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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"643",leadTitle:null,fullTitle:"Recent Advances in Theories and Practice of Chinese Medicine",title:"Recent Advances in Theories and Practice of Chinese Medicine",subtitle:null,reviewType:"peer-reviewed",abstract:"During the recent years, traditional Chinese medicine (TCM) has attracted the attention of researchers all over the world. 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He graduated from the Meiji Pharmaceutical University, obtaining his PhD in the field of pharmaceutical chemistry. So far he has been awarded a number of honorary titles for his contributions to Traditional Chinese Medicine (TCM) development in China, including: state-level teaching; winner of the State Council Special Allowance; supervisor of National Excellent Doctoral Dissertation; member of the China Pharmacopoeia Committee; China Food and Drug Administration's Commissioner's special citation, and China new drug appraisal expert. Prof. Kuang is always engaged in Chinese Medicine research and has acquired a significant number of achievements in natural product research, theory of TCM property, and creative drugs. He has led many multidisciplinary research programs and published over 50 scientific papers in international journals in the TCM filed. 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Now, he is working as the Leading Researcher of PIAPMM of NAS of Ukraine. In 2014, he held an academic degree of Senior Research Fellow (Algebra and the Theory of Numbers) from Ministry of Education and Science of Ukraine that is equivalent to Associate Professor. He obtained the award for significant achievements in the field of science from the Lviv Regional State Administration and Regional Council (2019, 2021). His research interests are mostly in Algebra, Linear Algebra and their Applications. He has more than 80 scientific publications, from them more than 60 are papers with the high science citation index that have been published in well-known professional scientific journals and editor\'s books. 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It surrounds by hard tissues called dentin. Nutrients and oxygen supply are acquired from blood vessels passing through apical and accessory foramen of the teeth’s root. Dental pulp originates from cranial neural crest cells [1]. Dental pulp tissues are composed of extracellular matrix and various cell types, e.g. fibroblasts, odontoblasts, endothelial cells, pericytes, immune cells and stem cells. When injured, cells in dental pulp tissues are capable of differentiating odontoblasts or odontoblast‐like cells, leading to the promotion of tertiary dentin formation. The formation of tertiary dentin is a mechanism which can protect the tooth vitality. Dental pulp tissues remaining in physiological shedding of deciduous teeth are the alternative source of mesenchymal stem cells, due to the ease of accessibility and minimally invasive technique to obtain tissues [2]. Stem cells from human exfoliated deciduous teeth (SHEDs) are firstly identified by Miura et al. in 2003 [2]. SHEDs have high proliferation potency and are multipotent mesenchymal stem cells. These cells are able to differentiate into, not only, dental pulp‐related cells, but also, other cell lineages, for example osteoblasts, adipocytes, neuronal‐like cells and endothelial cells [2–8]. Taking these advantageous properties together, SHEDs are one of the candidate cell types for tissue regeneration study.
SHEDs are heterogeneous population of cells isolated from dental pulp tissues remained in exfoliated deciduous teeth. Similar to those mesenchymal stem cells (MSCs), SHEDs exhibit fibroblast‐like morphology, adhere on plastic tissue culture surface, express mesenchymal stem cell surface marker and have multipotential differentiation ability (Figure 1). SHEDs have higher proliferation rate compared to dental pulp stem cells (DPSCs) and bone marrow‐derived mesenchymal stem cells (BMMSCs) [2, 9]. This could be due to the high expression of genes related to cell proliferation and extracellular matrix in SHEDs comparing with DPSCs [9]. First, a study by Miura et al. demonstrated that SHEDs express mesenchymal surface markers, STRO‐1 and CD146 [2], though, the percentage of positive cells is low [2]. Later studies utilized various surface markers for SHEDs characterization protocol. SHEDs expressed CD44, CD73, CD90, CD105 and STRO‐1 [6]. In addition, these cells lack of CD45 expression [6]. Besides these markers described above, SHEDs also express other surface markers for example, CD166 and SSEA4. Lack of CD34 is also reported [10]. There is no specific surface marker to precisely identify SHEDs population.
Characteristics of stem cells isolated from human exfoliated deciduous teeth. The expression of stem cells markers was evaluated using flow cytometry and conventional semi‐quantitative PCR (A and B). The osteogenic, adipogenic and neurogenic differentiation were evaluated at day 14, 16 and 7 after induction, respectively (C–E). The mineral deposition and intracellular lipid accumulation were determined using alizarin red and oil red O staining, respectively (C and D). The β3‐tubulin protein expression was evaluated by immunocytochemistry staining (E). The expression of differentiation marker was examined using conventional semi‐quantitative PCR. Reprinted from Archives of Oral Biology, 60(3), Nunthawan Nowwarote, Prasit Pavasant, Thanaphum Osathanon, Role of endogeneous basic fibroblast growth factor in stem cells isolated from human exfoliated deciduous teeth, 408–15, Copyright (2015), with permission from Elsevier [
Up to date, MSCs can be isolated from many tissue types. Though, there is no specific marker to clearly identify these cells. According to the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy, the minimum criteria to identify MSCs are as follow [11]. First, the isolated MSCs should adhere to plastic tissue culture plate [11]. Second, MSCs must express several specific surface markers, namely CD105, CD73 and CD90 [11]. They also should not express CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA‐DR [11]. Finally, MSCs have to be able to differentiate into osteoblasts, adipocytes and chondroblasts
Two methods have been utilized for SHEDs isolation, namely an enzymatic digestion and a tissue explant. The enzymatic digestion is performed by digesting minced remaining pulp tissues from deciduous teeth, normally with type I collagenase and dispase mixed enzyme solution [12–14]. For tissue explant, minced pulp tissues are placed on the tissue culture dishes, allowing the outgrowth of the cells from the tissues [12]. Enzymatic digestion technique leads to more heterogeneous population of isolated cells than those obtained from tissue outgrowth protocol [14]. A study illustrated that there is no significant difference regarding cell morphology and proliferation between cells isolated using enzymatic digestion and tissue outgrowth [14]. Enzymatic digestion‐derived SHEDs had higher mineralization ability
Studies have shown that SHEDs possess multi‐differentiation potency similar to MSCs. Those lineages include odontogenic/osteoblastic, adipogenic, neurogenic and angiogenic differentiation [2].
The ability of SHEDs to differentiate into odontoblastic lineage is widely known [2, 15, 16]. Primitively, SHEDs were characterized by their
Evidence suggested that SHEDs might have the preference towards the odontoblastic lineage due to its origin. SHEDs can be induced to become functional odontoblasts
Neurogenic potential of SHEDs is expecting due to their neural crest embryonic origin. Several research studies focusing on differentiating dental stem cells to be used for neurodegenerative disease therapy. These cells are prone to undergo neurogenic differentiation both
Angiogenic potential of SHEDs is another aspect of interest for the benefit of connective tissue regeneration. The rapid and effective induction of vasculation is required for sufficiently supply of oxygen and nutrients as well as removing the toxic waste from the newly synthesized tissues. Unstimulated SHEDs expressed VEGFR1 and NP‐1, the known important receptors in angiogenesis and VEGFR1 signalling play an important role in VEGF‐induced capillary tube formation by SHEDs as shown by VEGFR1 gene silencing [30]. SHEDs cultured in the tooth slice/scaffolds in combine with VEGF expressed several endothelial differentiation markers such as VEGFR1, VEGFR2, platelet endothelial cell adhesion molecule‐1 (PECAM‐1) and vascular endothelial cadherin (VE‐Cadherin). When transplanted in immunodeficient mice, SHEDs actually lined the new blood vessels within the tooth slice/scaffolds close to the blood vessels of host [3]. Similar results were observed when SHEDs seeded in human tooth slice/scaffolds and transplanted into immunodeficient mice differentiate into human blood vessels that anastomosed with the mouse vasculature and VEGF induced the angiogenic differentiation of SHEDs through Wnt/β‐catenin signalling [31]. Another study also showed that SHEDs can differentiate into VEGFR2‐positive and CD31‐positive endothelial cells
Several studies have reported that SHEDs can be induced into adipogenic lineage [6, 32–34]. After cultured in an adipogenic medium, SHEDs’ morphology changed from spindle‐like to polygonal shapes and lipid vacuoles were observed, along with the increased in PPARγ2 and LPL mRNA [32]. However, the studies evaluated the adipogenic potential of SHEDs
Like other MSCs, SHEDs exhibit immunomodulatory properties. Though, the potency and mechanism are not exact the same to those of BMMSCs [10, 35]. SHEDs significantly reduced the percentage of IL17+IFNγ cells population in CD4+ T cells
Basic fibroblast growth factor (bFGF) is a member in fibroblast growth factor family [38]. It binds to fibroblast growth factor receptors (FGFR) and further initiates intracellular signalling [39]. bFGF has been shown to participate in the regulation of stemness maintenance and cellular differentiation. In human DPSCs, bFGF promotes pluripotent stem cell marker expression, corresponding with the increase of colony‐forming unit [40]. Furthermore, bFGF inhibits osteogenic differentiation by SHEDs, human DPSCs and human periodontal ligament stem cells (PDLSCs) when supplemented in osteogenic induction medium (Figure 2) [5, 40]. In this regard, alkaline phosphatase enzymatic activity and mineralization are markedly decreased under bFGF‐treated condition compared with the control [5, 40]. On the contrary, bFGF enhances the expression of neurogenic marker, βIII‐tubulin, via FGFR and PLCγ when human DPSCs are cultured in a neurogenic induction medium supplemented with bFGF [40].
