Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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1. Introduction
Thermophiles are organisms that are capable of growing at temperatures above 55°C. Archaeal thermophiles generally grow at much higher temperatures and thus comprise most extreme thermophiles and hyperthermophiles. These thermophiles are attractive organisms in biotechnological applications because they produce thermostable enzymes, which can be used as stable industrial catalysts even at high temperatures. Thermophile cells themselves are attractive as hosts for microbial processes at high temperatures.
High-temperature processes have several advantages compared with moderate processes using mesophiles, where an important advantage is that high temperature prevents the growth of animal pathogens, including all viruses, which are killed or at least prevented from proliferating at temperatures above 65°C [1]. High temperature also inhibits growth and/or metabolism by mesophiles, which may hinder processes of interests via involuntary reactions. The advantage is especially important for processes using crude biomass (e.g., sewage, municipal or agricultural waste, and materials from animal farms) because mesophiles and virulent pathogens are common in biomass from natural environments and they may increase during reactions performed under moderate conditions. In addition, high temperature facilitates the removal of volatile products (e.g., ethanol and butanol) while decreasing oxygen solubility; therefore, thermophiles are practical for fermentative production of alcohols [2–6]. Moreover, thermophiles often have remarkable properties useful for bioprocesses. A good example is the hyperthermophilic archaeon Thermococcus kodakarensis KOD1, which can use protons as an electron accepter in catabolism to generate molecular hydrogen and has been studied as a hydrogen production tool [7].
In this chapter, we will demonstrate the salutary effects of plasmid curing on thermophiles using as an example a prokaryotic thermophile that was isolated from deep sea sediments of the Mariana Trench, Geobacillus kaustophilus HTA426 [8, 9]. Its growth occurs at temperatures ranging between 42 and 74°C, with optimal growth at 60°C, and is as rapid as Escherichia coli and Bacillus subtilis. Genetic tools are available for this strain [10–16]. The whole genome sequence has been determined [17], showing that G. kaustophilus HTA426 harbors the circular plasmid pHTA426 (Figure 1). Because the members of the genus Geobacillus include strains that are useful for high-temperature processes, as demonstrated by strains that are capable of degrading hydrocarbons [18], long-chain alkanes [19–21], biphenyls [22], paraffin-wax [23], or nylons [24], we have studied biotechnological applications of the genus using G. kaustophilus HTA426 as a model and pilot strain.
Figure 1.
Structure of pHTA426. Genes for possible and hypothetical proteins are indicated by solid and faded arrows, respectively. The plasmid contains possible genes responsible for plasmid replication (gkp02 and gkp36), DNA restriction–modification (gkp08 and gkp09), and integrase/transposase (gkp12 and gkp13).
Aiming to construct a plasmid-free strain that may be useful for the genetic analysis of pHTA426, this study was originally designed to eliminate this plasmid from an HTA426 derivative, G. kaustophilus MK244. The resultant strain MK633 was then characterized to confirm that plasmid elimination (termed plasmid curing) had no effects on its microbial properties, but the analysis unexpectedly demonstrated that G. kaustophilus MK633 had advantages compared with the parent strain MK244 in terms of several properties. We suggest here that plasmid curing is a promising approach for improving diverse thermophiles.
2. Experimental procedures
2.1. Bacterial strains and culture conditions
The bacterial strains employed are summarized in Table 1. G. kaustophilus MK244 was previously constructed from G. kaustophilus HTA426 [14]. If not specified otherwise, G. kaustophilus strains were grown at 60°C in Luria–Bertani (LB) and minimal media (MM) with rotary shaking at 180 rpm. MM comprised 0.3 g l−1 K2SO4, 2.5 g l−1 Na2HPO4⋅12H2O, 1 g l−1 NH4Cl, 0.4 g l−l MgSO4, 3 mg l−1 MnCl2⋅4H2O, 5 mg l−1 CaCl2⋅2H2O, 7 mg l−1 FeCl3⋅6H2O, 0.1% trace element solution [25], 10 mM Tris-HCl (pH 7.0), 1 g l−1 casamino acids, and 10 g l−1 D-glucose. The media also contained 5 mg l−1 kanamycin, 10 mg l−1 uracil, 50 mg l−1 5-fluoroorotic acid, 1 g l−1 yeast extract, and/or 50 mg l−1 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal), as necessary. E. coli strains were grown at 37°C in LB medium supplemented with appropriate antibiotics (50 mg l−1 ampicillin, 50 mg l−1 kanamycin, 13 mg l−1 chloramphenicol, and/or 7 mg l−1 tetracycline). The optical cell density at 600 nm was monitored automatically using an OD-MonitorA instrument (Taitec, Saitama, Japan).
Derivative of the MK244 strain; ΔpyrF ΔpyrR ΔhsdM1S1R1 Δ(mcrB1-mcrB2-hsdM2S2R2-mrr) pHTA426 (Δgkp09::PsigA-bgaB)
This study
MK244bgaB
Derivative of the MK244 strain; ΔpyrF ΔpyrR ΔhsdM1S1R1 Δ(mcrB1-mcrB2-hsdM2S2R2-mrr) gk0707::Pgk704-bgaB pHTA426
This study
MK633
Derivative of the MK244 strain; ΔpyrF ΔpyrR ΔhsdM1S1R1 Δ(mcrB1-mcrB2-hsdM2S2R2-mrr)
This study
MK633bgaB
Derivative of the MK633 strain; ΔpyrF ΔpyrR ΔhsdM1S1R1 Δ(mcrB1-mcrB2-hsdM2S2R2-mrr) gk0707::Pgk704-bgaB
This study
Table 1.
Bacterial strains used in this study. pUB307 mediates the conjugative transfer of oriT-containing plasmids. This plasmid contains kanamycin and tetracycline resistance genes. pIR207 is a chloramphenicol resistance plasmid derived from pACYCDuet-1 (Merck KgaA, Darmstadt, Germany). The plasmid was used to construct pIR408, which contains the hsdM1S1 and hsdM2S2 genes from G. kaustophilus HTA426, and thus, it is responsible for heterologous DNA methylation in E. coli [18]. G. kaustophilus MK244 lacks genes related to pyrimidine biosynthesis (pyrF and pyrR) and DNA restriction–modification (hsdM1S1R1, mcrB1, mcrB2, hsdM2S2R2, and mrr). PsigA-bgaB and Pgk704-bgaB denote bgaB expression cassettes under the control of PsigA [19] and Pgk704 promoters [21], respectively.
2.2. Plasmids
The E. coli-Geobacillus shuttle plasmids are summarized in Table 2. To construct the pGKE25-bgaB plasmid, a gkp09 downstream region of pHTA426 was amplified using the primers 5′-GGAGTTTGCCAAACTCCGGATCCAGCTTGGATTTATC-3′ (BamHI site underlined) and 5′-CACAAGCTTGGGGCTGGATGTAATG-3′ (HindIII site underlined), and a gkp09 upstream region was amplified using the primers 5′-GGCGGATCCTTCCGATTAGGTTCCCATGC-3′ (BamHI site underlined) and 5′-GGCGAATTCGGCCTTTTCGCATTAC-3′ (EcoRI site underlined). In addition, a bgaB expression cassette encoding thermostable β-galactosidase under the control of PsigA promoter was amplified from the pGAM47-bgaB plasmid [13] using the primers 5′-AAGATCTCTTCGCCTCATCCGCACGATTTC-3′ and 5′-GCCAGATCTCTAAACCTTCCCGGCTTCATC-3′ (BglII site underlined). The downstream region was cloned between the BamHI and HindIII sites of the pGKE25 plasmid [14], and the upstream region was cloned between the BamHI and EcoRI sites. The bgaB expression cassette was then cloned in the BamHI site of the resulting plasmid to yield pGKE25-bgaB for replacing the gkp09 gene in pHTA426 with the bgaB cassette. The pGAM48-bgaB plasmid [15] was used to integrate a bgaB expression cassette under the control of the Pgk704 promoter at the gk0707 locus in the G. kaustophilus chromosome. The pUCG18T plasmid [12] was used to assess the transformation efficiency of G. kaustophilus.
Plasmid
Relevant description
Reference
pGAM47-bgaB
pUC19 derivative; pUC replicon, oriT, bla, pyrF, PsigA-bgaB flanked by gk0707 upstream and downstream regions
E. coli-Geobacillus shuttle plasmids used in this study. bla and TK101 genes confer resistance to ampicillin in E. coli and kanamycin in G. kaustophilus, respectively. pyrF encodes orotidine-5′-phosphate decarboxylase in G. kaustophilus HTA426. oriT is the conjugative transfer origin. PsigA-bgaB and Pgk704-bgaB denote bgaB expression cassettes under the control of PsigA [19] and Pgk704 promoters [21], respectively. The pUC and pBST1 replicons allow autonomous plasmid replication in E. coli and G. kaustophilus, respectively.
2.3. Plasmid introduction into G. kaustophilus
Plasmids were introduced into G. kaustophilus by conjugative plasmid transfer from E. coli BR408 [12]. Briefly, an E. coli donor (10 ml) and a G. kaustophilus recipient (100 ml) were grown in LB media. The cells were subsequently mixed, centrifuged, and spotted onto LB plates. After incubation at 37°C for 20 h, the resultant cells were collected and incubated at 60°C on appropriate media to isolate G. kaustophilus transformants. The transformation efficiency, as the number of transformants per 106 recipients, was determined as described previously [12]. Data were expressed as the mean ± standard error (n = 3).
2.4. pHTA426 curing from G. kaustophilus MK244
The gkp09 gene in pHTA426 was replaced by a bgaB expression cassette using pGKE25-bgaB with pyrF-based counterselection [13]. The resultant clone, strain MK244′, was successively cultured three times in LB media supplemented with 20 µM acridine orange to facilitate pHTA426 curing. In each culture, an aliquot (103 cells) was grown on LB plates supplemented with X-gal to identify candidates from which pHTA426 was eliminated along with the bgaB cassette. The candidates were purified using LB plates with X-gal.
2.5. Southern blot
Total DNA (25 µg) was digested using EcoRV and separated on an agarose gel by electrophoresis. DNA was transferred onto a nylon membrane and hybridized with digoxigenin-labeled DNA probes to detect the bgaB and gkp30 regions. Probes were synthesized using PCR DIG Probe Synthesis Kit (Roche, Basel, Switzerland) using the primers 5′-GCCGGATCCTGTTATCCTCAATTTGTTAC-3′ and 5′-GCCGGATCCTGTTATCCTCAATTTGTTAC-3′ (for bgaB probe) and 5′-CCGATATAGGCTGAGAACGC-3′ and 5′-CAGCTGGTAGACATGGGG-3′ (for gkp30 probe). Hybridized DNA was detected with the chromogenic method using DIG Nucleic Acid Detection Kit (Roche).
2.6. Construction of G. kaustophilus MK244bgaB and MK633bgaB
A bgaB expression cassette under the control of the Pgk704 promoter was integrated at the gk0707 locus in G. kaustophilus using pGAM48-bgaB, as described previously [15]. G. kaustophilusMK244 and MK633 were subjected to this process to generate strains MK244bgaB and MK633bgaB, respectively.
2.7. BgaB assay
G. kaustophilus MK244bgaB and MK633bgaB were cultured for 4 h in MM containing yeast extract but not D-glucose or casamino acids, and then for 20 h in the presence of 10 g l−1 maltose. Cells were subsequently harvested, sonicated in 50 mM sodium phosphate (pH 6.0), and clarified by centrifugation to obtain a lysate. The reaction mixture (100 µl) contained 50 mM sodium phosphate (pH 6.0), 2 mM p-nitrophenyl-β-D-galactopyranoside, and the lysate. The mixture was incubated at 60°C to react and then diluted with ice-cold 2 M sodium carbonate (900 µl) to terminate the reaction. p-Nitrophenol liberated in the mixture was quantified based on the absorbance at 405 nm and using an experimentally derived standard curve. One unit was defined as the amount of enzyme required to generate 1 µmol of p-nitrophenol per min. Proteins were quantified by the Bradford method using a protein assay kit (Nacalai Tesque, Kyoto, Japan). Data were expressed as the mean ± standard error (n = 4–5).
2.8. Plasmid stability assay
G. kaustophilus harboring pUCG18T was precultured in LB medium with kanamycin until the optical cell density at 600 nm reached 0.5. An aliquot (200 µl) was then cultured in LB medium (20 ml) without kanamycin until the stationary phase. The resultant cells were incubated on LB plates with or without kanamycin to determine the concentrations of kanamycin-resistant and viable cells, respectively. The plasmid retention rate was defined as the number of kanamycin-resistant cells per viable cells. Data were expressed as the mean ± standard error (n = 3).
