine of subjects on restricted diets [9, 11]. In addition quantification of the contribution from fruit and vegetable consumption to circulating SA levels in man had demonstrated, using a sensitive and specific method that <20% of the variability derived from these sources [31]. So some circulating SA in aspirin-naïve or -free individuals may derive from other dietary sources or be of non-dietetic origin.

#### **4.2 SA in animal blood**

Blood samples, serum or plasma, were obtained from animals at London Zoo or the Department of Biological Services, University of Glasgow in accordance with

their approved codes of practice. The results (**Table 2**) showed that species regarded as primarily carnivorous had blood SA levels comparable to those measured in herbivores [28]. The highest levels detected were in the range associated

*Concentration of salicylic acid (SA) in the blood or body fluid of a variety of animals.*

*a*

**Table 2.**

**183**

*Mean concentration in five animals.*

*\*Red faced spider monkey. \*\*Fed only meat.  Combination of such published data, which met these criteria, together with their in-house analyses resulted in a database of 27 types of fruit, 21 vegetables, 28 herbs, spices and condiments, 2 soups and 11 beverages—expressed as median values to reflect the non-normal distribution of

*Relative contributions of different food groups to total salicylate intake of a Scottish population. Source: [29].*

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

Subsequently dietary intake was assessed by applying this salicylate database, using a validated questionnaire, to 237 healthy individuals age range (17–72) from Aberdeen [29]. Estimated median total salicylate intakes for men and women were

corrected for energy. Primary food sources of salicylates as shown in **Figure 2** were alcoholic beverages (22%), herbs and spices (17%), fruits (16%), non-alcoholic beverages including fruit juice (13%), tomato-based sauces (12%) and vegetables (9%). Salicylate intake was significantly (p < 0.001) and positively associated with

There were clear suggestions in the literature that SA and SU in urine might not all derive from diet, given their presence in the urine of subjects on restricted diets [9, 11]. In addition quantification of the contribution from fruit and vegetable consumption to circulating SA levels in man had demonstrated, using a sensitive and specific method that <20% of the variability derived from these sources [31]. So some circulating SA in aspirin-naïve or -free individuals may derive from other

Blood samples, serum or plasma, were obtained from animals at London Zoo or the Department of Biological Services, University of Glasgow in accordance with

4.42 and 3.16 mg/day respectively, a gender difference not sustained when

intakes of fibre, potassium, vitamin C and alcohol!

dietary sources or be of non-dietetic origin.

**4. Endogenous salicylic acid**

**4.1 Background**

**4.2 SA in animal blood**

**182**

the results.

**Figure 2.**

*Concentration of salicylic acid (SA) in the blood or body fluid of a variety of animals.*

their approved codes of practice. The results (**Table 2**) showed that species regarded as primarily carnivorous had blood SA levels comparable to those measured in herbivores [28]. The highest levels detected were in the range associated with aspirin use in man and only the crustacean body fluid samples examined did not contain SA.

Set against the **total** SA + SU levels the extent of the SU 13C6 labelling found might be considered surprising but could, as well as confirming the in vivo synthesis of

The protean actions of aspirin in animals and man are here, in a short review by JRL an GJB, set against what is known of the role of its SA precursor in earlier life forms.

This complex area is here only briefly overviewed in relation to its potential for

There are many kinds of bacterial siderophores but SA or one of its hydroxylated metabolites (2,3DHBA) are at the core of the aryl- capped molecules found in *E. coli* (Enterobactin); *Yersinia* sp. and *Klebsiella pneumoniae* (Yersinibactin); *Pseudomonas* sp.(Pyochelin); *Vibrio* sp. (Vibriobactin/Vulnibactin) and *Acinetobacter baumanii* (Acinetobactin) [34]. These authors described a probe for the initial aryl acid activation enzymatic step in the synthetic pathways of these "bactins" (*via a nonribosomal peptide synthetase pathway initiated by adenylation*) and suggested lack of human homologues makes this a potential drug target—but see Section 5.3.4. Intriguingly investigation into the bioinorganic chemistry of bacterial siderophores has revealed that many have functional capacities other than mere iron homeostasis. Examples include interactions with other metals such as zinc, copper and boron; signalling agents (referred to as "ferrimones") in the regulation of genes related to iron metabolism; protection—by those with catecholate structures—from oxidative stress and an antibiotic function in sideromycins [35].

Finally bacterial growth in the presence of salicylate can be both beneficial and detrimental. On the one hand an intrinsic multiple antibiotic resistance phenotype can be induced and on the other reduced resistance to some antibiotics might result and bacterial virulence factors may be affected [36]. While the in vivo consequences of these observations is speculative the findings highlight, the authors suggest, the ability of salicylate to alter gene expression; they claim that the only life

While salicylic acid (initially from plant sources) has been used in therapeutics for millennia detailed knowledge of its role in plants is relatively recent. Although plant phenolics are diverse and ubiquitous they were traditionally assumed to be unimportant secondary metabolites but SA in plants is a critical hormone playing a direct role in the regulation of many aspects of growth and development as well as

form not yet (then) shown to be affected by salicylate is the Archaea!

Para-aminosalicylic acid (PAS), the earliest truly effective anti-tuberculous agent, was long thought an analogue for para-aminobenzoic acid and so an inhibitor of folic acid biosynthesis. That was before the discovery of the mycobacterial siderophore (iron binding molecule) mycobactin, and that SA (also formed, as an extracellular metabolite, by mycobacteria in iron deficient conditions) is its direct precursor. It appears PAS primarily inhibits the conversion of SA into myobactin. Possible secondary roles for SA are the transfer of Fe2+ across the cell membrane, either for direct incorporation into various porphyrins and apoproteins, or for storage of iron within the cytoplasm in bacterioferritin (both roles also potential

SA, point to possible bioregulation of the levels of endogenous serum SA.

pointing to possible effects of SA preserved into animals.

**5. Salicylic acid in the biosphere**

*Salicylic Acid Sans Aspirin in Animals and Man DOI: http://dx.doi.org/10.5772/intechopen.91706*

**5.1 Bacteria**

targets for PAS) [33].

**5.2 Plants**

**185**

As some bacteria, notably *Mycobacterial*, *Yersinia* and *Pseudomonas* species, synthesise SA to enhance iron chelation (see Section 5.1) the possibility of a gastrointestinal particularly colonic, bacterial source for SA was assessed in two animal models. Pooled serum from six mice treated with neomycin 100 mg/kg/day for 4 days had a serum SA concentration which was, at 0.309 μmol/L, slightly higher than the level of 0.268 μmol/L measured in six untreated animals. Other measurements were done on serum samples from Sprague-Dawley rats delivered by caesarean section, raised in a sterile environment and fed sterilised food. A group of 8 such germ free animals had a pooled serum SA level which was, at 0.166 μmol/L, 2.5 greater than the level of 0.069 μmol/L in serum from a group of control animals [28].