bFGF inhibited
In SHEDs, long‐term culture
Regarding osteogenic differentiation, bFGF attenuated osteogenic differentiation. In this regard, bFGF attenuated alkaline phosphatase enzymatic activity and mineralization in SHEDs after osteogenic induction [5, 43]. The inhibition of endogenous bFGF in SHEDs either by a chemical inhibitor for FGFR or lentiviral shRNA against bFGF resulted in the enhancement of osteogenic differentiation [6]. It was also demonstrated that bFGF attenuated alkaline phosphatase mRNA expression and mineral deposition via FGFR and MEK signalling pathway [5].
Several possible mechanisms were reported. Firstly, bFGF might attenuate osteogenic differentiation in SHEDs via decreasing Notch signalling [5]. Notch signalling activation led to the enhancement of mineralization in SHEDs [7]. Treatment with bFGF attenuated Notch receptor, ligand and target gene expression which may participate in bFGF attenuated osteogenic differentiation in SHEDs [5]. Secondly, bFGF inhibited matrix metalloproteinase (MMP) expression, for example
Canonical Wnt signalling also has a significant role in tooth development and stem cells self‐renewal through β‐catenin [46, 47]. Inactivation of β‐catenin in the mesenchyme of developing tooth results in arrested tooth developmental at the bud stage [48]. Various studies established the influence of canonical Wnt signalling pathway to promote the osteogenic differentiation of dental stem cells, i.e. DPSCs, PDLSCs, stem cells from apical papilla (SCAPs) and dental follicle stem cells (DFSCs) [49–52]. However, the effect of the canonical Wnt/ β‐catenin on SHEDs is very limited. The involvement of Wnt/β‐catenin on SHEDs‐mediated mineralized tissue regeneration was investigated with the addition of basic fibroblast growth factor (bFGF) [43]. Treatment with bFGF attenuated SHEDs‐mediated mineralized tissue regeneration via activation of ERK 1/2 pathway and consequently inhibited Wnt/β‐catenin pathway, leading to osteogenic deficiency of SHEDs [43].
A recent
Activation of β‐catenin by LiCl in SHEDs led to the significant decrease of colony formation by SHEDs [55]. In addition, LiCl enhanced subG0 population in SHEDs [55].
Notch signalling controls various function of stem cells, ranging from stemness maintenance to cell‐specific differentiation [56]. It is a highly conserved pathway, firstly identified in Drosophila. Notch signalling is initiated by the binding between membrane‐bound Notch receptors and ligands of neighbouring cells [56–58]. Further, Notch receptors are cleaved by a γ‐secretase enzyme, leading to the release of Notch intracellular domain (NICD) [56–58]. Subsequently, NICD translocates into nucleus and forms complex with other transcriptional molecules, resulting in the activation of Notch target genes [56–58]. Common Notch signalling target genes are Hes and Hey families [56–58]. In the canonical Notch signalling pathway, four receptors and five ligands are identified [56–58]. The four types of Notch receptors are Notch1, Notch2, Notch3 and Notch4. Five ligands are Delta‐like‐1 (Dll‐1), Delta‐like‐3 (Dll‐3), Delta‐like‐4 (Dll‐4), Jagged1 and Jagged2 [56–58].
Notch signalling participates in odontogenesis, dental pulp repair and regeneration. Mice lacking of Jagged2 expression exhibited defective enamel formation of incisors and malformation of molars [59]. The expression of Notch receptors and ligands was upregulated in response to calcium hydroxide, a material for direct pulp capping treatment [60]. Human DPSCs over‐expressing Jagged1 exhibited the reduction of osteogenic differentiation ability and mineralization
Studies illustrated that indirectly immobilized Notch ligands, Jagged1 or Dll‐1, on tissue culture surface increased
Effects of Dll‐1 and Jagged1 on osteogenic differentiation. The alkaline phosphatase enzymatic activity (A) and mineralization (B) were evaluated at day 7 and 14 after osteogenic induction, respectively. For osteoblast marker gene expression, cells were cultured on Dll‐1, Jagged1 or hFc treated surface for 7 days after osteogenic differentiation. The graphs demonstrated the relative mRNA expression of
It has been shown that bFGF inhibited the mRNA expression of Notch signalling components. In this regard, bFGF significantly reduced the mRNA levels of
Dental pulp tissues are surrounded by hard tissues, namely dentin. During inflammation, an interstitial fluid pressure increases [65, 66], causing biological changes in local cells and tissues. In addition, fluid movement in dentin‐pulp complex during normal occlusal force may expose cells to mechanical stimuli [67]. Mechanical forces are shown to regulate biological functions in many cell types, for example osteoblasts, osteocytes, periodontal ligament cells and dental pulp cells. Different types and magnitude of force lead to different cell responses. In human DPSCs, uniaxial cycle stretching inhibited odonto/osteogenic differentiation but increased cell proliferation [68, 69], while cyclic hydrostatic pressure synergistically enhanced BMP‐2‐induced DSPP expression by human DPSCs
SHEDs are the good candidate for the stem cells used in regenerative therapy due to their high plasticity as well as ability to cross lineage boundaries and differentiate into several specialized cells. Current progresses have been made for tissue engineering‐based therapies involving a large number of tissues. However, dentin-pulp complex and neuronal tissue seem to be the most promising aspects for the application of SHEDs in regenerative therapy.
The first evidence to show that SHEDs can differentiate to become the functional odontoblasts with the ability to generate the mineralized tissue resemble to dentin was shown in mice [3]. SHEDs were seeded within a scaffold in a tooth slice and implanted into the dorsum of mice. Dental pulp‐like tissue was observed in the central area of the pulp chamber of the tooth slice [3]. The expression of odontoblastic differentiation markers such as DSPP and DMP‐1 was detected [3]. Remarkably, the newly deposited dentin was observed and suggested that SHEDs can differentiate into fully functional odontoblasts
Current possible experimental approaches for dentin pulp complex regeneration using SHEDs.
In addition to dentin-pulp complex regeneration, SHEDs also show the potential to be used in neuroregeneration. Stem cell therapy is the promising therapeutic options for treating the neurodegenerative diseases due to the limited regenerative capacity of the specialized cells in the nervous system. The neural crest cell in origin makes SHEDs the candidate cell model for neuron tissue regeneration. These cells are prone to undergo neurogenic differentiation both
In a focal cerebral ischemia rat model induced by permanent middle cerebral artery occlusion, intranasal administration of supernatants from the medium used to culture SHEDs significant decreased in the motor disability score and significantly reduced in the infarct volume [72]. Moreover, positive signals for neuronal nucleus, neurofilament H, doublecortin and rat endothelial cell antigen in the peri‐infarct area were observed in the rats treated with SHEDs conditioned media compared to the DMEM control from approximately 140 mm3 in DMEM control to 50 mm3 in SHEDs conditioned medium [72]. These results suggest that SHEDs might secrete some compounds that positively influence the recovery of the brain lesion in focal cerebral ischemia [72].
Studies have shown that SHEDs have remarkable neuroregenerative activity and promote functional recovery in a spinal cord injury animal model [29, 75]. Rats that received SHEDs transplantation within the lesion created at the 9th–11th thoracic vertebral levels exhibited higher scores in the locomotor rating scale compared to the bone marrow stromal cells or fibroblasts transplantation control [75]. In addition, the rescue of hindlimb locomotor function was prominent in the rats that received SHEDs. These animals were able to move hindlimb coordinately and walk, while the bone marrow stromal cells transplantation exhibited only subtle movements [75]. A similar trend was observed in another study, a complete recovery of hindlimb motor function was observed after implantation of neural‐induced SHEDs in a rat spinal cord injury [29] which suggested that preinduction of the undifferentiated SHEDs into the neural‐like cells before implantation might improve the efficiency of SHEDs in regenerating specialized neural cells. Taken together, these high neurogenic potential of SHEDs especially in animal models makes them the favourable source for stem cell regeneration treatment for neural diseases.