2.9. Cell density assay
G. kaustophilus cells were cultured in LB medium until the stationary phase. Cells were harvested by centrifugation and analyzed to determine the wet weight. Data were expressed as the mean ± standard error (n = 4–5).
2.10. Mutation frequency assay
The frequency of spontaneous mutations was assessed based on the generation of rifampicin- and streptomycin-resistant cells via rpoB and rpsL genes, respectively [26]. G. kaustophilus (103 cells) was cultured at 60°C in LB medium until the stationary phase. The resultant cells were then incubated on LB plates with or without efficacious rifampicin or streptomycin (10 mg l−1) to determine the concentrations of mutant (rifampicin- or streptomycin-resistant) and viable cells, respectively. The colonies were counted to calculate the ratio of mutant cells relative to the viable cells incubated, which was defined as the mutation frequency. Data were expressed as the mean ± standard error (n = 3).
2.11. Nucleotide stability assay
Deoxyribonucleoside triphosphates (1 mM) were incubated for 24 h in 20 mM sodium phosphate (pH 7.0) at 30, 60, 80, and 90°C. The residual nucleotides in samples (5 µl) were analyzed using reversed-phase high-performance liquid chromatography. The chromatography system comprised solvent delivery units (LC-10AT; Shimadzu, Kyoto, Japan), an ultraviolet absorption detector (SPD-10Avp; Shimadzu), a reverse-phase column (Cosmosil 2.5C18-MS-II; Nacalai Tesque), and a column bath at 30°C. Solvents A and B comprised 5 mM tetrabutylammonium bromide in 20 mM sodium phosphate (pH 7.0) and 90% (v/v) acetonitrile in water, respectively. After injecting the sample into a column that had been equilibrated with 15% solvent B, the column was isocratically developed at a flow rate of 0.5 ml min−1 for 1 min and then at a linear gradient of 15–60% solvent B over 15 min. The chromatogram was obtained by detection at 260 nm.
2.12. Genome data mining
Genome data were collected from the GenBank database (https://www.ncbi.nlm.nih.gov/genome) in December 2016. The collection was performed for bacterial thermophiles (Geobacillus spp.), bacterial mesophiles (B. subtilis), archaeal thermophiles (Pyrobaculum, Pyrococcus, Sulfolobus, and Thermococcus spp.), archaeal mesophiles (Haloarcula, Halococcus, Haloferax, and Halorubrum spp.), and archaeal methanogens (Methanobacterium, Methanobrevibacter, Methanocaldococcus, Methanocella, Methanococcoides, Methanococcus, Methanocorpusculum, Methanoculleus, Methanofollis, Methanogenium, Methanohalophilus, Methanolacinia, Methanolinea, Methanolobus, Methanomassiliicoccus, Methanomethylovorans, Methanomicrobium, Methanoplanus, Methanoregula, Methanosaeta, Methanosalsum, Methanosarcina, Methanosphaerula, Methanothermobacter, Methanothermococcus, Methanothermus, Methanotorris, and Methermicoccus spp.). The growth temperatures of archaeal methanogens were based on the Methanogens database (http://metanogen.biotech.uni.wroc.pl). Genome sizes were expressed as the mean ± standard deviation.
3. Results
3.1. Genetic features of the pHTA426 plasmid
The pHTA426 sequence suggested that the plasmid was a large circular plasmid (47.9 kb) comprising 1.3% of the circular chromosome of G. kaustophilus HTA426 (3.54 Mb) and that it encoded possible proteins for plasmid replication (gkp02) and plasmid partition (gkp36). A partition system has a role in the stable transmission of single-copy plasmids during cell division, so pHTA426 appeared to be present as a single copy in G. kaustophilus HTA426. In addition, the plasmid contained genes for a type II restriction–modification system, which was homologous to the AlwI restriction-modification system (gkp08 encoding methyltransferase and gkp09 encoding endonuclease). A type II restriction-modification system generally comprises an endonuclease and methyltransferase, where the endonuclease cuts exogenous DNA at specific sites, but not endogenous DNA that has been methylated by methyltransferase. In the AlwI system, AlwI methyltransferase is responsible for 5′-GG6mATC-3′ and 5′-G6mATCC-3′ methylation (6mA, N6-methyladenin), whereas AlwI endonuclease cuts 5′-GGATC-3′ and 5′-GATCC-3′ sites but not 5′-GG6mATC-3′ and 5′-G6mATCC-3′ sites. Because plasmids carrying a type II restriction-modification system have greater segregational stability [27], it is likely that the gkp08–gkp09 system contributes to the stable maintenance of pHTA426.
3.2. Construction of G. kaustophilus MK633
Figure 2A shows the process employed to eliminate pHTA426 from G. kaustophilus MK244. To facilitate plasmid curing and readily identify positive clones from which pHTA426 was eliminated, the gkp09 gene was preliminarily replaced by a bgaB expression cassette using pGKE25-bgaB. The resultant strain MK244′ was then cultured successively in the presence of a DNA intercalator, and we screened for positive clones by using the X-gal degradation assay. Fortunately, one positive clone was obtained from the first culture but not from the second culture. From the third culture, 24 positive clones were identified, which suggests that three successive rounds of culture were effective for pHTA426 curing. The positive clone obtained from the first culture was designated as G. kaustophilus MK633.
Figure 2.
Construction of G. kaustophilus MK633. (A) Schematic representation of pHTA426 curing from G. kaustophilus MK244. The gkp09 gene in pHTA426 was replicated by the bgaB expression cassette (PsigA-bgaB) to generate strain MK244′. The plasmid pHTA426 (Δgkp09::PsigA-bgaB) in strain MK244′ was subsequently eliminated using acridine orange. The positive clones from which pHTA426 was eliminated, including strain MK633, were identified using the X-gal degradation assay. (B) X-gal degradation assay. G. kaustophilus strains MK244 (1), MK244′ (2), and MK633 (3) were grown at 60°C on LB plates with (+) or without (−) X-gal. (C) DNA methylation assay of MK244, MK244′, and MK633 chromosomes. Total DNA from the strains was digested with restriction enzymes (1, none; 2, DpnI; 3, AlwI) and analyzed by agarose gel electrophoresis. (D) Southern blot analysis of pHTA426. Total DNA from strains MK244 (1), MK244′ (2), and MK633 (3) was digested with EcoRV, and detected by bgaB (left panel) and gkp30 probes (right panel).
G. kaustophilus MK244′ degraded X-gal to form blue colonies on LB plates with X-gal, whereas strains MK244 and MK633 did not (Figure 2B). This suggests that strain MK633 lacked the bgaB gene. The MK633 chromosome is resistant to DpnI (which digests 5′-G6mATC-3′ but not 5′-GATC-3′)but sensitive to AlwI (see above), in contrast to the chromosomes from strains MK244 and MK244′ (Figure 2C), so it is likely that strain MK633 lacked the gkp08 gene encoding an AlwI methyltransferase homolog. Southern blot analysis (Figure 2D) confirmed that strain MK633 lacked the bgaB and gkp30 genes, which are located on opposite sides of pHTA426 (Δgkp09::PsigA-bgaB). Based on these results, we concluded that G. kaustophilus MK633 lacked pHTA426.
3.3. Microbial properties of G. kaustophilus MK244 and MK633
G. kaustophilus MK244 and MK633 were characterized in detail (Table 3). Both strains grew in LB and MM with comparable doubling times. The difference in their mutation frequencies was also not significant. However, strain MK633 was more transformed efficiently with pUCG18T than strain MK244 and it maintained the plasmid with higher stability. Moreover, strain MK633 grew at higher cell densities than strain MK244. The cell density of G. kaustophilus MK244′ was lower than that of strain MK633 at 60°C (0.30 ± 0.03 g wet), but the pUCG18T retention rate was comparable (43 ± 14%).
MK244
MK633
Transformation efficiency (per 106recipients)
E. coli BR397 donor
<1
300 ± 75
E. coli BR398 donor
55 ± 17
22 ± 3
E. coli BR408 donor
87 ± 14
34 ± 14
Mutation frequency (per 106cells)
Rifampicin resistance
12 ± 2
42 ± 8
Streptomycin resistance
7 ± 4
7 ± 2
Doubling time in LB medium (min)
50°C
47 ± 6
42 ± 2
60°C
23 ± 2
21 ± 3
70°C
38 ± 7
32 ± 5
Doubling time in MM medium (min)
50°C
100 ± 9
130 ± 20
60°C
83 ± 6
89 ± 2
70°C
ND
ND
pUCG18T retention rate (%)
50°C
6 ± 3
58 ± 7
60°C
6 ± 4
79 ± 9
70°C
1 ± 1
64 ± 2
Cell yield (g wet weight per 20 ml culture)
50°C
0.41 ± 0.01
0.41 ± 0.01
60°C
0.30 ± 0.03
0.36 ± 0.01
70°C
0.38 ± 0.03
0.41 ± 0.01
Table 3.
Microbial properties of G. kaustophilus MK244 and MK633. Analyses were repeated more than three times. Data represent the mean ± standard error. ND, growth was not observed within 2 days.
When cultured at 60°C, strain MK633bgaB produced 220 ± 20 units of BgaB, whereas strain MK244bgaB produced 140 ± 10 units (Figure 3A). BgaB was also produced more abundantly by MK633bgaB at 50 and 70°C. Moreover, G. kaustophilus MK633bgaB had advantages in terms of the cell yield per culture (Figure 3B), protein yield per culture (Figure 3C), and BgaB-specific activity (Figure 3D). The higher specific activity suggests that MK633bgaB enhanced the BgaB productivity per cell.
Figure 3.
BgaB production by G. kaustophilus MK244bgaB and MK633bgaB. These strains were cultured at 50, 60, and 70°C in medium (100 ml) and analyzed to determine the total activity in terms of intracellular BgaB (A), cell weight (B), intracellular total protein (C), and BgaB-specific activity (D). Data are expressed as the mean ± standard error (n = 4–5).
3.4. Nucleotide stability
In bacteria and Archaea, DNA replication proceeds in cytosol (approximately at pH 7) using deoxyribonucleoside triphosphates as the building blocks. To assess their thermolability in cytosol, deoxyribonucleoside triphosphates (i.e., dATP, dCTP, dGTP, and dTTP) were treated at high temperatures and analyzed to determine residual amounts relative to those after incubation at 30°C. Most nucleotides were instable at 60°C (residual ratio: dATP, 68%; dCTP, 70%; dGTP, 71%; and dTTP, >99%). All of the nucleotides were clearly degraded into other forms when incubated at 80°C (dATP, 10%; dCTP, 26%; dGTP, 12%; and dTTP, 15%) and were completely degraded at 90°C (residual ratio, <0.2%). This suggests that the deoxyribonucleoside triphosphates are physicochemically unstable in the thermophiles.
3.5. Archaeal thermophiles: Smaller genomes
Genomic data were analyzed to compare the genome sizes of thermophiles (capable of growing at > 55°C) and mesophiles (capable of growing at 20–55°C). The genomes of thermophilic bacteria Geobacillus spp. (3.4 ± 0.3 Mb; n = 57) were smaller than those of phylogenetically related mesophiles, e.g., B. subtilis (4.1 ± 0.3 Mb; n = 100). The results were similar for archaeal methanogens, in which thermophiles had smaller genomes (1.7 ± 0.6 Mb; n = 20) than mesophiles (2.6 ± 0.8 Mb; n = 57). Archaeal thermophiles, such as Pyrobaculum (2.2 ± 1.6 Mb; n = 4), Pyrococcus (1.8 ± 0.1 Mb; n = 5), Sulfolobus (2.5 ± 0.2 Mb; n = 5), and Thermococcus (2.0 ± 0.1 Mb; n = 18) members, have much smaller genomes compared with archaeal mesophiles, such as Haloarcula (3.6 ± 1.2 Mb; n = 9), Halococcus (3.6 ± 0.4 Mb; n = 7), Haloferax (3.7 ± 0.4 Mb; n = 6), and Halorubrum (3.1 ± 0.8 Mb; n = 13) members. These data suggest that the thermophiles, especially archaeal thermophiles, tend to have smaller genomes than mesophiles.