#### **4.3 SA in diet-restricted and fasting human subjects**

A preliminary study followed serum SA and urinary SA + SU over 3 days on a water/milk diet (confirmed salicylate free on analysis) in a subject free of aspirin for at least 2 weeks. Excretion of SA + SU continued at a rate of 2.1 μmol/24 h throughout and serum SA did not fall—over the 72 h of the study—below 0.1 μmol/L (20 the limit of detection of the assay) [28].

In six patients who had total colectomy or rectal excision following standard preoperative bowel preparation low level serum SA (range 0.012–0.085 μmol/L) was detected and urinary SA + SU excretion persisted (median lowest level 0.613 μmol/ 24 h; range 0.184–7.607) in all subjects for up to 5 days postoperatively, rising only on refeeding [28]. These results also, of course, have some relevance to Section 4.2.

#### **4.4 SA formation from benzoic acid**

Benzoic acid (BA) is a natural constituent of plants, with high levels found in fruits and vegetables. In plants synthesis of SA derives—at least partially—from phenylalanine via cinnamic and benzoic acids. Prior work, using formula diet feeding, also demonstrated that hippuric acid, the main metabolite of BA, may be formed endogenously in man, while a Sprague-Dawley rat radiolabeled experiment showed phenylalanine as the likely precursor [32]. Sodium benzoate as a food preservative also contributes to human intake and very high doses have been used in hepatic encephalopathy. These considerations led us to determine whether addition of BA to a very carefully standardised diet produced any change in serum or urinary salicylates—see **Figure 1**.

A preliminary study, over 4 days in two subjects, suggested that BA, 1 or 2 g/day on days 3 and 4 might be associated with a modest increase in urinary SA + SU excretion. Subsequently a labelled study was undertaken over 3 days in six individuals (4 M, 2F) who received 1 g of uniformly ring-labelled 13C BA with each of their main meals on day 2. They replicated their carefully recorded day 1 diet throughout and had regular blood sampling with complete urine collections. The **total** SA + SU urinary excretion increased, but not significantly (p = 0.052) and only in the 8–16 h sample after the first dose of BA. While no 13C was detected in samples prior to ingestion of the BA, the 13C isotope was confirmed in the 8–16 h urine sample from all six subjects. Its presence was determined by preliminary GC fractionation before subjecting the relevant fractions to derivatization and GC–MS. The 13C isotope accounted, by selective ion monitoring, for 0.4–10.9% (median 3.4%) in the SA derivative and 6.8–43.1% (median 33.9%) in the SU derivative. In addition considerable amounts of the expected 13C6-labelled hippuric acid were found [28].

Set against the **total** SA + SU levels the extent of the SU 13C6 labelling found might be considered surprising but could, as well as confirming the in vivo synthesis of SA, point to possible bioregulation of the levels of endogenous serum SA.


**5. What are the improvements of social impairments in the treatments of patients with ASD?**

Social impairments in ASD have fundamentally different meanings from personality characteristics, such as introversion, interpersonal tension, or aloofness. Infants or preschool children with ASD may indicate very unique and impressive behaviors in the social context, which substantially reflect the disparity between typically developing children and children with ASD in social interaction. Here, we will describe pointing behaviors as an illustration.

When one points at something, others are invariably around. When one points at something, one invariably attempts to convey any information to others around. A toddler pulls his/her mother's sleeve, points to a miniature car on a shelf, and then looks at his/her mother's face (requesting pointing). When a preschool child sees a rainbow in the sky after rain, he/she runs up to his/her mother, takes her to the garden, and points to the rainbow while looking at her (declarative pointing). Liszkowski et al. found that twelve-month-old infants show different attitudes according to experimenter's reactions when infants point declaratively [47]. When experimenters responded to infants' declarative pointing but attended an incorrect referent with positive attitude, infants repeated pointing to redirect the experimenters' attention. When experimenters identified the correct referent with negative attitude, infants did not repeat pointing. When experimenters identified the correct referent and shared interest in it, infants appeared satisfied. Pointing is a prototypical behavior of interpersonal exchange, i.e., sociality.

102 Neuroendocrinology and Behavior

impairments [46].

**patients with ASD?**

behaviors as an illustration.

The Social Responsiveness Scale provides quantitative measurements of social impairments in ASD by assessing domain of sociality such as social awareness and social information processing [37], and has been used as an outcome measure for interventions [38, 39]. The Reading the Mind in the Eyes Test [36] measures an aspect of social cognition by having the subjects assess emotion through the look of an actor's eye in photographs and has been adopted in many experimental trials [35, 40]. The Diagnostic Analysis of Nonverbal Accuracy Scale measures receptive and expressive abilities for receiving and sending emotions in faces, gestures, postures, and prosody [41], and has been used in the researches of not only ASD [42] but also of other mental disorders [43]. The Childhood Autism Rating Scale helps to identify subjects with ASD and determine symptom severity and has been commonly used in research and clinical settings. The scale assesses various domains of symptoms in ASD, including social impairments. The Autism Diagnostic Observation Schedule is a tool for assessment of symptoms of ASD through structured and semistructured activities with subjects and provides scores in communication, social, and restricted and repetitive domains [44]. This tool has been regarded as the gold standard for assessing and diagnosing ASD. The Interaction Rating Scale Advanced assesses a practical index of social skills using five-minute video recorded interaction session [45]. It is interesting to note that this new tool may provide a validated measure of social impairments of ASD. The evaluations mentioned above provide quantitative values of social impairments

At present, there is no commonly used assessment of symptoms in ASD, especially social and communication domains, for any interventions in contrast to the Positive and Negative Symptom Scale in schizophrenia and Hamilton Rating Scale for Depression in major depressive disorder, which are widely used as almost definitive measures. In the wellknown research in which risperidone, a second-generation antipsychotic, was shown to be effective for reduction of irritability in subjects with ASD, the authors stated that they were unable to identify a validated measure for the core symptoms of ASD, i.e., social

A key question is whether these outcome measures could be used to sensitively assess improvements in sociality, which may only be subtle changes. This question remains

**5. What are the improvements of social impairments in the treatments of**

Social impairments in ASD have fundamentally different meanings from personality characteristics, such as introversion, interpersonal tension, or aloofness. Infants or preschool children with ASD may indicate very unique and impressive behaviors in the social context, which substantially reflect the disparity between typically developing children and children with ASD in social interaction. Here, we will describe pointing

of ASD based on caregivers' self-reports or behavioral observations.

unanswered before publication of the results of these trials.

Toddlers with ASD display a reduced incidence of declarative pointing compared to typically developing toddlers [48]. Declarative pointing constitutes a significantly diagnostic sign as well as social interest and joint attention for early detection of ASD [49]. Individuals with ASD have an innate disability in the social domain.

We consider that it would be essential to refer to one's own self and others if social impairments in ASD are discussed, because our own selves are embedded in a society full of others [20]. Individuals with ASD may be unable to mentalize the inner states of typically developing individuals, and this raises the question of whether typically developing individuals can mentalize the inner states of individuals with ASD. "Theory of mind" tasks would be regarded as tasks in ASD with "altered" self-consciousness proposed by individuals with "intact" self-consciousness.