Dental stem cells, including SHEDs, have been extensively studied in the past decades leading to the better understanding in their unique biological properties and therapeutic potential. As SHEDs can be easily obtained with limited ethical concern, their multi‐differentiation potentials have been demonstrated, which creates great opportunities for the application in the regenerative therapy. However, despite the intriguing results, we still need further study to deepen the understanding of the mechanisms underlying the differentiation processes to attain clinical reality. Also, the potential risks for the clinically use of SHEDs or other dental stem cells should be thoroughly studied for the safety of the patients who will greatly benefit from their regenerative ability.
The authors thank for support of the Faculty of Dentistry Research Fund, Chulalongkorn University. We would like to thank Dr. Pattarin Potisomporn for the illustration in Figure 4.
Akt | Protein kinase B |
ALP | Alkaline phosphatase |
ApoE | apolipoprotein E |
ATP | Adenosine triphosphate |
bFGF | Basic fibroblast growth factor |
BMMSCs | Bone marrow‐derived mesenchymal stem cells |
BSP | Bone sialoprotein |
CD | Cluster of differentiation |
COL1 | Collagen type 1 |
DAPT | N‐[N‐(3,5‐Difluorophenacetyl)‐L‐alanyl]‐S‐phenylglycine t‐butyl ester |
DDK | Dickkopf |
DFSCs | Dental follicle stem cells |
Dll | Delta‐like |
DMEM | Dulbecco’s Modified Eagle Medium |
DMP‐1 | Dentin matrix acidic phosphoprotein 1 |
DMP | Dentin matrix protein |
DPSCs | Dental pulp stem cells |
DSP | Dentin sialoprotein |
DSPP | Dentin phosphoprotein |
ERK | Extracellular signal‐regulated kinase |
FASL | Fas ligand |
FGFR | Fibroblast growth factor receptor |
GFAP | Glial fibrillary acidic protein |
HA | Hydroxyapatite |
Hes | Hairy and enhancer of split |
Hey | Hairy and enhancer of split related with YRPW motif protein |
HGF | Hepatocyte growth factor |
HLA‐DR | Human leukocyte antigen‐antigen D related |
IFN | Interferron |
IL | Interleukin |
JAK | Janus kinase |
LEF‐1 | Lymphoid enhancer binding factor 1 |
LiCl | Lithium chloride |
LPL | Lipoprotein |
MEK | Mitogen‐activated protein kinase kinase |
MEPE | Matrix extracellular phosphoglycoprotein |
MMP | Matrix metalloproteinase |
MSCs | Mesenchymal stem cells |
MSX2 | Msh homeobox 2 |
MT1‐MMP | Membrane type1‐ matrix metalloproteinase |
NICD | Notch intracellular domain |
Nurr1 | Nuclear receptor related 1 protein |
OCN | Osteocalcin |
OCT4 | Octamer‐binding transcription factor 4 |
OPN | Osteopontin |
OSX | Osterix |
P2Y1 | Purinergic receptor P2Y1 |
PCR | Polymerase chain reaction |
PDLSCs | Periodontal ligament stem cells |
PECAM‐1 | Platelet endothelial cell adhesion molecule 1 |
Pitx3 | Paired like homeodomain 3 |
PLCγ | Phospholipase C gamma |
PPARγ2 | Peroxisome proliferator‐activated receptor‐gamma 2 |
PRP | Platelet‐rich plasma |
REX1 | Reduced Expression Protein 1 |
RUNX2 | Runt‐related transcription factor 2 |
SCAPs | Stem cells from apical papilla |
SHEDs | Stem cells isolated from human exfoliated deciduous teeth |
shRNA | Short hairpin ribonucleic acid |
SOX2 | Sex determining region Y‐box 2 |
SSEA4 | Stage‐specific embryonic antigen‐4 |
TCP | Tricalcium phosphate |
TERT | Telomerase reverse transcriptase |
TWIST | Twist Family BHLH Transcription Factor |
VE‐Cadherin | Vascular endothelial cadherin |
VEGF | Vascular endothelial growth factor |
VEGFR | Vascular endothelial growth factor receptor |
Today, there is no controversy about considering acute and chronic pain based on a foundation of neurobiology influenced by and interacting with biological, psychological, and social/contextual factors [1, 2, 3]. Hence, modern clinical practice applies a biopsychosocial (BPS) framework in assessments and treatments [4, 5]. This approach is the result of developments that have occurred over the past 70 years.
Units dedicated to treat pain were developed in the USA based on physicians’ experiences with chronic pain in soldiers during and after World War Two. During this period, surgeons and anaesthesiologists attempted to alleviate both chronic and acute pain mainly using blockades and local anaesthesia [6]. Later, this type of unit expanded into Europe and Sweden. The first multidisciplinary pain clinic opened in the 1960s as a development of the pain clinic founded by John Bonica in the 1950s at the University of Washington in Seattle (USA) [7]. Bonica realised that patients with complex pain problems were not helped by single specialties, and during the 1950s he brought neurosurgeons, psychiatrists, and anaesthesiologists to his clinic. In 1959, Wilbert Fordyce, a psychologist hired by the Department of Physical Medicine and Rehabilitation at the same hospital, became interested in applying behavioural strategies in the assessments and treatments of chronic pain. Their collaboration led to the incorporation of psychologists in pain clinics and later other health care providers trained in different but related areas [6]. Bonica also led an international initiative that resulted in the formation of an association of researchers and clinicians dedicated to the understanding and treatment of pain (International Association for the Study of Pain, IASP).
In 1982, Fordyce’s psychological program and Bonica’s pain clinic merged under the direction of John Loeser [6]. Under this new arrangement, patients were evaluated and treated by teams, and the BPS model started to be used in pain programs. These early programs had to deal with medication problems and addiction, so inpatient treatment became the standard. During the 1970s, the number of multidisciplinary pain clinics following the example of Seattle’s clinic grew in the USA and later in Australia, New Zealand, and Europe. During the 1980s, psychologists began to add cognitive treatment strategies to the programs, which opened up treatment to a broader mix of patients. By 1990, cognitive-behavioural pain management programs were widespread and became the golden standard of care. During the 1980s and the 1990s, many studies focused on interdisciplinary pain programs (IPRPs), and new theories were launched [6, 8, 9].
The positive development in the USA slowed down at the beginning of 2000, and most units offering IPRPs closed their operations in the following decade, except for units in the Department of Veterans Affairs (VA). The Commission for the Accreditation of Rehabilitation Facilities (CARF) offers a specific set of standards that emphasise the interdisciplinary setting and the BPS model for the treatment of chronic pain. As the CARF standards remained focused on the BPS framework, the number of accredited programs illustrates the development in the USA. In 1998, there were 205 accredited chronic pain programs in the USA. By 2004, the number decreased to 125, 11 of which were VA programs [6]. These programs, excluding the VA IPRPs, decreased to 63 in 2010, 53 in 2015, and 32 in 2020 (Carolan Terrence, CARF, personal communication). However, outside the USA, the development has gone in the opposite direction. By the end of 1990 outside the USA, fewer than five tertiary pain units with CARF accredited pain programs were in operation; however, by 2021, this number had increased to 140 (CARF, personal communication). According to many reports, the decline in the USA was due to opioid use as a medication for chronic pain, but this approach, as the result of the opioid pandemic, is currently being replaced by initiatives to re-start IPRP.
Both evidence and clinical practice guided the development of how to face the problem of chronic pain—from viewing chronic pain as a symptom of underlying causes to viewing chronic pain as a dysfunction (i.e., from a biomedical approach to a biopsychosocial approach). Therefore, treatments have evolved from monodisciplinary to multidisciplinary treatments and from multidisciplinary treatments to interdisciplinary programs.
During the 1970s and 1980s, the novel approaches to chronic pain developed slowly in Sweden. As new methods and treatments were developed, national guidelines for chronic pain treatment were warranted. In 1994, an expert group formed by the Swedish National Board of Health and Welfare summarised the recommendations for treatment of chronic pain based on the International Association for the Study of Pain (IASP) guidelines and available evidence at the time. In 2006 and 2010, two compilations of evidence for chronic pain treatments, commissioned by the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU; see below), confirmed the conclusions of the 1994 report about appropriate methods and lack of evidence for methods still being used. In the 2006 and 2010 reports, one method was singled out as an evidence-based approach, the IPRP. These reports contributed to a governmental decision to financially support the development of IPRPs throughout Sweden. During this period, a registry for pain rehabilitation was formed through an initiative of the professions with the aim to analyse outcomes of pain rehabilitation. The registry with the support of the affiliated units and the national organisation of county councils (SKL) developed into a national quality registry that included all tertiary pain rehabilitation units as well as units operating at the primary care level.