3.6. Distribution of plasmids in archaeal thermophiles
Data mining showed that many thermophiles harbored plasmids, although not the majority. In Archaea, plasmids were identified frequently in Sulfolobus spp. (14 strains) and Thermococcus spp. (11 strains): pARN3 (26.2 kb), pARN4 (26.5 kb), pHEN7 (7.8 kb), pHVE14 (35.4 kb), pING1 (24.6 kb), pKEF9 (28.9 kb), pLD8501 (26.6 kb), pRN1 (5.4 kb), pRN2 (7.0 kb), pSOG1 (29.0 kb), pSOG2 (26.0 kb), pSSVx (5.7 kb), pXZ1 (7.0 kb), and pYN01 (42.2 kb) in Sulfolobus islandicus; pIT3 (5.0 kb), pMGB1 (28.0 kb), and pSSVi (5.7 kb) in Sulfolobus solfataricus; pTBMP1 (54.2 kb) in Thermococcus barophilus; an unnamed plasmid (3.6 kb) in Thermococcus eurythermalis; pTN1 (3.6 kb), pTN2 (13.0 kb), and pTN3 (18.3 kb) in Thermococcus nautili; an unnamed plasmid (49.1 kb) in Thermococcus peptonophilus; and pAMT7 (8.6 kb), pAMT11 (20.5 kb), pCIR10 (13.3 kb), pEXT9a (10.6 kb), pIRI33 (11.0 kb), pIRI48 (13.0 kb), and pT26-2 (21.6 kb) in Thermococcus spp. The other plasmids identified in archaeal thermophiles are as follows: pDSM2661_1 (58.4 kb) and pDSM2661_2 (16.6 kb) in Methanocaldococcus jannaschii; pMTBMA4 (4.4 kb) in Methanothermobacter marburgensis; pFV1 (13.5 kb), pFZ1 (11.0 kb), pME2001 (4.4 kb), and pME2200 (6.2 kb) in Methanothermobacter thermautotrophicus; pMETOK01 (14.9 kb) in Methanothermococcus okinawensis; pGT5 (3.4 kb) in Pyrococcus abyssi; and pTA1 (15.7 kb) in Thermoplasma acidophilum. In addition, several cryptic plasmids have been identified in archaeal thermophiles [28].
Plasmids are also distributed in bacterial thermophiles. In Geobacillus spp., seven strains of Geobacillus spp. harbored plasmids: pGS18 (plasmid length, 62.8 kb), pSTK1 (1.9 kb), pTB19 (11.9 kb), and an unnamed plasmid (21.7 kb) in Geobacillus stearothermophilus; pLW1071 (57.7 kb) in Geobacillus thermodenitrificans; pLDW-1 (48.7 kb) in Geobacillus thermoleovorans; and pBt40 (39.7 kb) in Geobacillus sp. In Thermus spp., 12 strains were identified as plasmid carriers. Their plasmids include pTA14 (14.4 kb), pTA16 (16.6 kb), pTA69 (69.9 kb), and pTA78 (78.7 kb) in Thermus aquaticus; pTB1 (342.8 kb) and pTB2 (10.3 kb) in Thermus brockianus; pTHEOS01 (271.7 kb) and pTHEOS02 (57.2 kb) in Thermus oshimai; pTP143 (143.3 kb) in Thermus parvatiensis; pTSC8 (8.4 kb) in Thermus scotoductus; and pTF62 (10.4 kb), pTHTHE1601 (440.0 kb), pTT8 (9.3 kb), pTT27 (232.6 kb), pTTJL1801 (265.9 kb), pTTJL1802 (142.7 kb), and pVV8 (81.2 kb) in Thermus thermophilus. In Parageobacillus thermoglucosidans, pGEOTH01 (80.8 kb), pGEOTH02 (19.6 kb), pNCI001 (83.9 kb), and pNCI002 (47.9 kb) were identified.
4. Discussion
In this study, we analyzed the effects of plasmid curing on thermophiles by characterizing G. kaustophilus MK244 and MK633 (Table 3 and Figure 3). Both strains exhibited comparable growth at 50–70°C in LB and MM; therefore, pHTA426 had no positive effects on cell growth under standard conditions. The mutation frequencies were largely comparable between strains MK244 and MK633, although G. kaustophilus MK633 lacked the gkp08 gene responsible for dam-like methylation (5′-GG6mATC-3′and 5′-G6mATCC-3′) and the dam methylation (5′-G6mATC-3′) is essential for DNA mismatch repair in E. coli [29]. In B. subtilis 168, DNA mismatch repair only involves mutS and mutL products, which do not depend on DNA methylation [30, 31], thereby suggesting that G. kaustophilus may use a mismatch repair system similar to the B. subtilis system rather than the E. coli system. In fact, the G. kaustophilus genome [17] contains mutS and mutL but not mutH, as found in B. subtilis 168.
A restriction-modification system generally protects the host microbe from transformation with exogenous DNA because the system cuts exogenous DNA that is not methylated by methyltransferase. However, a microbe can accept exogenous DNA that imitates the methylation pattern because a restriction-modification system is unable to cut this exogenous DNA [32]. In a previous study [12], we constructed E. coli strains BR397, BR398, and BR408 for conjugative plasmid transfer into G. kaustophilus HTA426. E. coli BR408 produces DNA that imitates the methylation pattern in G. kaustophilus HTA426. E. coli BR398 produces DNA with dam methylation, whereas E. coli BR397 produces methyl-free DNA. Although G. kaustophilus MK244 could not accept the pUCG18T plasmid transferred from the dam− strain E. coli BR397, G. kaustophilus MK633 accepted pUCG18T from E. coli BR397 as well as strains BR398 and BR408. These results can be explained by the elimination of gkp09 from strain MK633 because the gkp09 product digests methyl-free DNA but not DNA with dam methylation (5′-G6mATC-3′, which covers gkp08 methylation (5′-GG6mATC-3′ and 5′-G6mATCC-3′. In addition, G. kaustophilus MK633 maintained pUCG18T with higher stability than strain MK244. This observation is also attributable to the elimination of gkp09 because the gkp09 product can occasionally digest endogenous plasmids that have not undergone gkp08 methylation immediately after plasmid replication. This hypothesis is supported by the fact that G. kaustophilus MK244′ maintained pUCG18T as stably as strain MK633. Thus, G. kaustophilus MK633 acquired advantages compared with strain MK244 in terms of plasmid transformation and plasmid stability due to the elimination of a restriction-modification system along with pHTA426 curing.
An intriguing observation was that G. kaustophilus MK633 had a higher cell density in the stationary phase. In contrast to the advantages in terms of plasmid transformation and plasmid stability, this observation cannot be explained by the elimination of gkp09 because G. kaustophilus MK244′ grew less efficiently than strain MK633. It was also interesting that strain MK633bgaB produced higher amounts of BgaB than MK244bgaB (Figure 3A). This observation is attributable mainly to the higher cell density of MK633bgaB (Figure 3B), as observed with strain MK633, and thus the higher protein yields from strain MK633bgaB (Figure 3C). In addition, this observation can be attributed to the higher BgaB productivity per cell because strain MK633bgaB had a higher BgaB specific activity (Figure 3D). Thus, these results suggest that the elimination of pHTA426 improved the cell density per culture and BgaB productivity per cell, thereby remarkably enhancing the production of BgaB.
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that the crude extracts from G. kaustophilus MK244 and MK633 had negligible differences in terms of their protein compositions (data not shown). Therefore, it is unlikely that G. kaustophilus MK633 lost a nonessential protein that was abundantly synthesized from pHTA426, thereby reducing the energy burden to enhance the cell yield and BgaB productivity. Instead, these enhancements may be attributable to the reduced energy burden for plasmid replication. In fact, evidence suggests that plasmid maintenance places burdens on cell growth and/or metabolism [33–36]. Given that pHTA426 replicates as a single copy, this plasmid accounts for only 1.3% of total DNA; however, deoxyribonucleoside triphosphates are more unstable at higher temperatures, thereby suggesting that plasmid replication may place a considerable energy burden on thermophiles even though the plasmid is not extremely large or present in high copy numbers. This hypothesis is consistent with our genome data analysis, which showed that thermophiles have relatively smaller genomes than mesophiles, and the negative correlation between genome size and growth temperature reported by Sabath et al [37]. Overall, we consider that the lower energy burden incurred for DNA replication can explain why pHTA426 curing improved the cell density per culture and BgaB productivity per cell.
In conclusion, we demonstrated that pHTA426 curing was effective for improving the performance of a moderate thermophile, G. kaustophilus MK244. The cell density and protein productivity were presumably improved by the reduced amounts of energy required for DNA replication at high temperatures, so plasmid curing may be a simple approach for improving thermophiles in terms of these properties. In particular, this approach may be effective for archaeal thermophiles because they grow at extremely high temperatures and thus could have a greater energy burden on plasmid replication. Moreover, in archaeal thermophiles, plasmids may account for larger fractions of chromosomes than in moderate thermophiles because archaeal thermophile genomes are generally smaller. Therefore, plasmid curing could remarkably reduce the energy burden in archaeal thermophiles. We note that many archaeal thermophiles harbor plasmids, such as S. solfataricus P2 (carrying pSSVi) and T. barophilus MP (carrying pTBMP1), which have been studied as model acidophilic hyperthermophiles [38] and piezophilic hyperthermophiles [39], respectively. Even if these thermophiles harbor a single copy plasmid, our results suggest that plasmid curing can improve their performance in terms of the cell density and protein productivity.
Acknowledgments
The authors thank Dr. Hisashi Yagi of Tottori University for useful discussions. This study was supported by JSPS KAKENHI (Grant number 25450105).
\n',keywords:"genetic engineering, host improvement, plasmid curing, plasmid elimination, thermophile application",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/56339.pdf",chapterXML:"https://mts.intechopen.com/source/xml/56339.xml",downloadPdfUrl:"/chapter/pdf-download/56339",previewPdfUrl:"/chapter/pdf-preview/56339",totalDownloads:1421,totalViews:281,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:62,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"November 4th 2016",dateReviewed:"June 7th 2017",datePrePublished:null,datePublished:"October 11th 2017",dateFinished:"July 5th 2017",readingETA:"0",abstract:"Thermophiles are attractive as host cells for microbial processes to produce or degrade various compounds. In these applications, it is often desirable to improve the properties of thermophiles, such as their growth rate, cell density, and protein productivity, although this is rarely achieved because of the lack of general approaches. In this chapter, we describe the elimination of the pHTA426 plasmid from a moderate thermophile, Geobacillus kaustophilus HTA426, and its effects on the microbial properties. This process, called plasmid curing, was simply achieved using a DNA intercalator and confirmed by phenotypic and genotypic analyses. Of note, pHTA426 curing had beneficial effects on diverse properties, probably because of the reduced energy burden in terms of plasmid replication at high temperatures. The result suggests that plasmid curing is a simple and versatile approach for improving thermophiles. In particular, this approach may be effective for archaeal thermophiles because they grow at much higher temperatures and could have the greater energy burden on plasmid replication. Data mining has also shown that plasmids are distributed in archaeal thermophiles. This chapter provides a new tip for improving archaeal thermophiles, thereby increasing the opportunities for their use in various biotechnological applications.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/56339",risUrl:"/chapter/ris/56339",book:{id:"5733",slug:"archaea-new-biocatalysts-novel-pharmaceuticals-and-various-biotechnological-applications"},signatures:"Tatsuki Mizuno, Takashi Ohshiro and Hirokazu Suzuki",authors:[{id:"152236",title:"Ph.D.",name:"Hirokazu",middleName:null,surname:"Suzuki",fullName:"Hirokazu Suzuki",slug:"hirokazu-suzuki",email:"hirokap@xpost.plala.or.jp",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Tottori University",institutionURL:null,country:{name:"Japan"}}},{id:"200687",title:"BSc.",name:"Tatsuki",middleName:null,surname:"Mizuno",fullName:"Tatsuki Mizuno",slug:"tatsuki-mizuno",email:"tatsuki19921106@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"205148",title:"Prof.",name:"Takashi",middleName:null,surname:"Ohshiro",fullName:"Takashi Ohshiro",slug:"takashi-ohshiro",email:"ohshiro@bio.tottori-u.ac.jp",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Experimental procedures",level:"1"},{id:"sec_2_2",title:"2.1. Bacterial strains and culture conditions",level:"2"},{id:"sec_3_2",title:"2.2. Plasmids",level:"2"},{id:"sec_4_2",title:"2.3. Plasmid introduction into G. kaustophilus",level:"2"},{id:"sec_5_2",title:"2.4. pHTA426 curing from G. kaustophilus MK244",level:"2"},{id:"sec_6_2",title:"2.5. Southern blot",level:"2"},{id:"sec_7_2",title:"2.6. Construction of G. kaustophilus MK244bgaB and MK633bgaB",level:"2"},{id:"sec_8_2",title:"2.7. BgaB assay",level:"2"},{id:"sec_9_2",title:"2.8. Plasmid stability assay",level:"2"},{id:"sec_10_2",title:"2.9. Cell density assay",level:"2"},{id:"sec_11_2",title:"2.10. Mutation frequency assay",level:"2"},{id:"sec_12_2",title:"2.11. Nucleotide stability assay",level:"2"},{id:"sec_13_2",title:"2.12. Genome data mining",level:"2"},{id:"sec_15",title:"3. Results",level:"1"},{id:"sec_15_2",title:"3.1. Genetic features of the pHTA426 plasmid",level:"2"},{id:"sec_16_2",title:"3.2. Construction of G. kaustophilus MK633",level:"2"},{id:"sec_17_2",title:"3.3. Microbial properties of G. kaustophilus MK244 and MK633",level:"2"},{id:"sec_18_2",title:"3.4. Nucleotide stability",level:"2"},{id:"sec_19_2",title:"3.5. Archaeal thermophiles: Smaller genomes",level:"2"},{id:"sec_20_2",title:"3.6. Distribution of plasmids in archaeal thermophiles",level:"2"},{id:"sec_22",title:"4. Discussion",level:"1"},{id:"sec_23",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Wiegel J, Ljungdahl LG. The importance of thermophilic bacteria in biotechnology. Critical Reviews in Biotechnology. 1986;3:39-108'},{id:"B2",body:'Cripps RE, Eley K, Leak DJ, Rudd B, Taylor M, Todd M, Boakes S, Martin S, Atkinson T. Metabolic engineering of Geobacillus thermoglucosidasius for high yield ethanol production. Metabolic Engineering. 2009;11:398-408'},{id:"B3",body:'Georgieva TI, Ahring BK. 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Growth temperature and genome size in bacteria are negatively correlated, suggesting genomic streamlining during thermal adaptation. Genome Biology and Evolution. 2013;5:966-977'},{id:"B38",body:'Berkner S, Lipps G. Genetic tools for Sulfolobus spp.: Vectors and first applications. Archives of Microbiology. 2008;190:217-230'},{id:"B39",body:'Thiel A, Michoud G, Moalic Y, Flament D, Jebbar M. Genetic manipulations of the hyperthermophilic piezophilic archaeon Thermococcus barophilus. Applied and Environmental Microbiology. 2014;80:2299-2306'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Tatsuki Mizuno",address:null,affiliation:'
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Japan
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Japan
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1. Introduction
Slovenia is usually counted among the countries whose health care financing system is Bismarckian. However, the Slovenian health care financing system is »bis-eridging« and getting more and more mixed. Most of the elements that are typical for a pure Bismarckian system, namely association of rights with labor status and no government interference, are not present anymore and lots of innovative elements entered the health care insurance space in the last decades.