According to the standpoint of traditional German psychopathology, self-consciousness (Ichbesstsein in German) is formally comprised of four prototypical representations. First, one's own self is identical at all times. Second, one's own self is always consistent. Third, all of one's own acts belong to one's own self. Finally, one's own self differs from others' own self. These representations deeply embedded in social interactions are intrinsically selfevident and underlie interpersonal exchange of sociality. While one exists almost without reflection on these representations in daily life, severe disruption of self-consciousness would have fairly serious consequences, such as dissociative identity crisis, doppelganger, xenopathic experiences and delusions of possession. Interestingly, children with ASD performed significantly less well on the self-test question than the other-person test question using tasks in which participants have to reflect an awareness of one's own prior belief [50]. These results suggest that individuals with ASD represent altered self-consciousness as mentioned above: "all of one's own acts belong to one's own self."

Although self-consciousness have been investigated using functional magnetic resonance imaging in ASD and healthy individuals [22, 23], the effects of OT on self-consciousness in humans have not been examined.

It is essential but difficult to answer questions regarding improvements of social impairments associated with treatment of patients with ASD. However, it may be useful to

assess self-consciousness, although there is as yet no suitable test to examine representations of self-consciousness available in ASD research.

Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder? 105

[3] Tobin VA, Douglas AJ, Leng G, Ludwig M (2011) The Involvement of Voltage-Operated Calcium Channels in Somato-Dendritic Oxytocin Release. PLoS one. 6: e25366. [4] Argiolas A, Melis MR (2005) Central Control of Penile Erection: Role of the

[5] Higashida H, Yokoyama S, Kikuchi M, Munesue T (2012) CD38 and its Role in Oxytocin

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**4.2. Development and validation of finite element fracture predictions with PUfoam based synthetic bones**

Acetabular fractures are one of the big challenges that trauma surgeons face today. Despite the great stride made in treating this fracture in the past few decades, one medical text book states that "fractures of the acetabulum remains an enigma to the orthopaedic surgeon(Tile et al., 2003)." The main reason for this difficulty lies on the complexity of acetabular fractures. Acetabular fractures are usually a result of indirect trauma where the major impact is transmitted via the femur after a blow to the greater trochanter, to the flexed knee or to the foot with the knee extended (Ruedi et al., 2007). Moreover acetabular fractures are dependent on a number of variables such as the type of force that caused the fracture, the direction of displacement, the damage to the articular surface as well as the anatomical types of the fracture (i.e. the shapes of the fragments). The relative rareness of acetabular fractures makes matters worse since general orthopaedic surgeons may not gain wide experience with them.

The past researches on acetabular fracture can be broadly divided into two categories. The first is experimental studies where the stability of different acetabular fracture fixation techniques was investigated with in-vitro mechanical experiments (Goulet et al., 1994, Konrath et al., 1998a, Konrath et al., 1998b, Olson et al., 2007). There are also clinical studies that examined the effectiveness and longer-term results of different fracture fixation techniques (Borrelli et al., 2005, Cole and Bolhofner, 1994, Giannoudis et al., 2005). Finite element (FE) models can enhance greatly the body of knowledge obtained from such experimental and clinical studies. FE models can overcome the limitations of in-vitro experimental studies because they can be used to simulate the behaviour of the fractured acetabulum under physiological loading conditions that include muscle forces. FE models can also elevate the results from clinical studies into a new dimension as they can be used to predict the outcome of particular fixation techniques after the surgery. If the model performance in fracture prediction is validated, it can be used to evaluate various fixation techniques depending on their fracture types. The problem is how to validate the model. If cadaver bone is to be used, the issue of sample variability and the requirement of ethics approval, special storage and high cost need to be resolved first. Therefore the aim of this study is to develop a finite element model of the pelvis that can accurately predict the fracture load and locations of acetabular fractures and validate its performance with synthetic PU-foam based bones(Shim et al., 2010).

#### *4.2.1. Fracture experiment with PU-foam synthetic pelvic bones*

182 Polyurethane

When the results from cancellous bone were compared with those from PU-foams, both showed surface fragmentation, continuous and discontinuous chip formations. During polyurethane foam cutting, chip types were influenced by rake angle and depth of cut. Bone cutting showed similar trend, however, resulting chip type were mainly influenced by the tool rake angle. We also identified the depth of cut that marked the transition from surface fragmentation to continuous or discontinuous chip types. In PU-foams, such a transition is indicated by a change in cutting forces. A similar trend was observed in bone; a depth of cut of 0.5 mm ~ 0.8 mm led to continuous or discontinuous chips. These values approximately correspond to the trabecular separation values. This is in accordance with our findings during the cutting of polyurethane foam, where depths of cut had to reach values of the

Therefore polyurethane foam was successfully used in identifying optimal parameters for designing minimally invasive bone graft harvester. The next section will describe how PU-

**4.2. Development and validation of finite element fracture predictions with PU-**

Acetabular fractures are one of the big challenges that trauma surgeons face today. Despite the great stride made in treating this fracture in the past few decades, one medical text book states that "fractures of the acetabulum remains an enigma to the orthopaedic surgeon(Tile et al., 2003)." The main reason for this difficulty lies on the complexity of acetabular fractures. Acetabular fractures are usually a result of indirect trauma where the major impact is transmitted via the femur after a blow to the greater trochanter, to the flexed knee or to the foot with the knee extended (Ruedi et al., 2007). Moreover acetabular fractures are dependent on a number of variables such as the type of force that caused the fracture, the direction of displacement, the damage to the articular surface as well as the anatomical types of the fracture (i.e. the shapes of the fragments). The relative rareness of acetabular fractures makes matters worse since general orthopaedic surgeons may not gain wide

The past researches on acetabular fracture can be broadly divided into two categories. The first is experimental studies where the stability of different acetabular fracture fixation techniques was investigated with in-vitro mechanical experiments (Goulet et al., 1994, Konrath et al., 1998a, Konrath et al., 1998b, Olson et al., 2007). There are also clinical studies that examined the effectiveness and longer-term results of different fracture fixation techniques (Borrelli et al., 2005, Cole and Bolhofner, 1994, Giannoudis et al., 2005). Finite element (FE) models can enhance greatly the body of knowledge obtained from such experimental and clinical studies. FE models can overcome the limitations of in-vitro experimental studies because they can be used to simulate the behaviour of the fractured acetabulum under physiological loading conditions that include muscle forces. FE models can also elevate the results from clinical studies into a new dimension as they can be used to predict the outcome of particular fixation techniques after the surgery. If the model performance in fracture prediction is validated, it can be used to evaluate various fixation

foam cell size diameter in order to be either continuous or discontinuous.

foam based synthetic bone was used in FE modeling of hip fracture.

**foam based synthetic bones**

experience with them.