In clinical practise, patients with complex chronic pain conditions with difficulties coping with their condition in daily life are referred to an IPRP. These patients’ ability to cope with their pain can be compromised by co-morbidities and/or their work situation. Often, these patients have tried monodisciplinary interventions and/or pharmacological treatments without marked improvements. The Swedish guidelines regarding indications for IPRP, which have been approved by several authorities and professional organisations, recommend that IPRP be offered to chronic pain patients with complex clinical presentations and when monodisciplinary interventions have not been effective [10].
In 2011, the IASP stated in the Declaration Montreal that ‘access to pain management is a fundamental human right’ [11]. This humanitarian approach is important; however, availability to IPRP is scarce, as mentioned above, in several parts of the world, and chronic pain is common in the general population—approximately 20% of the European and North American population has a significant chronic pain condition [12, 13]. In addition, as many patients with chronic pain rarely seek health care services, these patients seem to have adapted to their pain condition to lead lives with minor consequences to their function and well-being. This needs to be considered as IPRP is costly interventions in the short run and patients need to be fully invested in the process and very possibly have a sense of urgency to benefit from treatment and be motivated to engage in behavioural and cognitive change. The motivation to behavioural and cognitive change is fundamental as an indication for IPRP. For IPRP to be used with an ethical and humanitarian perspective, it needs to prioritise individuals who suffer from substantial consequences of their chronic pain condition regarding function, social, and/or psychological well-being.
The idea of treating chronic diseases with a broader approach than the biomedical approach was first launched by Engel in a biopsychosocial (BPS) model for the treatment of diseases, especially chronic diseases [14]. The model emphasises the mutual interactions between biological, psychological, and experiential or social factors that impact people’s perceptions of their overall health. This model lies at the core of the multidisciplinary and interdisciplinary approaches to the treatment of chronic pain. Similarities and differences between these approaches are described in detail elsewhere [7]. Although both rely on the BPS model, they differ regarding whether the goals of the professionals are integrated, whether professionals work collaboratively in teams, and whether their treatments are provided simultaneously or sequentially [9, 15]. The interdisciplinary treatment, which is based on the BPS approach [1], is the standard treatment used in IPRPs. According to IASP, interdisciplinary treatment is a:
The programs usually include experts working in an integrated manner with physical, social, psychological, and medical aspects to diminish the consequences of chronic pain in these or other areas [7, 16]. The principal components of IPRP are as follows:
a team assessment of the chronic pain problem and its consequences;
the establishment of a treatment plan, including interventions by different professions with goals to be achieved during the program;
communication between team members and between the team, the patient, and significant others;
deliveries of the different synchronised interventions of IPRP;
evaluation of the interventions;
documentation; and
a discharge process, including interaction with other stakeholders.
Other researchers have also identified the same content [17]. Although the areas covered by the interdisciplinary programs are well described elsewhere, there are very few descriptions of the interventions used in clinical practice in IPRPs, usually describing the interventions used in specific centres, such as Mayo Clinic or Chicago University Hospital [16]. In Sweden, it is possible to gather information on the interventions used in clinical practice from most of the IPRPs affiliated with the Swedish National Registry. Of the 39 affiliated units, 31 were included [18]. The usual contents of IPRP described by Swedish units are as follows:
dialogue and education (e.g., education, training in wellness and healthy living habits, meetings with families, video feedback, and couples therapy) and self-training (e.g., home lessons, activity diary, physical self-training, reflection time, and self-analysis);
activity training (activity training, graded activity training, and exposure training);
meetings (conferences with patients, rehabilitation team, vocational guidance, rehabilitation coordinator, goal-setting meetings, and meetings to check goal achievement);
cognitive behavioural therapy, other psychological treatments (e.g., supervised group therapy, pain or a stress coping course, psychological and social aspects, post-traumatic stress disorder (PTSD) treatment, and psychodynamic methods) and Acceptance and Commitment Therapy (ACT) (e.g., goal compass, training in ACT principles, and mindfulness);
relaxation techniques; and
physical exercise.
Only 14 of 31 programs reported using interventions in the workplace. All programs reported having follow-ups (1-year follow-up by mail or at the unit for completing the registry’s questionnaires). Usually, extra follow-up meetings were scheduled two to three months after discharge from rehabilitation (21 of 31 units).
The optimal composition of IPRP with respect to length, contacts with therapists, and intensity are insufficiently known according to a systematic review (SR) [19] and a meta-analysis (MA) [20]. The former concluded that because dose variables were not investigated separately in the RCTs, the reviewers could not disentangle the interrelationships between dose, content, and effects of IPRP on disability, work, and quality of life. Similarly, a longitudinal study of IPRP dosage (i.e., duration) could not establish an optimal dosage [21].
Generally, IPRP goals include improving important outcomes (4,5). There are several simultaneous general goals to be considered—decreased pain intensity and increased mental health; increased participation in work/studies and social life; and increased health and quality of life. These general goals are combined with the specific goals of the individual with chronic pain. Thus, goals should ideally be set at the level of the individual, the rehabilitation teams, and the socio-economic constraints. The latter is essential since IRRPs historically have been financial failures. For IRRP to prosper and receive funding, the considerable socio-economic costs of chronic pain need to be considered. Goals, such as return to work/studies and decrease in medication use, health care use, and surgery, will in the long run also benefit the individual move towards an active, independent lifestyle.
As chronic pain is a complex experience with possible adverse effects on function and social and psychological well-being, goal setting should include several aspects and involve a BPS perspective. The general goals for IPRPs are mentioned above. In addition to these goals, there is an increasing emphasis on cognitive areas that could mediate positive changes, such as catastrophizing, acceptance of the pain condition, avoidance of activity due to unrealistic concerns about harm, and expectations of pain treatment [22].
Researchers have debated whether pain intensity aspects should be amongst the main outcomes of pain treatments included in IPRP [23, 24, 25, 26]. Many patients consider reducing pain to be the most important aspect of treatments with respect to regaining a normal lifestyle; however, changing this view is considered an intrinsic component of IPRP. Many chronic pain patients eligible for IPRP have experienced how short-sighted attempts to control only pain intensity can lead to vicious cycles of increased physical and psychological disability and reduced quality of life. Thus, many IPRPs have largely adopted the idea of introducing acceptance as a cornerstone of the psychological component of IPRP (i.e., the willingness to experience pain as it is) and encouraging patients to set up activity-related rehabilitation goals and to risk initial pain flare-ups. This means that patients are advised against establishing pain reduction as the only or the most important goal. Paradoxically, in the long run, pain reduction is one of the more robust results of IPRP [27]. Nevertheless, in traditional CBT, a cornerstone and mainstream in IRPs, an array of strategies is presented, strategies that target the consequences of pain with non-pharmaceutical techniques for pain control.
The process of goal setting is vital and fundamental both for the individual and the team as goal setting has been shown to promote greater behavioural change across a wide range of behaviours [28]. At the individual level, a thorough assessment that is communicated to the patient and a collaborative goal-setting process will increase engagement and adherence to treatment. In addition, the rehabilitation team will benefit from formulating common goals for treatment, reviewing results, and improving plans to stay engaged and to be flexible. The latter should constitute an important goal for the team as role models for patients. Often, the goal is to attain goals that are SMART—i.e., Specified, Measurable, Attractive, Realistic, and Time-limited [29, 30]. However, possibly the most important quality for goals is to be personalised and agreed upon by the patient. The team should strive for a collaborative approach but must always bear in mind that the patient is in a more vulnerable position and might easily give in to goals that might, for example, not feel relevant or feel too demanding. Motivational Interviewing (MI) can be used to discover a patient’s motivation for a specific goal when a patient finds it difficult to specify goals. Patients are often more focused on avoiding unpleasant experiences and frequently the main wish of the patient is to be free of pain. As such, the goal-setting can constitute an acceptance of intervention as it models how to focus on the attainable and let go of the difficult to achieve a goal—i.e., pain relief.
Nevertheless, the SMART model for goal setting has lately been challenged by Acceptance and Commitment Therapy (ACT), the third wave CBT. ACT, which has increasingly been introduced in IRRP, emphasises identifying important values and not primarily setting specified, time-limited goals. However, the SMART model can be used as a step towards identifying important values.