Relatively, the Slovenian health care system ranks well across many indicators. Life expectancy has increased in the last two decades and is equal to the EU average of 80.6 years. Health spending is lower than the EU average (US$ PPP 2283 in 2019), and from the viewpoint of the benefits package, the accessibility to health services is almost universal. Due to its complementary health insurance and universal coverage, the financial protection is high-the out-of-pocket expenditures are one of the lowest in the EU, catastrophic spending is low, and unmet needs due to costs are low. The mounting problem is long waiting lists for specialist care and lack of health care personnel, especially in primary care [1].
In the following subchapter, we will describe the basic features of the health insurance system in Slovenia but will mostly focus on the concept of complementary health insurance and its role in the Slovenian health care system. On one hand, the institution of complementary health insurance brought Slovenia in front of the Court of Justice in Luxembourg; on the other hand, it played a crucial role in the economic protection of Slovenian citizens through the economic crisis between the years 2008 and 2013. Saying that it is necessary to point out that many adjustments have been introduced to complementary health insurance to ensure equal conditions for inclusion into the scheme for all citizens regardless of their age and gender and to ensure equal accessibility to complementary health insurance for all citizens is guaranteed without risk selection. In spite of all the adjustments, the nature of complementary health insurance is still ambiguous-it is declared voluntary but is in fact compulsory. Furthermore, it is run by private insurance companies while its package of services is completely dependent on the definition of services covered by compulsory health insurance does put the private providers into a subordinate position.
2. Health insurance system in Slovenia
According to the last available data, the public expenditures for health care in Slovenia amounted to 72.8% of THE (total health expenditures) in 2019, 69.4% being compulsory health insurance and 3.4% government expenditures. The private expenditures for health care amounted to the remaining 27.2%, from which 11.7% are out-of-pocket expenditures and the rest (15.5% of THE) are voluntary insurance schemes. The Health Care and Health Insurance Act (1992) defines more types of voluntary health insurance in Slovenia, which are as follows:
Complementary health insurance, which covers the difference between total price of the service and share of the price of this service covered by compulsory health insurance. This difference is in case of no complementary health insurance covered in a form of copayments.
Substitutive health insurance, which substitutes the coverage for services (and not more) that would otherwise be covered by the compulsory health insurance, including copayments. It is intended for persons that according to the legislation cannot be insured in the compulsory health insurance scheme. As substitutive health insurance is intended for specific population groups only that might for some reason be excluded from the compulsory health insurance – legislation in Slovenia does exclude any specific population groups, such as high-earners – therefore this type of insurance is not available.
Supplementary health insurance that covers costs of health care services that are not covered by compulsory health insurance, complementary health insurance or substitutive health insurance. They cover faster access to services or increased consumer choice.
Parallel health insurance is insurance for services that are covered by compulsory health insurance but are realized following different procedures and different conditions.
All persons who have a permanent residence in Slovenia must have compulsory health insurance in Slovenia. At the end of 2021, there were 3214 (0.15%) uninsured persons with permanent residence. Mostly, these are persons whose status is undergoing change, for example, students who finished their studies and are getting employed.
Compulsory health contributions are the largest source of income in the Slovenian health care system. Contribution rates, which are employment-based and paid from gross income, vary by group and type of employment of insured individuals. Employees pay 6.36% of their gross income, while employers pay 6.56% for illness and injury out of work plus an additional 0.53% for injuries at work and occupational diseases. The total contribution rate hence amounts to 13.45% of gross income. The contribution rates are the same for self-employed, though their contribution base is equal to the gross pension base and cannot be lower than 60% of the last-known average annual wage [2]. The contributions for the unemployed are covered by National Institute for Employment; the contributions for the pensioners are covered by Pension and Disability Insurance Institute at a 5.96% contribution rate from net pensions.
The Health Care and Health Insurance Act (1992) defines the rights to health care alongside their coverage within compulsory health insurance. The coverage ranges between 10% and 100%, depending on the services. A minimum of 90% of the cost of services is covered for organ transplantation and urgent surgeries, treatment abroad, intensive therapy, radiotherapy, dialysis, and other urgent interventions included in the basic benefits package; 80% of the cost of treatment for reduced fertility, artificial insemination, sterilisation, and abortion; specialist surgery; nonmedical care and spa treatment in continuation of hospital treatment with the exception of non-occupational injuries; dental care and orthodontics; orthopedics; hearing and other aids and appliances; 70% of the cost of medications from the positive list and for specialist, hospital and spa treatment of non–work-related injuries.
A maximum of 60% is covered for non-emergency ambulance transportation, medical and spa treatment; 50% of the cost of ophthalmological devices and adult orthodontic treatment; 25% of the cost of pharmaceuticals from the intermediate list.
The remaining shares of the services must be covered by out-of-pocket copayments. As these can reach quite high levels, 95% of the population, liable to purchase the coinsurance, is insured with complementary health insurance. Due to the high share of the population covered, complementary health insurance is by far the main type of voluntary health insurance in Slovenia and has been described as ‘compulsory’ or ‘de facto essential’ [3].
There are three companies that offer complementary health insurance in Slovenia: Vzajemna, Generali, and Triglav zdravje. The premium is a flat rate and equal for everyone. The monthly premium amounted to an average of 34 EUR in 2021.
To ensure that the companies do not offer coverage only to low-risk or healthy and young individuals, the Ministry of Health (MoH) introduced the risk-equalisation scheme in 2005. According to the scheme, contributions are reallocated among the insurance companies based on the age and gender of the insured. The aim is to equalize the portfolio structures (according to the age and gender) of the insurance companies. The funds are transferred from insurance companies with more favorable risk portfolios to insurance companies with less favorable portfolios, the intention being the equalisation of differences in risk structures.
Individuals who have taken out supplementary health insurance pay premiums to the insurance companies, who in turn pay the full costs directly to the respective health care provider. As the basic benefit package in the compulsory scheme comprises a wide range of services, there is little room for supplementary health insurance. Parallel insurance, which covers services such as faster access to medical treatment, nonmedical services in hospitals, and higher-quality materials, with providers already offering services within compulsory health insurance, gains in popularity. Since 2017, the share of other voluntary health insurance (VHI) policies has been increasing, mostly due to ever-lengthening waiting lists in the public health care system. In 2019, supplementary and parallel insurance was purchased by 26% of the population (2011: 5.6%; 2015: 18.9%); however, their premiums still represent a small share (4.55%) of all voluntary health insurance premiums.
3. Financial and coverage overview
In 2018, public expenditure on healthcare in Slovenia amounted to 5.8% of GDP (gross domestic product) [4]. Over the last 10 years (Figure 1), the evolution of public expenditure on health reflects the fluctuations related to the adoption of certain measures and the economic cycle, but during this whole period, it remained at around 6% of GDP. The same is true for total current health expenditure, which reached 7.9% of GDP in 2018, the lowest level in the last 9 years, which is also below the EU average of 8.4 % of GDP [1, 4, 5]. Existing policies have been successful in maintaining spending levels, but there have been problems with the financial performance of public health facilities, and waiting times have increased, worsening the accessibility of health services [1, 5].
Figure 1.
Health expenditure by financing scheme, in % of GDP, 2005–2018. Source: Institute for Macroeconomic Analysis and Development, 2019 [5].
Expenditure on VHI amounted to 1.2% of GDP in 2018, while it increased by about 0.1–0.3% of GDP between 2009 and 2018. Total health expenditure by functions and sources of funding in Slovenia (2006-2019) is shown in Figure 2. Complementary health insurance is an additional source of funding for the health system, as much as 95% of the population is enrolled. According to the Health Care and Health Insurance Act (Article 23), most health services involve high copayments for most of the population. Only certain diseases, children, and young people under 26 years of age enrolled in school are fully covered by compulsory health insurance. The risk of copayments is hence very high [1].
Figure 2.
Total health expenditure by functions and sources of funding, Slovenia, 2006-2019. Source: Zver HE, 2021 [5]; Statistical Office of the Republic of Slovenia, 2018 [8].
Since 1992, the share of copayments has gradually increased due to a lack of public funding, especially during the last economic crisis. The income-independent single premium is the largest weakness of complementary health insurance in the system. This means that the system is regressive, although it should be supported by income solidarity given the high risk of copayments. In 2016, for example, the annual premium was equivalent to 62% of the net monthly minimum wage, 33% of the average net wage, and 57% of the average net pension [4, 6]. The regressive nature of this source was significantly reduced in 2012 when new social legislation introduced the automatic transfer of user fees from the state budget for welfare recipients. This benefit had already been introduced in 2009, but until 2012, it was not automatically linked to eligibility for social assistance [1].
Almost every permanent resident of Slovenia is entitled to the health benefits covered by compulsory health insurance either as a contributing member or as a dependent person (e.g., children). Opting out is not possible. Permanent residence is one of the most important factors for defining entitlement to health benefits, but Articles 15–18 of the Health Care and Health Insurance Act [7] set additional conditions under which a person is compulsorily insured [1, 2, 8].
According to the available data, 2,116,739 people were compulsorily insured in 2019, representing more than 99% of the population [1, 9]. About 0.14% (3345) people were uninsured at the end of 2020 [1, 9]. Most of them were temporarily uninsured, for example, because they were waiting for their entitlement to pension or unemployment benefits to be recognised. The rest were mainly people who could not meet the formal residence requirements (e.g., undocumented migrants and ethnic minorities, such as the Roma population and homeless people). In addition, at the end of 2020, 15, 892 people had compulsory insurance but did not pay their contributions, which means that their entitlement to health services was suspended, and they could only access emergency services [1].
According to the Health Care and Health Insurance Act [7], there are 25 categories of insured persons. Each category has a different contribution rate, but contributions are mostly income-based. The first big group is employees (and their dependents), the second group includes the unemployed, other persons without a fixed income who are not registered as unemployed, pensioners, farmers, and the self-employed [1]. The National Institute for Employment pays the contributions for the unemployed; the state and/or municipalities for persons without income, prisoners, and war veterans. In addition, European regulations and bilateral agreements provide health insurance coverage for citizens from almost all EU countries. Special provisions apply to certain vulnerable groups [1, 7].