Ten synthetic male pelves made with polyurethane foam cortical shell and cellular rigid cancellous bone (Full Male Pelvis 1301-1, Sawbones, Pacific Research Laboratories, INC, Washington, WA, USA) were used for fracture experiment. A similar set-up as (Shim et al., 2008) was used where the pelvis was placed upside down in a mounting pane filled with acrylic cement. Two different loading conditions – seating (or dashboard) fracture and fall from standing fracture – were tested. When the angle (α) between the vertical line and the line formed by joining the pubic tubercle and the anterior superior point of the sacrum (Figure 10) was 30 °, the whole set-up mimicked the standing position, hence simulating standing fracture. When the angle α was raised to 45°, the set-up mimicked the position of the pelvis when seated, hence simulating seating fracture. Force was exerted from the femoral head attached to the crosshead of the Instron machine (Instron 5800 series, Norwood, MA, USA). The femoral head was also from a matching Sawbone femur (Large Left femur 1130, Sawbones, Pacific Research Laboratories, INC, Washington, WA, USA) to the pelvis used. The femur was first chopped at the neck region and then attached to a custom made holding device connected to the crosshead of the Instron machine (Figure 10). The femoral head was dipped into liquid latex to ensure a complete and stable seating of the femoral head to the acetabulum. The force was applied from the femoral head to the acetabulum at a constant speed of 40N/s until failure. Total ten pelves were used for testing. Five were tested for standing fracture and the rest was tested for seating fracture. The fracture loads and patterns were recorded for comparison with finite element simulations

**Figure 10.** Photos of the experiment: The photo on the left shows the angle alpha that determined seating or standing positions; the center photo shows the close-up of the chopped femoral head attached to the holding device that goes into the crosshead of the Instron machine; the photo on the right shows the overall set-up.


**1. Introduction**

Pumps consume about 20% of the electricity generated worldwide [1]. Most of the life cycle cost of a pump is the cost of the electricity it consumes. Therefore, pumps are one of the most promising applications for the implementation of energy-saving technologies. At the same time, maintenance and repairs account for a significant part of the life cycle costs of a pump unit (Figure 1a). Therefore, when optimizing the total life cycle costs, in addition to the initial cost of equipment and electricity costs, it is necessary to take into account also the costs of maintenance and repairs, which are affected by the reliability of the pump [2]. It was shown in [3,4] that mean time between failure (MTBF) can be used to quantify pump reliability. In turn, MTBF depends on the deviation of the pump flow rate Q from the Best Efficiency Point (BEP, Figure 1b) [5,6].

Parallel pumps are widely used in many applications, such as when high flow rates or wide flow control ranges are required. When using parallel pumps, it is possible to significantly reduce all components of the life cycle cost of a pumping station, in comparison with a single-pump unit of the same rated power [3,7]. At the same time, due to a large number of variable parameters and the nonlinearity of such systems, the problems of optimizing the energy consumption of parallel pumps, taking into account the reliability and cost of the life cycle, are complex and still not considered very often in the literature.

Many studies analyze the energy consumption of parallel pumps, without taking into account their reliability. Thus, in [8], parallel operation of two pumps with the same rated head and different rated flow is investigated. It is shown that the overall efficiency of the system decreases with an increase in the ratio of the rated flow rates of individual pumps. This study compared the performance of 28 different combinations of the pumping system parameters. In [9], parallel operation of a multi-pump system consisting of four pumps is considered, in which the flow is regulated by three different methods (throttling, bypass

**Citation:** Oshurbekov, S.; Kazakbaev, V.; Prakht, V.; Dmitrievskii, V. Improving Reliability and Energy Efficiency of Three Parallel Pumps by Selecting Trade-Off Operating Points. *Mathematics* **2021**, *9*, 1297. https://doi.org/10.3390/math9111297

Academic Editor: Nicu Bizon

Received: 5 April 2021 Accepted: 3 June 2021 Published: 5 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

and speed control). A genetic algorithm and various optimization criteria were used to find the most economical control strategy. It was shown that the lowest energy consumption is achieved when the rotational speed of all pumps is simultaneously controlled at the same value. In [10], an optimization of the total cost of systems of three parallel and three serial pumps without rotational speed control is considered, taking into account the cost of the pump, pipeline and energy consumption. In [11], an optimization of energy consumption of a system of seven parallel pumps with various ratings, some of which are equipped with variable speed drive (VSD), is considered. In [12], energy consumption of three parallel pumps when changing the number of VSDs is compared. In [13], energy consumption of pumping systems with 2–4 parallel pumps without speed control is compared. In [14], a predictive control algorithm is proposed for a system of 3 parallel pumps, each of which is equipped with a VSD, which allows, based on look-up tables, to increase the system efficiency.

**Figure 1.** Pump statistics: (**a**) Components of the pump lifetime cost [2]; (**b**) Pump head (*H*), reliability (MTBF) and efficiency (η) curves versus flow rate *Q* [3].

Several works on parallel pumps consider not only energy consumption, but also the deviation of the pump operating points from the BEP. In [15], an optimization of the energy consumption of a system of two parallel pumps using a genetic algorithm is considered. The results show that the lowest energy consumption of the system is obtained by equalizing the flows of the two pumps. Furthermore, [15] compares the energy consumption of the two pumps equipped with a different number of VSD: one or two. It is shown that in the latter case, it is possible to achieve a lower energy consumption. The deviation of the operating point of the pumps from the BEP in various considered cases is compared, but not optimized.

In [6], an optimization of a single-pump unit is considered to increase its reliability using a genetic algorithm. However, some aspects were not taken into account: the optimization criterion is only the maximum reliability of the pump unit. Achieving a trade-off between reliability and power consumption is not considered. The study also does not consider the use of bypass regulation to obtain a better operating point. The static head in the hydraulic system is assumed to be zero, which also reduces the range of cases to which the results of this study are applicable.

In [16], a control strategy is proposed for a variable speed multi-pump system to reduce energy consumption. It was shown that the system of parallel pumps has the highest efficiency when the pumps operate at the same speed and flow rate than when one of the pumps operates at the rated speed and the speed of the other one is adjusted to obtain the required flow rate. It is also shown that in the former case, the deviation of the pump operating point from the BEP is less.

In [17], an analysis of a single-pump unit with a power rating of 11 kW is carried out and the issues of reducing energy consumption and increasing reliability are investigated. A trade-off regulation is proposed that provides good pump reliability with the energy consumption close to the minimum. The energy consumption is calculated for three cases: the conventional rotational speed regulation, regulation with maximum reliability and trade-off regulation. It is shown that when using the trade-off regulation, it is possible to significantly reduce the energy consumption of the pump unit in comparison with the case of maximum reliability, while maintaining all pump operating points in the preferred operating range with sufficient reliability.