The variety of interventions used at most IPRPs in a single country [18] is in itself a challenge when it comes to measuring the outcomes of IPRPs delivered in clinical settings. Nevertheless, the areas addressed correspond to the areas proposed by the BPS model. In addition to the variety of interventions within IPRPs, many tools have been used both by researchers and clinicians to assess patients and to measure IPRP outcomes. Two well-known initiatives to bring consensus into the areas of evaluating clinical trials, including IPRP are the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [4, 31] and the validation and application of a patient-relevant core set of outcome domains to assess multimodal PAIN therapy (VAPAIN) initiatives (Table 1) [32].
IMMPACT’s domains | VAPAIN’s domains |
---|---|
Pain | Pain intensity and frequency |
Emotional function | Emotional well-being |
Physical function | Physical activity |
Productivity | |
Satisfaction with social roles and activities | |
Self-evaluation on overall improvement and satisfaction with the intervention | Patient’s perception of achieved treatments goals |
Symptom and side-effects of intervention | |
Participant disposition (including participation and discontinuation of participation) | Reasons for discontinuation of treatment |
Domains of IMMPACT and VAPAIN.
IMMPACT identifies relevant outcome domains for clinical studies and proposes reliable measurement tools for the study of treatments of chronic pain, including all possible modalities and approaches. IMMPACT has resulted in several studies evaluating clinical treatments. VAPAIN specifically targets IPRPs. These initiatives have some overlapping domains that are included in clinical trials (Table 1). VAPAINs focused on IPRPs led to the addition of two domains considered critical when the treatment is interdisciplinary—productivity and patient satisfaction with social roles and activities. VAPAIN renamed certain domains and extended their scope (e.g., the more inclusive ‘emotional well-being’ rather than ‘emotional function’).
A different approach taken by a Canadian research group focuses on the variables of interest for health care providers and the variables of interest for patients, according to lists of parameters from the Patient-Reported Outcomes Measurement Information System (PROMIS), the International Classification of Functioning, Disability and Health (ICF), and current guidelines [33]. Here, the initiative was to identify the set of variables that are important to both providers and patients. They triangulated the ICF and the PROMIS frameworks with the perspectives (both the patients’ and clinicians’ perspectives) and found a common list of ten variables—pain interference, pain intensity, physical function, sleep disturbance, anxiety, depression, ability to participate in social roles and activities, fatigue, sleep-related impairments, and self-efficacy. The authors conclude that these variables mirror the BPS model covering the physical, psychological, and social consequences of chronic pain on an individual’s life both from the perspective of people with chronic pain and the perspective of health care providers.
There is a need to develop clinically applicable, standardised, and accepted ways to evaluate IPRP. IPRP is a complex intervention with several general goals (see above) and is delivered by an interdisciplinary team of professionals in close collaboration with the patient and considering the patient’s specific goals. This is entirely different from a pharmacological intervention, which aims to alter a biochemical process to decrease pain intensity (Figure 1). In fact, an IPRP tries to influence several levels, including the behaviours of the patient with chronic pain. Hence, in clinical practice, there are several outcomes and to make things, even more, complicated the important goals for the individual patients may differ. Due to these circumstances, the concept of one or two primary outcomes and a few secondary outcomes applied in pharmacological randomised controlled trials (RCTs) do not reflect the complexity of IPRP. In a systematic review (SR) by SBU, the included RCTs on average had nine outcome variables and the variables were seldom divided into primary and secondary outcomes [23].
The complexity of IPRP versus a pharmacological intervention.
The evaluation of complex interventions, such as IPRP is not clear-cut [34]. Clinically applicable, standardised, and accepted ways to evaluate the multiple outcomes of IPRP in individual patients clinically and in trials, SRs/meta-analysis (MAs) and observational studies are lacking. If the changes in outcomes are intercorrelated (they often are, see below), it may be problematic to evaluate the outcome measures separately as sometimes is done [35]. In contrast, SBU defined a positive outcome of an RCT when the
Because evaluations of several outcomes often raise an issue of multiple comparisons, Bonferroni corrections may be recommended [42, 43]. This is a conservative approach when the number of tests increases and can reduce the chances to detect real treatment effects [42, 44, 45]. Moreover, such corrections are intended for corrections of
The available SRs and MAs indicate that IPRP is an evidence-based intervention. Table 2 lists and briefly describes the results of available SRs and MAs based on only RCTs according to Dragioti et al.’s [47] search strategy.
First author, year, and reference | Type | Patients | No. of RCTs* | Main results and comments |
---|---|---|---|---|
Nielson 2001 [48] | SR | CP with separate analysis for CLBP, FM, and other | 21 |
|
Guzman 2002 [49] | SR+MA | CLBP | 10 |
|
SBU 2006 [23] | SR | CP with separate analysis for FM | 46 |
|
van Geen 2007 [50] | SR | CLBP | 10 |
|
Scascighini 2008 [37] | SR | CP with separate analyses for CBLP and FM | 36 |
|
Norlund 2009 [51] | SR+MA | CLBP | 7 |
|
Häuser 2009 [52] | SR+MA | FM | 9 |
|
SBU 2010 [36] | SR | CP with separate analyses for CLBP and FM | Partial update of 2006 SBU**
| |
van Middelkoop 2011 [53] | SR+MA | CLBP | 83 |
|
Kamper 2014 [35] | SR+MA | CBLP | 41 |
|
Gianola 2018 [54] | SR+MA | CBLP | 22 | Partial reanalyses of Kamper et al.’s review [35] using minimal important differences units (MIDs). Using this approach, they concluded that IPRP led to improvements in an appreciable number of patients in the short- and medium-term after IPRP. In the long term, IPRP probably had little or no benefit for most patients. |
Casey 2020 [55] | SR+MA | CP | 27 |
|
Martinez-Calderon 2020 [56] | SR+MA | CP | 60 | Investigates the outcome pain self-efficacy.
|
Martinez-Calderon 2020 [57] | SR | CLBP | 61 | Investigates outcomes of fear.
|
Martinez-Calderon 2021 [58] | SR | FM | 12 | Investigates the outcome of pain-related fear.
|
Brief conclusions from Systematic Reviews (SR) and Meta-Analyses (MA) of IPRP identified using Dragioti et al.’s search strategy [47].
Not all RCTs may be used for the analyses of IPRP outcomes.
Note that GRADE was used in the 2010 SBU report but not in the 2006 SBU report.
SR = Systematic Review with narrative synthesis of data; MA = Meta-Analysis; RCT = Randomised Controlled Trial; IPRP = Interdisciplinary Pain Rehabilitation; CLBP = chronic low back pain; FM = fibromyalgia; CP = non-specific chronic pain conditions; TAU = treatment as usual; and WLC = waiting list controls.
SRs and MAs using several simultaneous outcomes report positive outcomes for IPRP for chronic pain conditions [23, 35, 36, 37, 48, 49, 52, 53, 55]. Studies using overall assessments of outcomes and therefore considering that IPRP is a complex intervention agree that IPRP has positive outcomes with moderate to strong evidence [23, 36, 37]. There is no consensus regarding the duration of the effects after IPRP (follow-up time) [23, 35, 36, 37, 48, 52, 53, 54, 55]. When outcome variables are evaluated independently, the outcomes associated with positive effects differ across studies [50, 53, 56, 57, 58]. Articles reporting results for fibromyalgia separately reported positive outcomes for IPRP. However, both evidence levels and follow-up periods (short, medium, or long term) differed [23, 36, 37, 52, 58]. The conclusions regarding the effects of IPRP on vocational variables, such as return to work (RTW) and sick leave were heterogenous according to these reviews [23, 35, 36, 48, 49, 50, 51].
The authors of these reviews identify several problems and limitations. Most SRs report that there is heterogeneity in study settings, interventions, and control groups. It is difficult to compare the patient groups included in the identified RCTs since there is no internationally accepted way to describe the patient groups. In addition, the number of comorbidities and duration of sick leave can differ, and external factors, such as the social security situation can differ considerably across studies from different countries and years. Some of the variables suggested by IMMPACT and VAPAIN can be useful for the development of a standardised set of variables that can be used to describe chronic pain patient cohorts [4, 31, 32]. Moreover, because there is no internationally accepted definition of IPRP, authors of SRs and MAs must create their own operational definitions to identify the relevant RCTs. In the quality assessments of RCTs, the issue of blinding might be problematic, and IPRP studies may be classified with lower quality since it is impossible to blind IPRP for patients. Different results in the reviews might also depend on the specific criteria for inclusion and the fact that parts of reviews are based on judgements of researchers.