4. The introduction and development of complementary health insurance
Slovenia had historical experience with copayments since they existed already in the previous political and health system, which was in force until 1990. They were introduced in the early 1980s, mostly as flat rates on top of services. As the period of 1980s was marked by very high inflation rates, such an approach resulted in copayments becoming a negligible contribution (estimated only at around 1% of THE in 1989) as well as not an important burden on the patients. Still, this experience—together with the exceptions from copayments—fed directly into the solutions proposed by the new legislation adopted in 1992 [1, 10, 11].
When the legislation was being prepared in the period 1990−1992, different solutions to copayments were discussed. Considerations were given to the following options:
Flat rate copayments, which would be levied on a wide range of health services (counter argument was that any significant inflation might reduce their impact).
Percentage-based copayments (coinsurance), which would allow for flexibility and stratification.
Introduction of exceptions—these were eventually simply copied from the previous system described above.
One of the important issues in the introduction of copayments in Slovenia, however, is the absence of capping. The latter would prevent chronic patients from incurring excessive expenditure simply due to their real health needs, related to the management of their existing conditions. In turn, this might have been also one of the contributing factors to high coverage by the CHI [1, 10, 11].
CHI gained popularity, acceptance, and advocacy with the introduction of copayments into the system in 1992 under the Health Care and Health Insurance Act [7]. However, the most important regulations chronologically presented in the market development of CHI are listed below (Table 1) [1, 10, 11]. CHI served to raise additional funds for health care in addition to the funds from the compulsory health insurance and served to diversify the sources of funding. Originally, there were two providers of CHI: HIIS, and Adriatic, a for-profit commercial provider [11, 12].
1992
The HCHI (1992), the Health Services Act (1992), and the Pharmacies Act (1992) enable the introduction of private financing (CHI as VHI is introduced in 1993).
1999
The Act amending the Health Care and Health Insurance Act (HCHI, 1998) established Vzajemna as a separate legal entity, completely separated from the HIIS.
2000
The Insurance Act (2000) declares that CHI serves the public interest; risk equalisation is introduced. In 2003, the White Paper (2003) is published and a reform proposal by the MoH calls for the abolition of CHI, which covers copayments.
2004
The Insurance Act (2004) again announced the introduction of a risk equalization mechanism. However, the mechanism was not implemented, and risk-based premiums were still allowed.
2005
The HCHI Amendment Act (2005) introduces community-based premiums for CHI to cover the copayments, risk equalisation CHI and penalties for late joiners to CHI (for every 12 months without CHI, calculated from the month a person becomes liable for paying the copayments, the premium increases by 3%, up to a maximum of 80%).
Adriatic Slovenica (in October 2005) and Vzajemna (in December 2005) challenge the risk equalisation scheme in the Supreme Court. Adriatic Slovenica argues that the scheme would lead to higher average premiums and that this would undermine competition as it would lead to a monopoly in the long run; Vzajemna argues that the scheme does not consider the differences in the health status of persons insured with a given company and treats the companies unequally; the court upholds the government and confirms the legality of the adopted risk equalisation scheme.
2006
The HCHI Amendment Act (2005) comes into force; in response to the introduction of community rating, CHI premiums increase by 18%; a further 5% increase in premiums is attributed to rising health costs.
In June 2006, Vzajemna complains to the EC about the following shortcomings of CHI covering user fees: (1) insurers offering CHI must be included in the compensation scheme; (2) the insurance supervisory authority must be informed of any change in the conditions of CHI; (3) any increase in these premiums must be confirmed in writing by a certified actuary and can only be made under the supervision of the appointed Authority; (4) the premiums for CHI to cover the access must be the same for all subscribers of a given insurer and the contracts must not be shorter than 1 year; (5) insurers may only terminate a CHI contract if the policyholder fails to pay the premiums; (6) the revenue generated by the CHI scheme may only be used for the implementation of this scheme; (7) half of all profits generated must be used for the implementation of the CHI scheme; (8) before an insurer enters the CHI market, it must obtain the written approval of the Minister of Health.
2007
In March 2007, the EC issued an official warning regarding Slovenia\'s health insurance legislation. The government had argued that CHI, which covers the copayments, despite its voluntary nature, was an integral part of the compulsory health insurance system and therefore a matter of public interest justifying government intervention to protect the general interest. The EC rejects this and argues that complementary health insurance is not a full or partial alternative to compulsory health insurance and cannot be considered part of the compulsory social security system based on EU law.
2011
The legislation on CHI is not changed and the EC refers Slovenia to the ECJ. The new reform proposal of the MoH. The modernisation of the health system by 2020 envisages the abolition of copayments and the introduction of a redefined, publicly financed benefits package.
2012
The Public Finance Balancing Act (2012) shifts costs from compulsory to complementary insurance (from public to private sector) which leads to a 13% increase in premiums for CHI.
The ECJ confirms that Slovenian legislation on the CHI does not fully comply with the Directives on non-life insurance. The ruling concerns, among other things, the use of profits, systematic reporting, and prior authorisation; it does not concern risk equalisation.
Table 1.
Development and regulation of CHI in Slovenia, 1992–2012.
Note: EC—the European Commission; ECJ—the European Court of Justice; CHI—complementary (voluntary) health insurance; HCHI—The Health Care and Health Insurance Amendment Act; MoH—Ministry of Health; VHI—voluntary health insurance.
Source: European Commission, 2012 [10]; Sagan A, Thomson S, 2016 [11].
In 1993−1994, mainly large companies concluded collective agreements with CHI for their employees. After initial fears that a two-class medical system would emerge, this later became a matter of individual choice. However, it was argued that the introduction of the CHI system would put an end to unlimited entitlements and the use of the compulsory health insurance system, as consumers would have to raise additional funds [11, 12].
In 1998, the Health Care and Health Insurance Act [7] was amended in such a way that the HIIS had to separate its compulsory insurance and CHI. As a result, a new non-profit mutual insurance company, Vzajemna, was established, independent of the HIIS, which subsequently became the largest provider of CHI. Ever since CHI has been on the market, there have been clear signs of imbalances between the various CHI companies. The equity problems became apparent when CHI introduced a regressive element into the system due to its flat-rate premiums (i.e., not risk-based). At that time, premiums for CHI were not risk-based and two companies (Adriatic and Vzajemna) charged identical premiums [11, 12].
When the two commercial companies offering CHI entered the Slovenian market in 2004–2005, they launched an obvious advertising campaign for younger and healthier policyholders with risk-based premiums. CHI is regulated by the Insurance Supervisory Authority (premiums level) and the MoH (market entry, approval of initial premiums, risk equalisation procedure). It does not receive tax subsidies. The CHI market is subject to relatively strict regulation, and some argue that these rules violate EU regulations [11, 12].
In 2006, the amendment to the Health Care and Health Insurance Act 2005 [7] came into force. In response to the introduction of the Community Rating, premiums increased by 18% and by a further 5% due to rising health costs. In June 2006, Vzajemna complains to the European Commission (EC) about the shortcomings of CHI (Table 1). In 2007, the EC issued an official warning regarding Slovenia\'s health insurance legislation. The government had argued that CHI, which covers the copayments for most of the services in the basic benefit package, despite its voluntary nature, is an integral part of compulsory health insurance and a matter of public interest for the protection of the common good.
In 2011, EC took Slovenia to the European Court of Justice (ECJ) for failing to amend the CHI legislation. As a result, the MoH proposed to reform the health system by 2020 and abolish CHI with a redefined publicly funded benefits package. In 2012, the Public Finance Balancing Act was passed, resulting in a shift of costs from the public to the private sector and a 13% increase in CHI premiums to cover user fees [11]. The European Court of Justice confirms that Slovenian legislation on the CHI does not fully comply with the non-life insurance directives. The ruling concerns, among other things, the use of profits, systematic reporting, and prior authorisation; it does not concern risk equalisation [11]. After several reminders, EC decided to refer the issue of this non-life insurance (health insurance) to the ECJ, which resulted in a ruling by the ECJ declaring that the provision of CHI in Slovenia is in breach of the Non-Life Insurance Directive. No direct penalty was imposed, but the Slovenian government was ordered to put an end to the infringement and to inform EC of the decision [10].
5. Advantages and disadvantages of complementary health insurance
5.1 Complementary health insurance in economic crisis
Slovenia was hit by an economic crisis a little bit later than some EU countries, at the end of 2008, when the business orders from abroad began to decline and consequently, the unemployment started to increase. As 98% of all incomes for compulsory health insurance are represented by contributions paid from wages and other incomes by the population, these changes had a big impact on the health insurance income. To assure that compulsory health insurance can still cover all its expenditures, numerous measures had to be passed. Among these measures, CHI played an important role. Compared to 2010, in 2015 expenditure on compulsory health insurance increased by € 49.17 M or 2.3%, while expenditure on CHI increased by € 66.31 M or 16.3% (Figure 3).
Figure 3.
Expenditures of compulsory and complementary health insurance, in M€, 2010–2015. Source: Health Insurance Institute of Slovenia, Annual report for years 2013 and 2015 [13, 14]; Slovenian Insurance Association, Statistical insurance report 2016 [15].
The average annual growth rate of compulsory health insurance expenditure in this period was 0.46%, while CHI expenditure was 3.07%. The growth rate of CHI expenditure was, hence, seven times higher than the growth rate of compulsory health insurance.
Despite stricter business conditions and the same contribution rate and equal (or at least not lower) access of insured persons to health services, the HIIS must comply with the commitment of the Stability and Growth Pact adopted by the EU in 1998 and subsequently upgraded several times. The Stability and Growth Pact is a set of rules that ensure that countries in the European Union maintain sound public finances and coordinate fiscal policies. According to the rules, HIIS must ensure the balance of revenues and expenditures without borrowing. As this was simply not possible in times of economic crisis, HIIS adopted and implemented innovative measures in 2009 to ensure its stable business operation. In determining the measures, the focus was on finding reserves in the compulsory health insurance system, without compromising the access of insured persons to services and without changing the rights from compulsory health insurance. The measures were primarily aimed at lowering the prices of health services and reducing the share of the price covered by compulsory health insurance and increasing the share of the price covered by CHI for medicines, medical devices, services, sickness benefits. The changes in the coverage shares happened at two levels.
The first transfer of financial obligations from compulsory onto CHI happened when HIIS passed the Decision on determining the percentage of the value of health services provided in compulsory health insurance, on 18 July 2009, namely for a spa treatment that does not represent the continuation of hospital treatment and for medicines from the interim list. The validity of the amendment to the resolution on determining the percentage of the value of health services provided in compulsory health insurance was extended to the whole of 2010. On 15 February 2010, HIIS additionally extended the reduction of the share of services at the expense of compulsory health insurance to the field of non-emergency ambulances, spa treatment other than hospital treatment, dental prosthetic services, and eye accessories for adults.
The second package of changes was brought about by the Fiscal Balance Act (2012) with the following measures:
Reduction of the share of the value of health services covered by compulsory health insurance (from 1 January 2013 onwards), meaning the transfer of the financial burden to CHI, namely:
Around 90% of the value (instead of 95%) for organ transplants, the most demanding surgical procedures, regardless of the reason, treatment services abroad, intensive care, radiotherapy, dialysis, and other most demanding diagnostic, therapeutic and rehabilitation services,
Around 80% of the value (instead of 85%) for health services related to the provision and treatment of reduced fertility and artificial insemination, sterilisation, and abortion; specialist outpatient, hospital, and spa services as a continuation of hospital treatment, except for injuries outside work, non-medical part of care in hospital and spa within the continuation of hospital treatment, except for injuries outside work, treatment of dental and oral diseases, medical devices, and injuries outside work,
Around 70% of the value (instead of 75%) for specialist outpatient, hospital, and spa services as a continuation of hospital treatment and non-medical part of the hospital and spa care as a continuation of hospital treatment, medical devices related to the treatment of injuries outside work, medicines from the positive list.
The increase in complementary health insurance is evident also from the increase of the share of complementary health insurance expenditure in GDP between 2010 and 2015: while this share increased by 0.10 percentage points, the share of compulsory health insurance decreased by 0.22 percentage points.
5.2 Complementary health insurance and inequities
CHI is purchased by more than 95% of the population liable for co-insurance, which means 73% of the population. The premiums are flat-based and regressive and cover copayments in the range between 10% and 90% of the price of the services. Due to flat-based premiums, CHI has always been criticized from the equity viewpoint. In time, many adjustments have been made to the flat-based premium, such as coverage of costs of copayments for the socially vulnerable, who cannot afford to purchase CHI. Copayments are also covered for war veterans and prisoners. As the copayments are covered at the point of the service, the inequities caused by flat-based premiums are largely tackled, except for around 5% of the population right above the income limit, which would enable them to receive social benefits. For these citizens, the insurance is out of reach and might face higher unmet needs.