In [3], an optimal trade-off control method using particle swarm optimization is proposed for a system of two identical parallel pumps, each equipped with a frequency converter (FC). The optimization parameters are the number of simultaneously operating pumps and the rotational speed of the pumps. The optimization criterion is the minimization of energy consumption. The deviation of the pump operating point from the BEP is used as an optimization constraint. It is assumed that both pumps rotate at the same speed at each operating point, and the throttle is used to regulate the flow in the common pipeline section of the parallel pumps. However, the results of this study are only applicable when the speed of both parallel pumps is controlled by VSD. Meanwhile, in practice, parallel pumping systems are often used in which some of the pumps do not have a VSD and are powered directly from the mains [18]. The literature overview carried out shows that not all configurations of parallel pump systems have been analyzed from the point of view of reliability. In particular, multi-motor pumping stations with a single frequency converter (multi-pump single-drive systems), which are also actively used in practice to reduce the total cost of a multi-pump system, were not considered.

This paper analyzes the effectiveness of applying the trade-off regulation method proposed in [17] to a system of 3 parallel pumps. This trade-off method is compared with the traditional regulation and regulation with maximum reliability proposed in [3]. In contrast to [3], a pumping system of the "multi-pump single-drive" type is considered, in which only one frequency converter is used to alternately drive several pump units (in this case, 3 units). Such systems are widely used in parallel pumping stations equipped with low-power electric motors. However, analysis of such systems is not very common in the literature [7].

In such pumping systems, one frequency converter controls two or more pumps. At the same time, in contrast to systems without a frequency converter, a smooth start-up of each pump unit and a smooth flow/pressure adjustment are ensured. In contrast to the case where each pump unit is equipped with an individual frequency converter, the capital cost of the system is significantly reduced. This advantage is especially important if the system uses low-power pump units, for which the cost of the frequency converter is the largest part of the total cost, as well as in systems containing a large number of pumping units [18,19].

Since in multi-pump single-drive systems it is possible to control the rotational speed of only one pump at a time, the load range of the pumps in such a system is significantly different from the case when each of the pumps is equipped with a VSD. Therefore, the conclusions carried out in [3] cannot be directly applied to the multi-pump single-drive systems.

Therefore, the contribution of this article is as follows: the effectiveness of the control principle, which provides a trade-off between reliability and energy efficiency, was theoretically verified in the case of a multi-pump single-drive system, which was not covered in previous studies on the topic.

It should be noted that many studies discuss the selection and setting of dynamic controllers for pumping systems [6,20–25]. Several studies show the effectiveness of fractional-order proportional-integral-derivative control (FOPID) [20] for improving the dynamics of complex non-linear pumping systems. Thus, [21] provides a theoretical and experimental comparative study of a simple single-pump system with different types of regulators, including PI, PID and FOPID. Several papers [22,23] show the advantages of the FOPID over conventional PIDs in controlling pumping systems that provide liquid level in a connected tank system. Further improvement of pumping system dynamics can be achieved by adding fuzzy logic to the FOPID [24,25].

Our paper does not discuss the selection and setting of dynamic controllers; however, it evaluates the benefits of applying the proposed approach to the selection of operating points for pumps in a multi-pump system. The novelty of the proposed approach is that it considers both the energy efficiency of the system and its reliability. At the same time, it is assumed that a controller is used that provides a satisfactory quality of transients.

Using the traditional mathematical model of parallel pumps and polynomial interpolation of data from the manufacturer's catalogs, the energy consumption and reliability of the considered multi-pump single-drive system using different regulation methods are compared. The conventional rotational speed regulation and the previously proposed method providing maximum reliability [6] are considered. The benefits of using the proposed trade-off regulation method for the considered pumping system are also evaluated.

The aim of this study is to develop a regulation method that increases the reliability of multi-pump single-drive systems, in which, as will be shown below, when using the traditional control method, individual pumps can operate for a long time in conditions that shorten their service life. Reliability issues have already been discussed in detail in the literature for both single pump systems and systems of parallel pumps, each of which is equipped with a frequency converter [3,6,15]. The objective of this study is a comparative analysis of a particular case of a pumping system consisting of three parallel low-power pump units, one of which is powered by a frequency converter and the other two are powered directly from the grid, using different control methods.

#### **2. Mathematical Equations of the System and Methodology of the Study**

The article uses the traditional analytical method of mathematical analysis of pumping systems, based on the calculation of *Q-H* (head versus flow) and *Q-P* (mechanical shaft power versus flow) characteristics, to analyze the performance of the pumping system with various regulation methods. The characteristics corresponding to the rated rotational speed are interpolated using polynomials according to the pump datasheet. The characteristics at the arbitrary rotational speed are calculated using the characteristics at the rated speed and the affinity laws [26]. This study examines the change in energy consumption of the considered multi-pump single drive system when applying to it various restrictions on the deviation of its operating points from the BEP curve which is also the maximum reliability curve.

The parallel pump system serves to provide the required flow rate *Qreq* with a constant static head *Hst* in an open hydraulic system from point *A* to point *B* (Figure 2) [26].

**Figure 2.** Hydraulic diagram of the pumping system.

Depending on the geometric dimensions of the pipelines (length, section, shape, etc.), the physical properties of the pumped liquid (density, viscosity, etc.) and the difference

in heights of the basins *A* and *B*, a curve of the hydraulic system is constructed, which is described by the Equation (1) [26]:

$$H\_{REQ} = H\_{ST} + k \cdot Q\_{REQ} \, ^2 \, \text{s} \tag{1}$$

where *HREQ* is the required hydraulic head; *HST* is the static head; *k* is the hydraulic friction coefficient.

Figure 3 shows the various characteristics of the hydraulic system. Curves labeled with 1 and 2 are the curves of the system at a non-zero value of the static head *HST* at different values of *k*. Numbers 3 and 4 mark the curves of the hydraulic system, at different values of *k* and *HST* = 0. Number 5 marks the dashed curve on which the BEP points lie at different pump speed (BEP curve). The maximum reliability and maximum efficiency of the pump are reached when the system curve matches the BEP curve (dashed curve 5 in Figure 3). The BEP curve is defined according to the affinity laws by the following equation [3]:

$$H = k\_{BEP} \cdot \underline{Q}^2 \,, \tag{2}$$

where *QBEP* and *HBEP* are the flow and the head of the pump at the BEP with *n* = *nrate*; *kBEP* = *HBEP/QBEP*. *QBEP* and *HBEP* are defined according to the pump datasheet.

The selection of the pump unit is carried out based on the maximum values of the required flow rate and head.

In practice, however, they do not match, and the pump operating point may be far from the BEP curve. Therefore, depending on the parameters of the hydraulic load curve (1), it is necessary to shift the pump operating point closer to the BEP curve to increase the pump reliability.

If the hydraulic system curve is located to the right of the BEP curve (as curve 4 in Figure 3), then to increase the pump reliability, it is necessary to regulate the water flow by adjusting the rotational speed and throttling [6]. If the hydraulic system curve is located to the left of the BEP curve (as curve 3 in Figure 3), then bypass also must be applied. However, the use of throttling and bypass along with the regulation of the pump rotational speed leads to additional energy consumption.

This study considers a hydraulic system with a curve like curve 2 in Figure 3. With this relationship between the system curve and the BEP curve, for maximum reliability, it is necessary to regulate the water flow by bypassing and throttling along with speed variation. It is assumed that in the considered parallel system centrifugal monoblock pumps Calpeda-B-50/12A with a power rating of 4 kW and a rated rotational speed of 2900 rpm are used. Table 1 and Figure 4 show the catalogue characteristics of this pump [27].