The results from RCTs, SRs, and MAs must be confirmed in real-life consecutive flow of patients in clinical settings. Direct clinical application of the results from RCTs is not suitable in all situations as these studies might be associated with bias and the patients investigated in RCTs might not represent real-world patients (i.e., insufficient external validity) [59]. Hence, the results from RCTs and SRs must be confirmed in real-life settings, for example, using registry data. This methodology is labelled
Most real-world observational evaluations of IPRP are based on within-group analyses over time. However, such observational studies are often associated with bias. Creating an objection-free control group in clinical practice in association with registries of IPRP is ethically, economically, and practically impossible. To date, attempts using other types of registries for creating a control group have not been successful [61]. Fortunately, methods have been developed that emulate randomisations based on observational data, which allows comparisons between interventions [62]. Target trial emulations are increasingly applied (e.g., in clinical pharmacology, oncology, cardiovascular diseases, critical care, and rheumatology) and can under appropriate circumstances give valid effect estimations compared to RCTs [63, 64]. When target trial emulations can be adequately performed, they generally yield stronger evidence than other types of observational research designs [63]. However, these are not simple methods or without limitations and biases [65, 66, 67]. Although criticised, a first attempt has been made that focuses on sick leave associated with IPRP using data from the SQRP (see below) [68]. If further research and refinements of registries covering IPRP conclude that this methodology is applicable, it would be a great advantage. It would further increase the importance of registries for improving the clinical results of IPRP and other complex interventions for patients with serious chronic pain conditions.
There are usually two approaches to building a registry, and both influence the architecture and content of the registry. Registries are either built to answer research questions or to provide clinical evaluations to providers at each site. SQRP was built primarily around the second approach. The initiative to start SQRP was taken within the professionals’ network, the decision made by the leadership of the units delivering IPRP around 1997. Since its inception, in 1998, the registry has addressed the description of what was being offered at the clinical settings, the overall situation of the patients being admitted, and the changes reported in the included instruments at discharge and 1-year follow-up. Therefore, the SQRP has always worked very closely with the clinicians providing treatment as they are a source of knowledge to be used in the assessment of patients and the evaluation of their progress in the programs as well as describe data at the organization’s level. The general goals are given in Table 3.
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|
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General goals of SQRP.
The registry aims to highlight data on structure, processes, and outcomes. Outcomes are retrieved at the individual, group, unit, and national levels (Table 4).
Type of intervention | |||
Number of registrations | |||
Time | |||
Reasons for discharge | |||
Level of the individual (patient profile and reports) | |||
Level of the unit (group reports) | |||
Level of the country (yearly reports) | |||
R 1 | |||
R 2 | |||
R 3 | |||
R 4 |
Clinical evaluations (levels of analysis).
R = Report.
Every year SQRP follows how the registry is used at the clinical level and promotes plans for improvements. Examples of improvement work, using measures of the registry (according to answers to the 2019 survey) are presented in Table 5.
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Examples of improvement work using measures of the registry.
An overview of the variables and instruments included in the registry (2021) is presented in Table 6. Hence, SQRP is mainly a patient-reported registry, including mostly patient-related outcome measures (PROM data) as well as patient-related evaluation measures (PREM data). The PREM variables concern satisfaction with reception/encounter, the site information, degree of participation in the rehabilitation plan, teamwork, and family participation in the program.
Type | Variables and instruments |
---|---|
Self-report and background information | |
Socio-demographic data | |
Work | |
Sick leave | |
Pain duration Pain extent | |
Attitude towards the future | |
Self-report, Instruments, and variables | |
Numeric Rating Pain Scale (NRPS) | |
The Hospital Anxiety and Depression Scale (HAD) | |
Multidimensional Pain Inventory (MPI) | |
Health-related life quality (RAND-36) | |
Perceived health (the EuroQol Group) (EQ-5D) | |
Chronic Pain Acceptance Questionnaire (CPAQ 8) | |
Insomnia Severity Index (ISI) | |
Perceived work ability index (WAI) | |
Kinesiophobia (TAMPA) | |
Perceived physical activity (3 items) | |
Changes in pain experience (retrospective items) | |
Changes in ability to handle life situations (retrospective items) | |
Patient satisfaction (six items) | |
Professional-evaluated variables | |
Diagnosis | |
Pain mechanisms | |
Expected future financial-support form | |
Swedish language ability | |
Rehabilitation plan |
Variables of SQRP.
The registry also includes self-reported background information. There are some variables that are evaluated by the professionals in the program (Table 6).
Some other Swedish quality registries were built to answer research questions and are now working to adapt the output of information to the needs of clinicians at the sites where healthcare is provided. On the other hand, SQRP has been working to improve its operations to allow for research questions to be explored by improving the validity of its information, reducing dropouts, and enhancing routines to avoid missing values and registration errors. In 2011, a national research network (SQRP research group) was formed through initiatives developed by the SQRP’s steering group. This group has developed different research programs focused on the registry, leading to grants from different research funds, dissertations, and many publications. In this way, SQRP is becoming a source of knowledge for researchers interested in finding answers to the complex interventions included and the heterogeneous group receiving treatment.
SQRP collects a large amount of self-reported mandatory data concerning pain aspects, psychological distress, interference, health aspects, etc. together with background data from patients referred to specialist pain care in Sweden. The information covering the BPS framework complements information included in the clinical assessments. To determine which variables are generally important in patients with chronic pain, one approach investigates variables important for health aspects.
Pain severity, pain interference, and pain intensity were the most important regressors of health (N > 37 000 patients at baseline) followed by two variables that focus on control of pain and coping with pain, and four variables (also significant) reflecting mood aspects according to a cross-sectional SQRP study (Figure 2) [69]. Extent and duration of pain, age, gender, and background variables were not significant regressors.
OPLS regression of health (EQ5D-index) using other self-reported variables at baseline as regressors. Only significant variables are shown. Data are from [
Another approach is to use PCA to identify variables associated with prominent variations—i.e., high scores. Pain aspects, such as intensity and interference, psychological distress, coping, and health aspects, are the most important and therefore carry the most information for the clinical presentation according to SQRP studies [70, 71].
It is a clinical experience that patients with the same diagnosis show considerable variations in their presentations and consequences. Therefore, in the context of improving outcomes of interventions, there is a great interest to identify relevant subgroups of chronic pain patients. Most studies have been hypothesis-driven with respect to the input variables for subgrouping. Based on some mandatory variables covering the BPS framework, two subgroups/clusters of patients have been identified from SQRP data (N = 37 100) [70]. The subgroup with the most intense pain intensity/severity had the worst situation regarding psychological distress, interference in daily life, and least life control [70]. Furthermore, according to variables not used as input variables, this subgroup had more pain extent (spreading of pain) and more people born outside Europe. Also, smaller SQRP studies report that the patient group is not homogenous and different subgroups have been identified [71, 72].
The Multidimensional Pain Inventory (MPI) classifies patients into subgroups [73, 74]. These subgroups—Adaptive Coper (AC), Dysfunctional (DYS), and Interpersonally Distressed (ID)—were identified in a large cohort from the SQRP (N = 34 513) and the validity of these subgroups of MPI was partially confirmed [75]. However, in contrast to results reported by Turk and Rudy, the subgroups differed in socio-demographic characteristics, pain duration, and pain extent [73]. Hence, factors other than psychosocial may be important for understanding MPI responses.
In an SQRP sample (N > 38 000), the presence of severe anxiety symptoms was detected in 39.5% and the corresponding outcome for depression was 35.2% according to established cut-offs for the Hospital Anxiety and Depression Scale (HAD) [70]. Although psychological distress was common, the strength of the intercorrelations between pain intensity and anxiety and depression scales of HAD were low. The explained variations (r2) were between 3 and 11%. Two SQRP studies from different times investigated the prevalence of clinical insomnia according to Insomnia Severity Index (ISI) and reported a prevalence between 65 and 66% [76, 77]. Hence, it is important to assess insomnia in patients with complex chronic pain. A network analysis (N = 2 241) reported that psychological variables, such as acceptance and depression mainly were associated with pain interference, whereas the associations with pain intensity and extent together with insomnia were weak [78]. These results taken together may be important for expectations about treatment results (i.e., improvements in psychological distress may not necessarily lead to important improvements in pain intensity).
The pain extent is registered using 36 predetermined anatomical regions in the SQRP, which were summarised and divided into four categories: 1–6 regions with pain (20.6% of patients), 7–12 regions (26.8%), 13–18 regions (22.0%), and 19–36 regions (30.6%) (N = 39 916) [79]. A higher extent of pain spreading was associated with a more severe clinical picture at baseline and longer pain duration with the strongest associations emerging in relation to health and pain aspects (pain intensity, pain interference, and pain duration) [79]; generally, there were at least medium effects sizes (ESs) when comparing the two extreme groups. A cross-sectional multivariate analysis found that pain spreading correlated strongest with general health, vitality, female gender, physical function, pain interference, pain intensity aspects, and pain duration [79].