Since 2006, the share of CHI in total household consumption levelled around 2.9%. In 2012, the regressive nature of CHI premiums was importantly limited, when automatic coverage of CHI claims for all socially vulnerable populations from the central budget was introduced (Figure 4).
Figure 4.
CHI expenditure as share of total household consumption, according to income quintiles, 2008–2018. Source: Zver et al. [16].
Due to the widely defined basic benefits package, covered by two financial sources, the demand for additional services, that are not included in the basic benefit package, is very low. The out-of-pocket payments are, consequently, the lowest in the European region and amounted to 12% according to the last available data from 2018.
5.3 Complementary health insurance and risk selection
In Slovenia, a system of risk equalisation and the creation of an efficient model for the long-term sustainability of the health care financing system was prepared by the MoH and included in the law in 2005 [7, 12, 17]. Risk equalisation or compensation schemes are necessary to support community-rated health insurance and were created for the market CHI. Basically, health insurers receive credits or subsidies from a national fund or authority to compensate for the additional costs of insuring older and less healthy members. The Health Care and Health Insurance Act in Article 23 regulates the basket of health benefits for a compulsorily insured person [7], albeit very substantial, from 100% to 10% of the value of the healthcare service for most adult insured persons; payment of the difference or balance up to 100% of the value of the healthcare service is the responsibility of the insured person who received the healthcare service (also depending on the type of treatment or activity) [17]. To prevent ‘cream-skimming’, companies have been obliged to participate in risk equalisation to compensate for differences in health care costs between insurance companies [7, 12].
Quite restrictive legislation [7] stipulates that insurers are obliged to cover the costs of all publicly financed health services. Children are exempt from the copayments and therefore do not need CHI. CHI appears to be compulsory for adults, as they must pay penalties if they do not take out CHI once they become liable for the copayments. For each full year (12 months) that they do not have CHI, the penalty is 3% of the premium. The maximum penalty is 80% of the premium. [17, 18]. The uniform flat premium for all CHI-insured persons established by the Health Care and Health Insurance Act [7] is independent of gender, age, or health status. However, equality is guaranteed between the different providers of CHI and between the insured person and the insurance conditions of CHI regarding the duration and termination of CHI contracts (Table 2) [12].
Triglav zdravje
Vzajemna
Generali (Adriatic)
Basic premium
€ 35.55
€ 34.60*
€ 34.50
Table 2.
Monthly premiums for CHI (€), April 2022.
Note: *Due to the circumstances of COVID-19, the premium CHI in December 2021 was €12.1 instead of €34.6, as Vzajemna returned €22.5 to policyholders. The average monthly CHI premium was thus €32.72 in 2021, but rose again to €34.6 in January 2022, as the other two CHI companies returned profits to shareholders in the form of dividends. Source: e-Zavarovanja, 2022 [19].
The monthly basic insurance premium for the three companies in the Slovenian market of CHI shows a sustained upward trend over the period 2006–2019, despite a slight price decrease from 2013 to 2014 (Figure 5). Between 2006 and 2013, the premium increased by €93 per insurance policy [12, 20]. Apparently, Generali and Triglav zdravje are slightly higher than Vzajemna, which could be a form of risk selection [19, 20].
Figure 5.
Monthly premiums for CHI (€), March 2016—December 2019. Source: Data from CHI companies (authors’ own calculations).
The experience with risk equalisation shows that all three companies make regular payments to CHI, as would be appropriate given their risk profiles. However, these payments are quite small, amounting to only €12 M in 2014. This corresponds to about 3% of the total premium income [19, 20].
The simplest risk adjustment factors used to balance premium risk are based on age and gender. They are easy to collect and monitor, but they are a poor measure of expected health care costs [21]. Improving the risk equalisation formula should be a focus of government action to ensure that the market CHI functions efficiently [20].
5.4 Complementary health insurance and administration costs
In general, although monthly basic insurance premiums fell slightly from 2013 to 2016, they have shown a sustained upward trend in recent years. It seems that the austerity measures during the economic crisis had little impact on the price level (Figure 5). To understand the reason for the escalation of premium costs, it is useful to examine the relationship between premium income and claims costs. This helps in analysing the efficiency of CHI in financing health care. The discrepancy between revenue and claims costs shows the transaction costs of using CHI for this key role in health care financing. If this discrepancy increases, it indicates inefficiency as the same number of people is insured but with higher administrative costs. Moreover, in due course, this may undermine the affordability of CHI, especially for poorer households [20].
Figure 6 shows how claims costs increased between 2007 and 2013 and then decreased slightly in 2014 (due to lower reserve costs, partly due to government pricing policies and covered benefits). Premium income has generally increased since 2006 (with slight decreases in 2010 and 2014). The difference between premiums and claims rose sharply before the crisis, reaching a peak of €64 M in 2009. As a result of the crisis, the premiums declined slightly in 2010, while claims kept on increasing, resulting in the lowest difference between both (€34 M in 2010). In the next 4 years, the revenues from premiums kept on increasing and the difference almost reached the pre-crisis level again in 2014. Another drop in the difference between revenues and claims can be observed in 2016 and 2019, the difference was again back to €65 M. [20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35].
Figure 6.
Revenues and costs in the markets of CHI €, 2006-2019. Source: Slovenian Insurance Supervisory Authority, Annual Report for the years 2007–2020 [22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35] (authors’ own calculations).
Figure 7 shows a breakdown of the difference between premium income and non-claims expenditure, suggesting that much of this is due to actual operating costs rather than profits. However, the official profit figures may not fully reflect the difference between revenues and costs [20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]. However, compared to other countries that provide similar resources to CHI, transaction costs in Slovenia are very low [20]. This may not be too surprising, as Slovenian insurers do not purchase services and should therefore have lower administrative costs. There are also concerns that new solvency requirements could push up transaction costs further, although the extent is not yet fully known. Rising transaction costs should be a focus of regulation to ensure that CHI remains affordable for everyone and that the CHI market is administratively efficient [20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35].
Figure 7.
Profits and non-claims costs in the markets of CHI, 2006–2019. Source: Slovenian Insurance Supervisory Authority, Annual Report for the years 2007–2020 [22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35].
It should also focus on better monitoring so that the market is more transparent for regulatory authorities and consumers. In a truly competitive market, insurers would automatically correct prices downwards when their cost base is reduced. A helpful piece of regulation would be to set a minimum claims ratio so that insurers must spend a minimum share of premium income on health care costs. This would limit transaction costs and help secure affordability in the CHI market. The government should also tighten reporting requirements [20].
Although the administrative costs of CHI are low by international standards, CHI on the other hand incurs transaction costs related to insurers\' profits and administrative costs, and indirectly to the costs of government regulation. The main risk of CHI is that transaction costs will continue to increase over time, reducing the administrative efficiency and affordability of this option, especially due to the new solvency requirements [20].
5.5 Complementary health insurance and efficiency
An increase in the efficiency of the health care system in Slovenia had been one of the declarative goals of the introduction of the CHI. It was supposed to reduce the ‘unnecessary’ demand for health services while also raising some additional financial resources for its functioning. One of the reasons for such reasoning lies in the fact that the structure of expenditures of CHI by categories is significantly different from compulsory health insurance. Namely, around 45% of the CHI expenditures are for the reimbursement of copayments on medicines (cf. the expenditures on medicines represent only 11.7% of the expenses of HIIS [36].
One of the disadvantages of CHI, which is rarely mentioned and discussed, is the impact of CHI on the efficiency of health services provision. As discussed above, the levels of copayments differ for different services. While they amount to 10% of the price for most important services, they can amount to as much as 90% of the price for services, less important for health (such as non-urgent transportation). While HIIS as a single provider of compulsory health insurance restricts the health care providers and pays the volume of their services up to a defined plan, the private health insurers offering CHI have no such restrictions. Intuitively, the providers can hence provide an unlimited number of less important services as they are 90% covered by CHI, resulting in less efficient and less cost-effective care provision. While a study, confirming such a theory, has not been conducted yet, the logic of the idea remains.
Another disadvantage of CHI to which not enough attention has been paid is surely its stabilisation role. As discussed in other sections of this chapter, CHI had a huge stabilisation impact in an economic crisis, buffering the negative impacts of higher unemployment. Resulting in a higher premium, the CHI managed to alleviate the impact of the lower incomes and contributions to compulsory health insurance. On the other hand, this enabled the health system, HIIS, and health care providers not to implement organisational changes, cost-effective measures, or increases in efficiency. The waste in the system remained the same, the outcomes are still not discussed and measured, and necessary reforms that would put the patient in the centre of integrated care still seem non-urgent in spite of long waiting times.
As had been established with a specially commissioned analysis of the performance of the Slovenian health system in 2015 by the World Health Organization (WHO) and the European Observatory on Health Systems and Policies [37], CHI played an important role in buffering the shocks experienced by the health system in the times of austerity (the period between 2009−2010 and 2014). These shocks were reflected primarily in a rapid decline in paid contributions against compulsory health insurance as unemployment rose dramatically between the end of 2009 and the first half of 20121 [38]. In that period, the Government intervened at various levels to stabilize public finance (e.g., by reducing salaries in the public sector) but in doing so it also further reduced the contributions to health insurance. HIIS acted in two ways—partly their payments were positively affected by the reduction in salaries, but they still reduced payments to hospitals by 15% in 2 years and they shifted some expenditure to CHI. This was possible as HIIS had the authority of establishing the percentage coverage of a range of services, which attracted copayments. Such an approach reduced pressure on HIIS and introduced further ‘cost-sharing’ between HIIS and the insurance providers of CHI.
6. Health policy and complementary health insurance
CHI has remained one of the main focuses of health policy in Slovenia since its introduction. As much as it has been praised at its introduction and as much as it has been criticized all along the way, no government so far was able to significantly modify it in either way (e.g., either abolishing it or turning it into a more extensive mixed mutual health insurance). The first serious and organized attempt had been done with the Health Reform proposal published in 2003 [39].
According to that initiative and reform, the CHI would be entirely integrated into the compulsory health insurance and would thus cease to exist. After a fierce debate and controversies within the government itself, it was not implemented. There were two more attempts, which were systematically carried out by the Government, more precisely by the MoH. The first of the two was the initiative of the MoH in 2012 to seek reconstruction of this insurance and explore the possibility of it extending its scope. A policy dialogue was organised together with the European Observatory on Health Systems and Policies (Observatory). It resulted in the conclusions of not liberalising the market of these insurance and not extending their role to additional services, for example, long-term care. Finally, in the MoH term between 2014 and 2018, the minister was focused strongly on transforming the CHI into parallel compulsory insurance, which would be stratified in contributions by the income brackets, established by the IRS. This initiative ran close to its completion, but there were significant reserves. One of the important ones was in the report commissioned by the MoH to the Observatory and WHO, where the main conclusion was that the CHI contributed to the stabilisation of health financing in the times of austerity and shortages in public funding (see also above and [40]).
Remaining at very high levels of coverage and effectively covering around 83% of the total population and around 95% of those who are obliged to pay copayments it represents an important instrument for raising additional financial resources and collecting them in a transgenerational manner. The latter is the main factor why the CHI remains an asset and not a burden for the decision- and policymakers.
7. Conclusion
Although CHI had not been envisaged as such at the very beginning of the transitional reforms in Slovenia from the old political, social, and economic system to a new one in 1990–1992, it has taken ground over the past 30 years. This development occurred despite several attempts at abolishing it or transforming it into a different conceptual framework (especially in view of the need for a system approach to long-term care insurance). It has proven to be robust, and it has served to the purpose of buffering some potential negative fallout of the economic crisis from 2009 to 2014. Furthermore, contrary to the most significant and often repeated criticism, namely, that it was a regressive type of health insurance, it has proven to have a good level of transgenerational solidarity. Flat-rate premiums were the trigger to claims of regressivity, but the fact that a healthy population of persons in their 20s and 30s paying the same premiums as those above 65 years of age clearly shows an important lever for solidarity. A very high level of coverage through the inclusion of much of the adult population in the CHI enables such a situation. The intervention with which the Government around 15 years ago protected persons, who for economic reasons cannot pay for the premiums of the CHI serves as another example of solidarity and social correction of socio-economic differences. The more covert aspects of inefficiency, namely, the structure of the provided services and delay in cost-effectiveness measures, are visible only upon a systematic understanding of the health care financing system and therefore rarely discussed and put forward. Generally, productivity is dealt with only indirectly through the pricing of reimbursement criteria set up by HIIS, which has not been updated and endorsed by the medical professional societies.
The most adverse effect of a potential abolishment of CHI would very likely be a system of uninsurable copayments, which would affect the vulnerable layers of the population in Slovenia to a much more significant degree than the flat-rate premiums, with all the introduced adjustments for socially vulnerable, do. We can conclude that amidst strong pressures for either its abolishment or its expansion, the CHI in Slovenia has proven to be an important resource for the stabilisation of health expenditure. Despite it being a private insurance as it is paid after taxes, it bears a very strong public and social component.