**Table 1.** Catalogue characteristics of centrifugal pump Calpeda-B-50/12A (4 kW, 2900 rpm).

**Figure 4.** Data sheet characteristics for the pump Calpeda-B-50/12A versus flow rate (**a**) head; (**b**) mechanical power; (**c**) efficiency [27].

The maximum required flow rate of the pumping system is *Qmax* = 120 m3/h. To simplify calculations, the *Q-H* pump characteristic and characteristic of the pump required mechanical power *P* = *f* (*Q, s*) are interpolated as polynomials with two variables of the 2nd and 3rd order, respectively [10]:

$$H = a \cdot \underline{Q}^{\cdot 2} + b \cdot \underline{Q} \cdot \text{s} + c \cdot \text{s}^{\cdot 2};\tag{3}$$

 to

$$P = \mathbf{c}\_0 \cdot \mathbf{Q}^{\;^3} + \mathbf{c}\_1 \cdot \mathbf{Q}^{\;^2} \cdot \mathbf{s} + \mathbf{c}\_2 \cdot \mathbf{Q} \cdot \mathbf{s}^2 + \mathbf{c}\_3 \cdot \mathbf{s}^3,\tag{4}$$

where *s = n/nrate* is the relative rotational speed; *a* = −0.0012, *b* = 0.166, *c* = 21.505, *c0* = −0.0047, *c*1 = −0.053, *c*2 = 60.76, *c*3 = 1449 are the coefficients of Equations (3) and (4). Figure 5 shows the pump *H-Q* curve at the rated speed (*nrate*), the hydraulic system andtheBEPTheBEPisdefinedaccordingEquation(2).

 curve

curve

 curve.

**Figure 5.** *Q-H* pump characteristic, hydraulic load characteristic and BEP curve.

#### **3. Calculation of Characteristics of the Pumping System at Different Methods of Regulation**

This section describes the results of calculating the characteristics of the pumping system under consideration with three considered regulation methods: maximum efficiency, maximum reliability and trade-off.

Due to the wide range of variation in water flow and head in a real pumping system, the pump operating point is very rarely near the BEP. However, to ensure an acceptable service life, the pump operating point must be in the so-called preferred operating region (POR). According to [5], the POR is located between the points 0.7·*QBEP* and 1.2·*QBEP* on the *Q-H* characteristic. This condition can be considered as a constraint when regulating the pumping system. Therefore, this paper compares the energy consumption of the pumping system in three cases:

In all three considered cases, when the flow rate changes from 0% to 40%, only the regulated pump runs, then the second (unregulated) pump turns on. When the flow rate reaches 80%, the third (unregulated) pump also turns on.

The rest of this section describes the results of calculating the pump operating points for each of the considered regulation methods.

#### *3.1. Characteristics of the Pumping System with the Maximum Efficiency Regulation (Conventional Speed Regulation)*

The rotational speed of the first pump in the parallel system can be adjusted. The speeds of the second and third pumps running in parallel are not adjusted. With this control, the operating points of the variable speed pump are along the hydraulic load curve ("head required" curve) and the operating points of the fixed speed pumps are along the catalog *Q-H* curve (Figure 6).

**Figure 6.** Operating points of the pumps when using the conventional rotational speed regulation.

The characteristics of the pumps when using this regulation method are determined as follows. The head of the variable speed pump *H*1 = *HREQ* is determined by Equation (1),the head of the unregulated pumps is determined by Equation (3), the pump mechanical power *P* is determined by Equation (4). The rotational speed of the variable speed pump *n* is determined by Equation (5) [7], the pump efficiency is determined by Equation (6) and the deviation of the operating point from the BEP is determined by the Equation (7):

$$m\_1 = m\_{\rm rate} \cdot \frac{-b \cdot Q\_1 + \sqrt{(b \cdot Q\_1)^2 - 4 \cdot c(a \cdot Q\_1^2 - H\_{\rm req})}}{2 \cdot c};\tag{5}$$

$$
\mathfrak{m}\_{\mathfrak{l}} = \mathfrak{g} \cdot \mathfrak{p} \cdot Q\_{\mathfrak{j}} \cdot H\_{\mathfrak{j}}/P;\tag{6}
$$

$$
\Theta\_{\rm j} = (Q\_{\rm j} - Q\_{BEP}) / Q\_{BEP\_{\prime}} \tag{7}
$$

where *g =* 9.81 m/s<sup>2</sup> is the gravitational acceleration; ρ = 1000 kg/m<sup>3</sup> is the water density; *Qi* and *Hi* are the flow and the head of *j*-th pump; ηj and θj are the efficiency and the operating poit deviation of *j*-th pump; *j* = 1 ... 3; *QBEP* = *f(n)* is the flow of the pump at BEP according the BEP curve Equation (2); *a*, *b* and *c* are coefficients from Equation (3).

Table 2 shows the calculation results for flow rate in the range from 10% to 100% of the maximum flow rate *Qmax* = 120 m3/h. In Table 2 and below the following characteristics of pumps 1–3 are indicated: *Q1* ... *Q*3 are their flow rates; *Qreq* = *Q*1 + *Q*2 + *Q*3; *H1* ... *H*3 are their hydraulic heads; *P1* ... *P*3 are their mechanical powers; *n1* ... *n*3 are their rotational speeds; PΣ = *P*1 + *P*2 + *P*3; η1*–*η3 are their efficiencies; θ 1 ... θ 3 are the deviations of the operating point of the pumps. From Figure 6 and Table 2, it can be seen that the estimated deviations θ exceed 30.8% and reach 63.9%, which are outside the POR in Table 2.

Such points with the large deviations occur at all stages of the flow regulation: when the required water flow is less than 20% of the *Qmax* (when only the first pump is running), at the flow rate in the range of 50–80% (the second pump turns on), and also when the flow rate is more than 80% (the third pump turns on). If the flow rate is below 0.7·*QBEP* pump operation may become unstable due to the flatness of the *Q-H* curve: a small deviation in the rotational speed leads to a large deviation in the flowrate. In addition, due to the unstable shape of the *Q-H* characteristic, the latter intersects the hydraulic system curve in two points which leads to the occurrence of a surge. In this case, the pump operates alternately in different operating points, the whole system is unstable, the loading on the pump changes and hydraulic shocks occur [28,29].

**Table 2.** The characteristics of the parallel pumping system using the conventional speed control.

#### *3.2. Characteristics of the Pumping System with the Maximum Reliability Regulation*

For maximum pump reliability, the operating points of the variable speed pump must be on the BEP curve (dashed line in Figure 3), and fixed-speed pumps must always run at the BEP point on the catalog pump *Q-H* curve, regardless of the required flow rate. This can only be achieved by using all three of the above-mentioned water flow regulation methods together.