Patients with chronic pain generally have a higher Body Mass Index (BMI) than healthy controls. Obese patients had a worse pain profile (e.g., pain intensity, pain extent, and pain duration) and more depressive and insomnia symptoms than normal-weight patients according to another SQRP study (N = 3 310) [80].
Most patients referred to the specialist departments in Sweden are women (about 70%). The reasons for this overrepresentation are unclear and are only partially explained by the higher chronic pain prevalence in the population [81, 82]. It is unclear whether sex/gender differences for pain severity exist [83, 84, 85]. According to SQRP data, there were generally small differences (generally insignificant ESs) in clinical presentation according to self-reported data between the two genders [86, 87]. Generally, patients born outside Europe had a more severe clinical picture than those born in Europe, for example, with respect to pain intensity and psychological distress (medium ESs) [87]. Patients with only an elementary school education generally reported a worse clinical situation than those with a university education (most variables small to medium ESs).
A cluster analysis using gender, country of birth (Europe vs. outside Europe), and education level (three categories) as input variables identified five subgroups—three subgroups of European women and different education levels, one subgroup of European men, and one subgroup of non-European men and women and different education levels [87]. Prominent differences in clinical presentations, such as pain intensity, psychological distress, interference, life control, and health aspects, were noted between European women with university education and the non-European subgroup (worst situation) (ESs generally medium to large). European women with only elementary school also displayed a worse situation than those with university education.
To summarise, patient groups referred to specialist pain care in Sweden are not homogenous with respect to clinical presentations as distinct subgroups are evident. The clinical presentations show clear associations with pain extent, BMI, and socio-demographic variables.
Not all patients assessed and registered at baseline in SQRP are selected or choose to participate in IPRP. Unfortunately, the registry does not contain data that can separate these two reasons and other possible reasons, nor does it collect detailed information about assessments, all interventions offered (including IPRP), the interventions’ contents and dosages, and patient-related preferences and choices. Assessments of patients, including establishing treatment plans, are clinically necessary and perceived as important by patients. The assessment including a treatment plan with follow-up in primary care per se appears to be associated with positive significant effects on several aspects of the clinical presentation [88]. However, the ESs were insignificant to small.
The Swedish guidelines recommend that IPRP at the specialist level is offered to chronic pain patients with complex clinical presentations, for example, with respect to comorbidities [10]. However, the subgroup with the most severe clinical situation was somewhat underrepresented [70, 89]. Similar results were found for the DYS subgroup of MPI, male gender, and the non-European subgroup [75, 87]. In agreement with this SQRP, data from two university hospital departments showed negative correlations between participation/selection and pain intensity but positive correlations with pain extent [90]. The reasons for these selections are currently unclear and further research is needed.
IPRP in clinical settings is associated with improvements on the group level with small to medium effect sizes for the majority of the mandatory self-reported outcome variables, for an overall score and retrospective items. Sick-leave data retrieved from the Swedish Social Insurance Agency database show important decreases after IPRP.
The outcomes of IPRP were investigated in a study of more than 14 000 patients (Table 7) [27]. Significant improvements were generally found except for one or two of the three scales of the second part of MPI (how husband/wife reacts when a patient has pain). Most outcomes showed small ESs and some outcomes were associated with moderate ESs (Table 2). For the pre vs. post-IPRP comparisons, three variables had moderate effects sizes—two pain intensity variables and vitality (Table 7). At the 12-month follow-up, the same pain intensity variables were associated with moderate effect sizes; this was also the case for pain interference and a health aspect (Table 6). The variables of the second part of MPI had insignificant ESs both post IPRP and at the 12-month follow-up.
Pre vs. post-IPRP | Pre vs. FU | |||||||||||
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Pre | Post IPRP | Pre | FU | |||||||||
Outcome variables | Mean | SD | Mean | SD | ES | Mean | SD | Mean | SD | P-value | ES | |
NRS-7days | 6.86 | 1.72 | 5.95 | 2.09 | <0.001 | 0.45 | 6.84 | 1.72 | 5.78 | 2.32 | <0.001 | 0.47 |
HADS-Anxiety | 9.00 | 4.76 | 7.78 | 4.55 | <0.001 | 0.32 | 8.73 | 4.69 | 7.38 | 4.70 | <0.001 | 0.33 |
HADS-Depression | 8.49 | 4.44 | 6.70 | 4.31 | <0.001 | 0.47 | 8.18 | 4.37 | 6.74 | 4.66 | <0.001 | 0.35 |
MPI-Pain-severity | 4.39 | 0.93 | 3.87 | 1.16 | <0.001 | 4.36 | 0.91 | 3.71 | 1.33 | <0.001 | ||
MPI-Pain-interference | 4.38 | 1.02 | 3.94 | 1.19 | <0.001 | 0.49 | 4.34 | 1.02 | 3.73 | 1.37 | <0.001 | |
MPI-Life Control | 2.72 | 1.10 | 3.30 | 1.18 | <0.001 | 0.47 | 2.77 | 1.10 | 3.28 | 1.27 | <0.001 | 0.40 |
MPI-Distress | 3.46 | 1.26 | 2.89 | 1.38 | <0.001 | 0.42 | 3.42 | 1.27 | 2.92 | 1.45 | <0.001 | 0.35 |
MPI-Social support | 4.16 | 1.34 | 3.95 | 1.35 | <0.001 | 0.21 | 4.17 | 1.33 | 3.77 | 1.42 | <0.001 | 0.35 |
MPI-punish | 1.74 | 1.36 | 1.72 | 1.33 | 0.037 | 0.02 | 1.69 | 1.34 | 1.69 | 1.35 | 0.676 | 0.01 |
MPI-protect | 2.98 | 1.40 | 2.85 | 1.38 | <0.001 | 0.12 | 2.96 | 1.39 | 2.78 | 1.40 | <0.001 | 0.16 |
MPI-distract | 2.54 | 1.19 | 2.56 | 1.17 | 0.043 | 0.02 | 2.52 | 1.17 | 2.45 | 1.17 | <0.001 | 0.06 |
MPI-General activity index | 2.44 | 0.84 | 2.63 | 0.82 | <0.001 | 0.26 | 2.47 | 0.83 | 2.64 | 0.86 | <0.001 | 0.20 |
EQ-5D-index | 0.26 | 0.31 | 0.39 | 0.33 | <0.001 | 0.40 | 0.27 | 0.31 | 0.44 | 0.34 | <0.001 | |
EQ-VAS | 41.22 | 19.09 | 50.99 | 21.38 | <0.001 | 0.44 | 41.90 | 19.29 | 52.96 | 22.87 | <0.001 | 0.46 |
sf36-pf | 52.76 | 20.58 | 57.67 | 21.17 | <0.001 | 0.30 | 53.07 | 20.30 | 59.73 | 22.57 | <0.001 | 0.36 |
sf36-rp | 12.53 | 24.40 | 22.46 | 33.12 | <0.001 | 0.30 | 13.07 | 24.91 | 27.74 | 36.32 | <0.001 | 0.39 |
sf36-bp | 24.36 | 14.49 | 32.96 | 17.41 | <0.001 | 24.60 | 14.11 | 35.41 | 20.05 | <0.001 | ||
sf36-gh | 41.70 | 20.22 | 46.69 | 21.88 | <0.001 | 0.29 | 42.59 | 20.49 | 47.35 | 23.52 | <0.001 | 0.25 |
sf36-vt | 23.95 | 18.48 | 35.67 | 22.76 | <0.001 | 24.96 | 18.79 | 34.41 | 23.85 | <0.001 | 0.41 | |
sf36-sf | 47.29 | 25.19 | 54.93 | 25.91 | <0.001 | 0.30 | 48.95 | 25.50 | 57.66 | 27.05 | <0.001 | 0.32 |
sf36-re | 42.77 | 42.92 | 51.15 | 43.48 | <0.001 | 0.18 | 44.69 | 43.17 | 55.60 | 43.53 | <0.001 | 0.22 |
sf36-mh | 55.03 | 21.35 | 62.55 | 21.55 | <0.001 | 0.38 | 56.34 | 21.15 | 62.70 | 22.53 | <0.001 | 0.30 |
Mandatory outcome variables at baseline (pre) and immediately after IPRP (post IPRP) (left part; N = 12 999–14 772) and at baseline and at 12-month follow-up (FU) (right part; N = 7 784–8 904). Statistical comparisons are presented with effects sizes (ES, i.e., Cohen’s d). Effect sizes in bold were moderate, i.e., Cohen’s d ≥ 0.50. These data have been reported in Ringqvist et al. [27].