List of abbreviations
WHO
World Health Organization
CHI
Complementary Health Insurance
MoH
Ministry of Health
VHI
Voluntary Health Insurance
THE
Total Health Expenditures
GDP
Gross Domestic Product
HIIS
Health Insurance Institute of Slovenia
ECJ
European Court of Justice
EC
European Commission
\n',keywords:"complementary health insurance, Slovenia, risk selection, inequality, efficiency",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81988.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81988.xml",downloadPdfUrl:"/chapter/pdf-download/81988",previewPdfUrl:"/chapter/pdf-preview/81988",totalDownloads:12,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 24th 2022",dateReviewed:"May 4th 2022",datePrePublished:"June 14th 2022",datePublished:null,dateFinished:"May 27th 2022",readingETA:"0",abstract:"Almost all health care services in the Slovenian basic benefits package are paid for from two financial sources: compulsory and complementary health insurance (CHI). Although this is unusual, around 90% of the population is insured under CHI. CHI covers the costs of copayments for most of the services. One of the advantages of the CHI is that it enables the public sector to shift the costs of service onto the private sector, which can compensate for the higher costs through premiums. Its administrative costs are low, the risk selection is low due to the equalisation schemes in place, and costs of copayments for the socially weak are covered by the state budget. Out-of-pocket costs are low due to most of the population being insured in CHI. On the other hand, there are many disadvantages of this unique amphibian health system. Besides the higher complexity and costs of such a health insurance system, CHI premiums are flat and regressive. The voluntary nature of CHI is highly questionable as the copayments can be as high as 90% of the total service costs. And last, but not least, CHI removes an incentive for the providers and payer to aim for efficient services.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81988",risUrl:"/chapter/ris/81988",signatures:"Tit Albreht, Marjeta Kuhar and Valentina Prevolnik Rupel",book:{id:"11223",type:"book",title:"Health Insurance",subtitle:null,fullTitle:"Health Insurance",slug:null,publishedDate:null,bookSignature:"Prof. Aida Isabel Tavares",coverURL:"https://cdn.intechopen.com/books/images_new/11223.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-871-4",printIsbn:"978-1-80355-870-7",pdfIsbn:"978-1-80355-872-1",isAvailableForWebshopOrdering:!0,editors:[{id:"196819",title:"Prof.",name:"Aida Isabel",middleName:null,surname:"Tavares",slug:"aida-isabel-tavares",fullName:"Aida Isabel Tavares"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Health insurance system in Slovenia",level:"1"},{id:"sec_3",title:"3. Financial and coverage overview",level:"1"},{id:"sec_4",title:"4. The introduction and development of complementary health insurance",level:"1"},{id:"sec_5",title:"5. Advantages and disadvantages of complementary health insurance",level:"1"},{id:"sec_5_2",title:"5.1 Complementary health insurance in economic crisis",level:"2"},{id:"sec_6_2",title:"5.2 Complementary health insurance and inequities",level:"2"},{id:"sec_7_2",title:"5.3 Complementary health insurance and risk selection",level:"2"},{id:"sec_8_2",title:"5.4 Complementary health insurance and administration costs",level:"2"},{id:"sec_9_2",title:"5.5 Complementary health insurance and efficiency",level:"2"},{id:"sec_11",title:"6. Health policy and complementary health insurance",level:"1"},{id:"sec_12",title:"7. Conclusion",level:"1"},{id:"sec_13",title:"List of abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Zgrablić B. The equalization scheme of the residual voluntary health insurance in Slovenia. Ars Mathematica Contemporanea. 2015;8(1):225-234. DOI: 10.26493/1855-3974.667.fec'},{id:"B2",body:'Albreht T, Turk E, Toth M, Ceglar J, Marn S, Pribaković Brinovec R, et al. Slovenia: Health system review. Health Systems in Transition. 2009;11(3):1-168. Available from: http://www.euro.who.int/en/home/projects/observatory/publications/health-system-profiles-hits/full-list-of-hits [Accessed: April 17, 2022]'},{id:"B3",body:'Fiscal Balance Act. Official Gazette of the Republic of Slovenia, No 40/2012 with amendments, 11 May 2012 [Internet]. 2012. Available from: http://www.pisrs.si/Pis.web/pregledPredpisa?id=ZAKO6388 [Accessed: April 06, 2022]'},{id:"B4",body:'Slovenian Insurance Association. Statistical insurance report for year 2015 [Internet]. 2016. Available from: https://www.zav-zdruzenje.si/wp-content/uploads/2017/10/Statisti%C4%8Dni-zavarovalni%C5%A1ki-bilten-2015.pdf [Accessed: April 03, 2022]'},{id:"B5",body:'Zver E, Nagode M, Srakar A. Access to health care and long-term care. In: Gabrijelčič Blenkuš M et al. editors. Inequalities in Health: Future Challenges for Intersectoral Cooperation [Internet]. National Institute of Public Health Slovenia; 2021. Available from: https://www.nijz.si/en/publikacije/inequalities-in-health-future-challenges-intersectoral-cooperation [Accessed: April 03, 2022]'},{id:"B6",body:'Prevolnik Rupel V. ESPN Thematic Report on Inequalities in Access to Healthcare Slovenia, 2018. Brussels: European Commission [Internet]; 2018. Available from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwi_zdW2pc7xAhWGOuwKHY4DfYQFjABegQIBBAD&url=https%3A%2F%2Fec.europa.eu%2Fsocial%2FBlobServlet%3FdocId%3D20347%26langId%3Den&usg=AOvVaw2lLlcbjtFq1B3Qy_rs68uE [Accessed: April 06, 2022]'},{id:"B7",body:'Albreht T, Polin K, Pribaković Brinovec R, Kuhar M, Poldrugovac M, Ogrin Rehberger P, et al. Slovenia: Health system review. Health Systems in Transition. 2021;23(1):i-188'},{id:"B8",body:'Institute for Macroeconomic Analysis and Development. Economic issues 2019 [Internet]. 2020. Available from: https://www.umar.gov.si/fileadmin/user_upload/publikacije/izzivi/2019/angleski/a_EI_2019_cel.pdf [Accessed: April 10, 2022]'},{id:"B9",body:'Sagan A, Thomson S. Voluntary health insurance in Europe: Country experience. Obs Stud Ser [Internet]. 2016;42:157-161. Available from: http://www.euro.who.int/__data/assets/pdf_file/0011/310799/Voluntary-health-insurance-Europe-country-experience.pdf?ua=1 [Accessed: April 10, 2022]'},{id:"B10",body:'Statistical Office of the Republic of Slovenia. Health expenditure and sources of funding, Slovenia, 2018 [Intranet]. 2019. Available from: https://www.stat.si/StatWeb/en/News/Index/8916 [Accessed: September 01, 2021]'},{id:"B11",body:'Health Insurance Institute of Slovenia. Annual report for year 2019 [Internet]. 2020. Available from: https://www.zzzs.si/zzzs-api/e-gradiva/vsa-gradiva/?vrsta=BR39ZT328 [Accessed: April 06, 2022]'},{id:"B12",body:'Martin P, Del Sol M. The uncertain and differentiated impact of EU law on national (Private) Health Insurance Regulations. Priv Heal Insur Eur Union. 2021:85-127. DOI: 10.1007/978-3-030-54355-6_4'},{id:"B13",body:'Health Care and Health Insurance Act. Official Gazette of the Republic of Slovenia, No 72/2006 with amendments, 12 February 1992. [Internet]. 1992. Available from: http://pisrs.si/Pis.web/pregledPredpisa?id=ZAKO213 [Accessed: April 04, 2022]'},{id:"B14",body:'European Commission. Judgment of the Court (Eighth Chamber) of 26 January 2012 - European Commission v Republic of Slovenia (Case C-185/11) [Internet]. 2012. Available from: https://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX:62011CJ0185 [Accessed: April 17, 2022]'},{id:"B15",body:'Health Insurance Institute of Slovenia. Annual report for year 2015 [Internet]. 2016. Available from: https://www.zzzs.si/zzzs-api/e-gradiva/vsa-gradiva/?vrsta=BR39ZT328 [Accessed: April 06, 2022]'},{id:"B16",body:'Zver EH. Ekonomika zdravstva, Viri in izdatki za zdravstvo v Sloveniji in državah EU (English: Health economics, resources, and expenditure on health care in Slovenia and EU countries) [Internet]. Institute for Macroeconomic Analysis and Development. 2021. Available from: https://www.nijz.si/sites/www.nijz.si/files/uploaded/ekonomika_zdravstva_viri_in_izdatki_za_zdravstvo_v_sloveniji_in_eu_eva_zver_24.5.pdf [Accessed: May 24, 2021]'},{id:"B17",body:'e-Zavarovanja. Complementary health insurance [Internet]. 2022. Available from: https://www.dopolnilnozavarovanje.si/pogosta-vprasanja/kaj-je-dopolnilno-zdravstveno-zavarovanje/ [Accessed: April 17, 2022]'},{id:"B18",body:'Ellis RP. Risk Adjustment in Health Care Markets: Concepts and Applications. Financing Health Care: New Ideas for a Changing Society. Weinheim: Wiley-VCH Verlag; 2008. pp. 177- 222. DOI: 10.1002/9783527611294.ch8'},{id:"B19",body:'Slovenian Insurance Supervision Agency. Annual report for year 2007 [Internet]. 2008. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2007.pdf [Accessed: April 10, 2022]'},{id:"B20",body:'Thomas S, Thomson S, Evetovits T. Making sense of complementary health insurance, Final report WHO [Intranet]. 2015. Available from: https://www.euro.who.int/__data/assets/pdf_file/0011/336395/Making-Sense-of-Complementary-Health-Insurance-report-Slovenia.pdf [Accessed: April 17, 2022]'},{id:"B21",body:'Slovenian Insurance Supervision Agency. Annual report for year 2008 [Internet]. 2009. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2008.pdf [Accessed: April 10, 2022]'},{id:"B22",body:'Slovenian Insurance Supervision Agency. Annual report for year 2009 [Internet]. 2010. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2009.pdf [Accessed: April 10, 2022]'},{id:"B23",body:'Slovenian Insurance Supervision Agency. Annual report for year 2010 [Internet]. 2011. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2010.pdf [Accessed: April 10, 2022]'},{id:"B24",body:'Slovenian Insurance Supervision Agency. Annual report for year 2011 [Internet]. 2012. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2011.pdf [Accessed: April 10, 2022]'},{id:"B25",body:'Slovenian Insurance Supervision Agency. Annual report for year 2012 [Internet]. 2013. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2012.pdf [Accessed: April 10, 2022]'},{id:"B26",body:'Slovenian Insurance Supervision Agency. Annual report for year 2013 [Internet]. 2014. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2013.pdf [Accessed: April 10, 2022]'},{id:"B27",body:'Slovenian Insurance Supervision Agency. Annual report for year 2014 [Internet]. 2015. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2014.pdf [Accessed: April 10, 2022]'},{id:"B28",body:'Slovenian Insurance Supervision Agency. Annual report for year 2015 [Internet]. 2016. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2015.pdf [Accessed: April 10, 2022]'},{id:"B29",body:'Slovenian Insurance Supervision Agency. Annual report for year 2016 [Internet]. 2017. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2016.pdf [Accessed: April 10, 2022]'},{id:"B30",body:'Slovenian Insurance Supervision Agency. Annual report for year 2017 [Internet]. 2018. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2017.pdf [Accessed: April 10, 2022]'},{id:"B31",body:'Slovenian Insurance Supervision Agency. Annual report for year 2018 [Internet]. 2019. Available from: https://www.a-zn.si/wp-content/uploads/AZN-Letno-porocilo-2018.pdf [Accessed: April 10, 2022]'},{id:"B32",body:'Slovenian Insurance Supervision Agency. Annual report for year 2019 [Internet]. 2020. Available form: https://www.a-zn.si/wp-content/uploads/AZN-Letno-porocilo-2019.pdf [Accessed: April 10, 2022]'},{id:"B33",body:'Slovenian Insurance Supervision Agency. Annual report for year 2020 [Internet]. 2021. Available from: https://www.a-zn.si/wp-content/uploads/letno_porocilo-2020.pdf [Accessed: April 10, 2022]'},{id:"B34",body:'Health Insurance Institute of Slovenia. Annual report for year 2021 [Internet]. 2022. Available from: https://www.zzzs.si/?id=126&detail=12ED7829B4BE74DCC12587F80044EABD [Accessed: April 10, 2022]'},{id:"B35",body:'Thomson S, Evetovits T. Preučitev smiselnosti dopolnilnega zdravstvenega zavarovanja (English: A study on the rationale for the complementary health insurance). WHO Europe and European Observatory on Health Systems and policies, October 2015 [Internet]. 2015. Available from: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/viewer.html?pdfurl=https%3A%2F%2Fwww.gov.si%2Fassets%2Fministrstva%2FMZ%2FDOKUMENTI%2FOrganizacija-zdravstvenega-varstva%2FAnaliza-zdravstvenega-sistema-v-Sloveniji%2FSLO_Preucitev-upravicenosti-dopolnilnega-zdravstvenega-zavarovanja.pdf&clen=963295 [Accessed: April 22, 2022]'},{id:"B36",body:'Employment Service of the Republic of Slovenia. Statistical data on unemployment in Slovenia, monthly statistics from 1992 to 2022 [Internet] 2022. Available from: https://www.ess.gov.si/_files/14934/Mesecno_gibanje_BO_1992-2022.xls [Accessed: April 24, 2022]'},{id:"B37",body:'Keber D, Leskovar B, Petrič V-K. Zdravstvena reforma: pravičnost, dostopnost, kakovost, učinkovitost: osnutek (English: Health Reform: fairness, access, quality, and performance: a draft). Ljubljana, Slovenija: Vlada Republike Slovenije, Ministrstvo za zdravje; 2003'},{id:"B38",body:'Klemenčič Š. Financiranje sistema zdravstvenega varstva na temelju solidarnosti in socialne pravičnosti (English: Funding of the health care system based on solidarity and social justice). Master’s thesis. Kranj: University of Maribor, Faculty of Organisational Sciences [Intranet]. 2018. Available from: https://dk.um.si/Dokument.php?id=130631&lang=eng [Accessed: April 06, 2022]'},{id:"B39",body:'Health Insurance Institute of Slovenia. Annual report for year 2020 [Internet]. 2021. Available from: https://www.zzzs.si/zzzs-api/e-gradiva/podrobnosti/?detail=A998991F0F548B4BC125868C0040BA61&id=126&cHash=e92a64e133c52989eb1e41a24796ecc6 [Accessed: April 06, 2022]'},{id:"B40",body:'Health Insurance Institute of Slovenia. Annual report for year 2013 [Internet]. 2014. Available from: https://www.zzzs.si/zzzs-api/e-gradiva/vsa-gradiva/?vrsta=BR39ZT328 [Accessed: April 06, 2022]'}],footnotes:[{id:"fn1",explanation:"In September 2008, the number of unemployed was at its lowest level since January 1992 at 59,303, only to rise in the wake of the crisis to a peak of 129,843 unemployed in January 2014, an increase of 219% [38]."}],contributors:[{corresp:null,contributorFullName:"Tit Albreht",address:null,affiliation:'