As shown in Figure 6, variable speed pump operating points 1–3, 5–7 and 9–10 are located to the left of the BEP curve. To implement the condition of maximum reliability, these points are to move horizontally until they coincide with the BEP curve. All operating points of the fixed-speed pumps are also located to the left of the BEP curve. They need to be moved along the catalog *Q-H* curve up to the BEP. This means that the pump flow rate *Qi* will increase from *Qi'* to *QBEP* at the same head. Excess flow *Qi* − *Qi'* flows back through the bypass to the suction pipe, where. In this case *Qreq* = *Q1*- + *Q2*- + *Q3*- *.*

Points 4 and 5 are located to the right of the BEP curve. To move these points up to the BEP curve, at a constant flow rate *Qreq*, the head at the pump outlet must be increased by throttling (Figure 7).

**Figure 7.** Operating points of the pump when using the maximum reliability regulation.

The required head *Hreq* is determined by the Equation (1). *Hreq* is the same for all switched on pumps as they operate in parallel. The flow Q *j* and the head *H j* are determined by Equation (8) when regulating the bypass together with speed regulation or by Equation (9) when regulating only the pump rotational speed. The rest of the parameters are determined in the same way as in the previous section:

$$\mathcal{Q}\_{\rangle} = \sqrt{(\mathbb{H}\_{\text{req}}/\text{k}\_{\text{BEP}})}; \mathbb{H}\_{\text{j}} = \mathbb{H}\_{\text{req}}.\tag{8}$$

$$\mathbf{Q}\_{\rangle} = \mathbf{Q}\_{\text{req}\uparrow} \mathbf{H}\_{\text{j}} = \mathbf{k}\_{\text{BEP}} \cdot \mathbf{Q}\_{\text{req}\uparrow} \mathbf{2}\_{\text{A}} \tag{9}$$

where *Qreq* and *Hreq* are the required output flow and head; Q*j* and H*j* are the flow and head of *j*-th pump.

Table 3 shows the calculated characteristics of the pump system with the maximum reliability regulation. As the results in Figure 7 in Table 3 show, when the throttling and bypass are used in combination with the speed control, the maximum pump reliability can be achieved. Operating point deviation θ is zero.

**Table 3.** The characteristics of the parallel pumping system using the maximum reliability regulation.

The pump efficiency throughout the entire flow regulation range remains at its maximum (74.2%). However, power consumption increases compared to the conventional speed regulation due to the increase in *QPUMP* when using the bypass and the increase in *HPUMP* when using the throttling.

#### *3.3. Characteristics of the Pumping System with the Trade-Off Regulation*

It is also possible to apply a trade-off regulation method to reduce energy consumption and, at the same time, reach sufficiently high reliability. To achieve this, it is necessary to ensure that all pump operating points are located within the POR. According to Figure 6, when using only the speed control, points 1, 2 of the first regulated pump, points 5, 6 of the second pump and point 9 of the third pump are outside of the POR.

In this case, as in the case of the maximum reliability regulation, points 1, 2 of the first pump are moved horizontally but only to the right to the border of the POR (1.2·*QBEP* line) using a bypass (Figure 8). Furthermore, points 5, 6 of the second pump and point 9 of the third pump move along the *Q-H*-curve to the left border of the POR (0.7·*QBEP* line). Thus, all operating points are restricted by the POR. As in the previous case, *Hreq* is the

same for all switched on pumps as they operate in parallel and *Qreq* = *Q1*- + *Q2*- + *Q3*- *.* This ensures high reliability and low power consumption. Throttling is not applied in this case. The characteristics of pumps with the trade-off regulation are determined as follows. The required head of the variable speed pump *Hreq* is determined using Equation (1).

**Figure 8.** Operating points of the pumps when using the trade-off regulation.

The flow through the pump *Qj* and the head *Hj* are determined by Equation (10) with bypass regulation. The rest of the parameters are determined in the same way as in the case of the conventional speed regulation:

$$\mathbf{Q}\_{\mathbf{j}} = \sqrt{\langle H\_{\rm REQ}/k\_{0.7\,\rm{BEP}} \rangle};\\ H\_{\mathbf{j}} = H\_{\rm REQ}. \tag{10}$$

where *k0.7BEP* = *H*(0.7·*QBEP*)/(0.7·*QBEP*).

Table 4 and Figure 8 show the calculated characteristics of the pump system applying the proposed trade-off regulation. As the results in Table 4 show, with the proposed tradeoff regulation method, the efficiency of the pumps in the entire range of the flow control is not less than 68.8%. The flow deviation θ of the operating points from the BEP is no more than 30%, and the energy consumption is reduced compared to the maximum reliability regulation method.

**Table 4.** The characteristics of the parallel pumping system using the trade-off regulation.

#### **4. Comparison of Energy Consumption and Reliability of the Parallel System with Different Regulation Methods**

Figures 9–12 summarize the results of Tables 2–4. Figure 9 compares the flow rates of individual pumps with different control methods. With the maximum efficiency method, the flow of each pump is minimized, but the deviations of θ at some points are below the POR limit. When applying maximum reliability regulation, the pump flow is always increased by applying a bypass to keep all pumps running at the BEP. When applying the trade-off regulation, if θ < −30%, then the pump flow increases so that θ = −30%.

**Figure 9.** Comparison of flow rates of individual pumps with different regulation methods (**a**) pump 1 (*j* = 1); (**b**) pump 2 (*j* = 2); (**c**) pump 3 (*j* = 3).

Figure 10 compares the efficiency of individual pumps with different control methods. With the maximum reliability method, the efficiency of all pumps is always maximized since they always run at the BEP. However, the total energy consumption of the pumping system in this case is also maximum (Figure 11) since the additional energy consumption from throttling and bypass exceeds the benefit from improving the efficiency of the pumps.

Figures 11 and 12 compare the required mechanical power and the pump operating point deviation from BEP θ at the various regulation methods considered. Figure 11 shows that when using the maximum reliability regulation, the required mechanical power significantly increases compared to the conventional speed regulation due to the use of bypass and throttling. At the same time, when using the trade-off regulation, the required mechanical power only slightly increases at two operating points.

According to the proposed trade-off regulation principle, it is necessary to correct only the operating points which deviations θ are outside the POR boundaries (marked in red in Table 2). As Figure 6 and Table 2 show, most of the operating points of the three pumps are already within the POR when the "maximum efficiency" control is applied. Therefore, when the trade-of regulation is applied, most of the operating points remain

unchanged, in comparison with the maximum efficiency regulation method. In addition, 4 of 6 points with an unacceptable deviation θ have a deviation value of 30.8%, which is very close to the permissible limit value of 30%. Therefore, the correction of these points when using the trade-off regulation does not require significant additional energy consumption. Significant deviations θ only need to be corrected for the first pump (*j* = 1) at point 1 (*i* = 1) and for the second pump (*j* = 1) at point 5 (*i* = 5). This results in a very similar shape of the graphs for PΣ and θ in Figures 11 and 12. Only for the correction of operating points 1 and 5 significant additional power consumption is required, which is reflected in Figure 11d. Figure 12 shows that the proposed trade-off regulation maintains pump duty points within POR over the entire required flow range.

**Figure 10.** Comparison of efficiencies of individual pumps with different regulation methods (**a**) pump 1 (*j* = 1); (**b**) pump 2 (*j* = 2); (**c**) pump 3 (*j* = 3).

**Figure 11.** *Cont*.

**Figure 11.** Comparison of the mechanical power of the pumps with different regulation methods (**a**) pump 1 (*P*1); (**b**) pump 2 (*P*2); (**c**) pump 3 (*P*3); (**d**) sum of mechanical power (*P*Σ).

**Figure 12.** Comparison of deviations θ of individual pumps with different regulation methods (**a**) pump 1 (*j* = 1); (**b**) pump 2 (*j* = 2); (**c**) pump 3 (*j* = 3).

Based on the obtained results (Figure 11), the energy consumption of the parallel pumping system is compared when operating with a duty cycle corresponding to a typical open-type pumping system [26]. Figure 13 shows the diagram of the duty cycle. The duty cycle period is 24 h. Electricity consumption is compared at three regulation methods under consideration.

When calculating the electrical power consumption of a pump unit, it is also necessary to consider the characteristics of the components of its electric drive. It was assumed that Sinamics G120C frequency converter with the rated power of 4 kW [30] and Simotics 1LE1001-1CA6 induction motors with the power of 4 kW and rated speed of 2955 rpm [31] are used in the drive of the pump system. Data from SinaSave software [32] in 8 standard loading points are used to determine the power losses and efficiency of the drive (motor plus frequency converter) in the operating points with given values of the shaft torque

*T* and speed *n* that were calculated in the previous section (Tables 2–4). The standard loading points are determined according to IEC 61800-9-2, "Adjustable Speed Electrical Power Drive Systems—Part 9-2: Ecodesign for Power Drive Systems, Motor Starters, Power Electronics and Their Driven Applications—Energy Efficiency Indicators for Power Drive Systems and Motor Starters" [33]. These data are used because the standard [33] requires manufacturers to declare the loss values for variable frequency drives at these 8 operating points. Table 5 shows the results of calculating the losses in the electric drive using the SinaSave program at the standard points.

**Figure 13.** Flow-time diagram.

**Table 5.** Loss data for the 4 kW electric drive at the standard loading points.

In Table 5, *Trate drive* = 100% = 12.93 N·<sup>m</sup> is the rated torque of the electric drive; *nratedrive* = 100% = 2955 rpm is the rated rotational speed of the electric drive.

Using the data from Table 5, the sum of losses in the three pump drives ΔPΣ at the considered operating points (Tables 2–4) using polynomial interpolation [34,35] were found. The results of this calculation are shown in Table 6. Table 6 also shows the required total mechanical power PΣ from Tables 2–4.

**Table 6.** Results of the loss calculation in the electric drive of the pump system applying the different regulation methods.

Due to the results of calculating the mechanical power and interpolation of losses in the electric drive from Table 6, it can be concluded that the losses in the electric drive also make up a significant part of the energy consumption, about 20–30%, and strongly depend on the operating point of the pump. Therefore, the losses in the electric drive must also be taken into account when calculating the total energy consumption of the pumping system.

Using the results obtained (Tables 2–6), it is possible to calculate the electrical power consumed from the grid (*Pelec*), the daily consumed electrical energy (*Eday*), the annual consumed electrical energy (*Eyear*), the annual energy cost (*Cyear*) and the cost of energy over the entire life cycle of the pumping system (*CLLC*) [36]:

$$P\_{\text{clcc}} = \mathbf{P}\Sigma + \Delta\mathbf{P}\Sigma;\tag{11}$$

$$E\_{day} = \frac{t\_{\Sigma}}{1000} \cdot \sum\_{i=1}^{10} \left( P\_{elec}(i) \cdot \frac{t\_i}{t\_{\Sigma}} \right);\tag{12}$$

$$E\_{year} = E\_{day} \cdot \text{365};\tag{13}$$

*Cyear= EyearGT;* (14)

$$\mathcal{C}\_{\text{LCC}} = \sum\_{k=1}^{w} \left( \frac{\mathcal{C}\_{yeark}}{(1 + [y - p])^k} \right),\tag{15}$$

where PΣ is the mechanical power required by the pumps; ΔP is the loss in the electric drive; *t*Σ = 24 h is the whole operating period; *ti* is the operation time of *i*-th loading point; *GT* = 0.2036 €/kWh is the applied grid tariffs for non-household consumers for Germany in the second half of 2019 [37]; *Cyear* is the annual electricity cost; *Cyear k* is the annual electricity cost for *k*-th year; *y* = 0.06 is the interest rate; *p* = 0.04 is the expected annual inflation; *w* = 20 years is the lifetime of the pump system.

Annual and life cycle cost savings *Syear* and *SLCC* for a given regulation method compared to the maximum reliability method is calculated as:

$$S\_{y\text{near}} = \mathcal{C}\_{y\text{env}\text{ }\text{max. }reliab.} - \mathcal{C}\_{y\text{env}};\tag{16}$$

$$\mathcal{S}\_{LCC} = \mathcal{C}\_{LCC\\_max.\ rclinib.} - \mathcal{C}\_{LCC.'} \tag{17}$$

where *Cyear max. reliab.* is the annual energy cost with the maximum reliability control; *CLCC max. reliab* is the lifetime energy cost with the maximum reliability control.

*Syear* year *SLCC* percentage are calculated according to:

$$\text{Cs}\_{year} = 100\% \cdot \text{(\$C\_{year\ max.\ reliab.}\$ -- C\_{year})/C\$}\_{year\ max.\ reliab.'} \tag{18}$$

$$S\_{LCC} = 100\% \cdot \left( C\_{LCC\text{ max. relàab.}} - C\_{LCC} \right) / C\_{LCC\text{ max. relàab.}} \tag{19}$$

Tables 7 and 8 show the calculation results based on Equations (10)–(17).

**Table 7.** Results of the electric power calculation in the pump system at the different regulation methods.

**Table 8.** Results of the lifetime electricity costs in the pump system at the different regulation methods.

#### **5. Discussion and Results**

From the results obtained, as shown by the diagram in Figure 14, it can be concluded that the highest electrical power consumption is required for maximum reliability control under all considered load conditions. When applying trade-off regulation, a significant increase in electrical power consumption is required only at a flow rate of 10% and 50%.

**Figure 14.** Electric power depending on flow rate and regulation method.

Calculation of long-term energy indicators also confirms these conclusions. Figure 15 shows that the reduction in lifetime energy consumption compared to the maximum reliability method differs only slightly in cases of maximum efficiency regulation and tradeoff regulation (18% and 16.3%, respectively). At the same time, the trade-off method allows all pump operating points to be kept within the POR (Figure 12), which will significantly increase the reliability of the pumping system.

**Figure 15.** Energy savings: (**a**) Life-cycle energy cost depending on the regulation method; (**b**) life-cycle savings depending on the regulation.