National Institute of Public Health, Slovenia
Faculty of Medicine, University of Maribor, Slovenia
Faculty of Medicine, University of Ljubljana, Slovenia
Faculty of Social Science, Institute for Economic Research, Slovenia
DOBA Faculty, Slovenia
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The percentage of elderly over the age of 65 is expected to be more than 15% of the total world population by 2025. As the lifespan increases, there will be a need for maintaining a healthy state for these individuals. Our current knowledge on types and durations of potential anti-aging therapies is quite limited. Recently the zebrafish has emerged as a promising model for understanding the cognitive and neurobiological changes during aging, as well as its use with potential anti-aging interventions. Like humans this model organism ages gradually, displays similar behavioral properties and social characteristics, and in addition, there is a wealth of molecular and genetic tools to uncover the cellular mechanism that contribute to age-related cognitive declines. Drug effect and toxicity can be easily tested in the zebrafish. Therefore, this animal model can provide information about potential therapies that could be translated directly into human populations or provide a more focused treatment direction for testing in other mammalian animal models. The zebrafish will be a powerful tool for uncovering the mysteries of the aging brain.",book:{id:"6474",slug:"recent-advances-in-zebrafish-researches",title:"Recent Advances in Zebrafish Researches",fullTitle:"Recent Advances in Zebrafish Researches"},signatures:"Dilan Celebi-Birand, Begun Erbaba, Ahmet Tugrul Ozdemir, Hulusi\nKafaligonul and Michelle Adams",authors:[{id:"223775",title:"Associate Prof.",name:"Michelle",middleName:null,surname:"Adams",slug:"michelle-adams",fullName:"Michelle Adams"},{id:"224816",title:"BSc.",name:"Ergul Dilan",middleName:null,surname:"Celebi-Birand",slug:"ergul-dilan-celebi-birand",fullName:"Ergul Dilan Celebi-Birand"},{id:"224817",title:"MSc.",name:"Begun",middleName:null,surname:"Erbaba",slug:"begun-erbaba",fullName:"Begun Erbaba"},{id:"224819",title:"Ph.D. Student",name:"Ahmet Tugrul",middleName:null,surname:"Ozdemir",slug:"ahmet-tugrul-ozdemir",fullName:"Ahmet Tugrul Ozdemir"},{id:"224823",title:"Dr.",name:"Hulusi",middleName:null,surname:"Kafaligonul",slug:"hulusi-kafaligonul",fullName:"Hulusi Kafaligonul"}]},{id:"59711",title:"The Role of PSR in Zebrafish (Danio rerio) at Early Embryonic Development",slug:"the-role-of-psr-in-zebrafish-danio-rerio-at-early-embryonic-development",totalDownloads:1160,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"During development, the role of the phosphatidylserine receptor (PSR) in the professional removal of apoptotic cells that have died is few understood. Programmed cell death (PCD) began during the shield stage (5.4 hpf), with dead cells being engulfed by a neighboring cell that showed a normal-looking nucleus and the nuclear condensation multi-micronuclei of an apoptotic cell. Recently, in the zebrafish model system, PS receptor played a new role on corpse cellular cleaning for further normal development during early embryonic development, which also correlated with tissues’ or organs’ complete development and organogenesis. In the present, we summary new story that a transcriptional factor, YY1a, in the upstream of PSR is how to regulate PS receptor expression that linked to function of PSR-phagocyte mediated apoptotic cell engulfment during development, especially the development of organs such as the brain and heart. YY1a/PSR-mediated engulfing system may involve in diseases and therapy. This engulfing system may provide new insight into phosphatidylserine receptor how to dynamitic interaction with apoptotic cell during priming programmed cell death.",book:{id:"6474",slug:"recent-advances-in-zebrafish-researches",title:"Recent Advances in Zebrafish Researches",fullTitle:"Recent Advances in Zebrafish Researches"},signatures:"Wan-Lun Taung, Jen-Leih Wu and Jiann-Ruey Hong",authors:[{id:"66487",title:"Prof.",name:"Jiann",middleName:"Ruey",surname:"Hong",slug:"jiann-hong",fullName:"Jiann Hong"}]},{id:"60880",title:"Transient-Receptor Potential (TRP) and Acid-Sensing Ion Channels (ASICs) in the Sensory Organs of Adult Zebrafish",slug:"transient-receptor-potential-trp-and-acid-sensing-ion-channels-asics-in-the-sensory-organs-of-adult-",totalDownloads:1216,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Sensory information from the aquatic environment is required for life and survival of zebrafish. Changes in the environment are detected by specialized sensory cells that convert different types of stimuli into electric energy, thus originating an organ-specific transduction. Ion channels are at the basis of each sensory modality and are responsible or are required for detecting thermal, chemical, or mechanical stimuli but also for more complex sensory processes as hearing, olfaction, taste, or vision. The capacity of the sensory cells to preferentially detect a specific stimulus is the result of a characteristic combination of different ion channels. This chapter summarizes the current knowledge about the occurrence and localization of ion channels in sensory organs of zebrafish belonging to the superfamilies of transient-receptor potential and acid-sensing ion channels that are involved in different qualities of sensibility superfamilies in the sensory organs of zebrafish. This animal model is currently used to study some human pathologies in which ion channels are involved. Furthermore, zebrafish is regarded as an ideal model to study in vivo the transient-receptor potential ion channels.",book:{id:"6474",slug:"recent-advances-in-zebrafish-researches",title:"Recent Advances in Zebrafish Researches",fullTitle:"Recent Advances in Zebrafish Researches"},signatures:"Antonino Germanà, Juan D. Muriel, Ramón Cobo, Olivia García-\nSuárez, Juan Cobo and José A. Vega",authors:[{id:"59892",title:"Prof.",name:"José A.",middleName:null,surname:"Vega",slug:"jose-a.-vega",fullName:"José A. Vega"},{id:"227081",title:"Prof.",name:"Antonino",middleName:null,surname:"Germanà",slug:"antonino-germana",fullName:"Antonino Germanà"}]},{id:"41563",title:"Fish Cytokines and Immune Response",slug:"fish-cytokines-and-immune-response",totalDownloads:5552,totalCrossrefCites:20,totalDimensionsCites:60,abstract:null,book:{id:"3193",slug:"new-advances-and-contributions-to-fish-biology",title:"New Advances and Contributions to Fish Biology",fullTitle:"New Advances and Contributions to Fish Biology"},signatures:"Sebastián Reyes-Cerpa, Kevin Maisey, Felipe Reyes-López, Daniela Toro-Ascuy, Ana María Sandino and Mónica Imarai",authors:[{id:"92841",title:"Dr.",name:"Mónica",middleName:null,surname:"Imarai",slug:"monica-imarai",fullName:"Mónica Imarai"},{id:"153780",title:"Dr.",name:"Sebastian",middleName:null,surname:"Reyes-Cerpa",slug:"sebastian-reyes-cerpa",fullName:"Sebastian Reyes-Cerpa"},{id:"157025",title:"Dr.",name:"Kevin",middleName:null,surname:"Maisey",slug:"kevin-maisey",fullName:"Kevin Maisey"},{id:"157026",title:"Dr.",name:"Felipe",middleName:"Esteban",surname:"Reyes-López",slug:"felipe-reyes-lopez",fullName:"Felipe Reyes-López"},{id:"157027",title:"MSc.",name:"Daniela",middleName:null,surname:"Toro-Ascuy",slug:"daniela-toro-ascuy",fullName:"Daniela Toro-Ascuy"},{id:"157028",title:"Dr.",name:"Ana",middleName:null,surname:"Sandino",slug:"ana-sandino",fullName:"Ana Sandino"}]}],onlineFirstChaptersFilter:{topicId:"1380",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"June 25th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,annualVolume:11400,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,annualVolume:11401,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,annualVolume:11402,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:58,paginationItems:[{id:"81961",title:"Antioxidants as an Adjuncts to Periodontal Therapy",doi:"10.5772/intechopen.105016",signatures:"Sura Dakhil Jassim and Ali Abbas Abdulkareem",slug:"antioxidants-as-an-adjuncts-to-periodontal-therapy",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82357",title:"Caries Management Aided by Fluorescence-Based Devices",doi:"10.5772/intechopen.105567",signatures:"Atena Galuscan, Daniela Jumanca and Aurora Doris Fratila",slug:"caries-management-aided-by-fluorescence-based-devices",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81894",title:"Diet and Nutrition and Their Relationship with Early Childhood Dental Caries",doi:"10.5772/intechopen.105123",signatures:"Luanna Gonçalves Ferreira, Giuliana de Campos Chaves Lamarque and Francisco Wanderley Garcia Paula-Silva",slug:"diet-and-nutrition-and-their-relationship-with-early-childhood-dental-caries",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:27,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}}]},overviewPagePublishedBooks:{paginationCount:8,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7060",title:"Gingival Disease",subtitle:"A Professional Approach for Treatment and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/7060.jpg",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",publishedDate:"October 23rd 2019",editedByType:"Edited by",bookSignature:"Alaa Eddin Omar Al Ostwani",hash:"b81d39988cba3a3cf746c1616912cf41",volumeInSeries:4,fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention",editors:[{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. 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\r\n\tIf we aim to prosper as a society and as a species, there is no alternative to sustainability-oriented development and growth. Sustainable development is no longer a choice but a necessity for us all. Ecosystems and preserving ecosystem services and inclusive urban development present promising solutions to environmental problems. Contextually, the emphasis on studying these fields will enable us to identify and define the critical factors for territorial success in the upcoming decades to be considered by the main-actors, decision and policy makers, technicians, and public in general.
\r\n
\r\n\tHolistic urban planning and environmental management are therefore crucial spheres that will define sustainable trajectories for our urbanizing planet. This urban and environmental planning topic aims to attract contributions that address sustainable urban development challenges and solutions, including integrated urban water management, planning for the urban circular economy, monitoring of risks, contingency planning and response to disasters, among several other challenges and solutions.
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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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