The effect sizes >0.50 are given in bold. The significance (p-values) are reported in the columns to the left of the columns concerning effect sizes. NRS-7days = Pain intensity as measured by a numeric rating scale for the previous 7 days; HADS = Hospital Anxiety and Depression Scale; MPI = Multidimensional Pain Inventory; EQ-5D-index = The index of the European quality of life instrument; EQ-VAS = The European quality of life instrument thermometer-like scale; sf36 = The Short Form (36) Health Survey; subscales; pf = physical functioning; rp = role limitations due to pf physical functioning; bp = bodily pain; gh = general health; vt = vitality; sf = social functioning; re = role limitations due to emotional problems; and mh = mental health.
In 2008, the Swedish government introduced a rehabilitation guarantee to enhance, for example, the implementation of IPRP in primary care. The SQRP created a module to collect data from IPRP in primary care. A relatively small study (N = 397) of the clinical presentation of the patients treated at this care level found that patients presented a considerable complexity [91]. A small study (N = 234) evaluated the outcomes of IPRP in primary care 1 year after discharge for 10 of the 11 variables selected. Eleven outcomes reflecting a BPS approach were evaluated 1 year after IPRP and 10 of these showed significant improvements although ESs were small (0.20–0.49) [92]. A cost-utility analysis indicated that IPRP in primary care was cost-effective [93].
The intercorrelations of changes in the 22 mandatory outcome variables (cf. Table 7) were investigated using PCAs [27]. Two groups of variables (components), which were not correlated, were identified; the first showed significant intercorrelations between changes in 18 of the outcomes and the second mainly reflected the changes in the second part of MPI together with changes in social support of MPI. Using the score of the first component, a Multivariate Improvement Score (MIS) was defined reflecting changes in the 18 variables [27]. A cluster analysis of MIS was made, and three clusters were identified; retrospectively their baseline situation was analysed. Cluster 1—overall the worst situation pre IPRP—showed the most positive improvements in MIS. Cluster 3—no changes or deterioration in MIS—had the best situation at baseline. Cluster 2 was an intermediary group at baseline and was associated with overall slightly positive MIS improvements [27].
Both post-IPRP and at 12-month follow-up patients retrospectively estimate the degree of positive change in pain and in their ability to handle life situations in general (both rated on five-point Likert scales from markedly increased pain/markedly worsened life situation (score 0) to markedly decreased pain/markedly improved (score 4) [27]. At both time points, most patients reported that their pain situation (57% at both time points), as well as their ability to handle their life situation, had improved (84 and 77%); the two most positive alternatives were added [27].
All patients undergoing IPRP registered in SQRP between 2007 and 2011 (n=7 297) were linked to the Swedish Social Insurance Agency database and the development of sick leave was analysed [94]. Sick-leave benefits increased during the year before IPRP and decreased after IPRP (analysed up to 2 years after) (Figure 3). These reductions in benefits were significant for both men and women. It was concluded that IPRP could positively influence sick-leave benefits for these patients regardless of their sick-leave situation, sex/gender, or policy changes.
Level of sick leave at 90–0 days before (T1) IPRP, 320–410 days after (T2) IPRP, and 775–985 days after (T3) IPRP; N = 7 297 (Rivano Fischer et al. [
A larger study of sick absence for patients included in SQRP (N = 44 241) showed similar results—i.e., sick absence increased from 17% 5 years before to 48% at assessment at the specialist department and thereafter decreased to 38% [95]. Sickness absence history was the strongest predictor of future sickness. Decreases in pain intensity/severity and pain interference but not increases in life control and social support or reduced affective stress during IPRP were associated with decreased risk of being on full-time sick leave 1 year later according to another SQRP study (N = 1 468) from a university department [96]. The same authors reported from a cohort of 2 784 patients that the subgroup DYS of MPI decreased after IPRP [97]. Those belonging to AC or ID had less full-time sick leave 1 year later and therefore the DYS profile was associated with long-term sick leave.
Decreases in sick leave after IPRP were reported in a target trial emulation study using SQRP data (N = 25 613) [68], but the results were not significantly better than for the comparison group. The article was the first target trial emulation attempt using SQRP data (see above). This study has been criticised for its heterogenous comparator group and lack of data concerning other interventions and patient preferences [98]. In addition, this critique emphasised that very complex processes may exist after the assessment when preparing and establishing the rehabilitation/treatment plan. Hence, registries such as SQRP need to collect detailed data concerning assessments, all interventions offered (including contents and dosages), as well as patient-related preferences. More details about the clinical departments might also be beneficial [18]. Perhaps one might expect more prominent decreases of sick leave in IPRP than in the comparison group. According to Swedish guidelines, IPRP should be offered to the most complex chronic pain patients, but those participating in IPRP had gross sick leave days the year before IPRP, so that is necessarily not a correct expectation.
Long-term opioid therapy (LTOT) for chronic pain is unfortunately common in clinical practise despite lack of evidence and serious adverse consequences [99, 100, 101, 102, 103]. At a university hospital reporting to SQRP, 30% of the patients referred to a clinical department used opioids daily [104]. These patients had higher pain intensity, more pain interference, lower quality of life, lower activity engagement, and less satisfaction with life than the other patients referred (medium ESs) [104]. Svanberg et al. investigated the opioid prescriptions 2 years after chronic pain patients were assessed for IPRP [105]. Opioid prescriptions were prescribed for 55% of the cohort (N = 1334). The odds of receiving LTOT were similar for those participating and not participating in IPRP. Patient characteristics at baseline/assessment in both these groups could predict LTOT. In those participating in IPRP, dysfunctional pain coping was a predictor; however, in those not participating in IPRP, pain intensity and depressive symptoms were predictors. Taken together, these studies indicate that long-term pharmacological treatment is not optimal for patients who are eligible for IPRP.
Evidence is contradictory when it comes to clinical presentation pre-treatment. A recent meta-analysis on prognostic factors for IPRP outcome demonstrated that both higher levels of general emotional distress and pain-specific cognitive behavioural factors were related to worse long-term (>6 months) physical functioning post-treatment [106]. However, a similar pattern was not displayed in two large-scale SQRP cohort studies where patients reporting higher levels of perceived disability and suffering displayed slightly greater improvement [27, 70]. Hence, those with the most severe clinical presentations at baseline will display the largest improvements found in SQRP studies [70, 71, 75].
Pain distribution (i.e., spreading of pain) is another factor that needs consideration. Cross-sectional population studies have reported that spreading of pain is significantly associated with pain intensity, depressive disorders, and poor health [107, 108]. In a recent large-scale SQRP cohort study, spreading of pain was associated with poorer outcomes of treatment, but the effects were in the small range [79]. Thus, spreading of pain is important for understanding chronic pain as an indicator of severity, as previously described, and to some extent as a predictor of the poorer outcome of IPRPs.
Psychosocial coping profiles with three subgroups have been derived from the MPI and are commonly used to aid in the assessment of patients with chronic pain. Based on a BPS approach to chronic pain, MPI and its subscales are sensitive to changes in the severity of chronic pain and predict sick leave. The dysfunctional (DYS) subgroup reports high pain severity, marked interference in daily life, high affective distress, low perception of life control, and low levels of activity. The adaptive coper (AC) subgroup is characterised by less severe pain, less interference with activities, less affective distress, and positive perceptions of life control and activity level. The interpersonally distressed (ID) subgroup has been described as perceiving low social support and non-supporting behaviours from significant others [109, 110, 111]. Some reports suggest that the DYS and/or ID subgroups have better treatment outcomes than the AC group [109, 112, 113, 114, 115, 116], whereas other studies have found no significant differences in outcomes amongst subgroups [110, 111, 117, 118, 119, 120, 121]. These results are supported by a large-scale cohort study from the SQRP: DYS and ID subgroups that had the most severe clinical presentation at baseline showed the largest improvement following IPRP [75].
The existing literature regarding sex differences in outcomes of IPRP is conflicting—women benefit more [84, 122, 123], no sex differences [124, 125, 126], and men benefit more [127, 128]. The outcomes of IPRPs in a primary care study were better in women than in men [92]. A recent large-scale cohort study from SQRP found sex differences in outcomes—women had slightly better results than men [87]. The conflicting results in the literature may be due to different cohorts investigated as well as the choice of outcomes.
An important principle in healthcare is equity (i.e., prioritization of healthcare based on the need of the patient); however, social contexts are seldom considered in studies [129]. Several studies have reported that prevalence of chronic pain, the severity of pain, and disability are inversely related to the socio-economic position and low education, male sex, and/or non-European origin (in European studies), which appear to be associated with lower participation rates and worse IPRP results [129, 130, 131, 132].
One-fifth of the European adult population lives with at least
As described in previous passages, results from IPRP demonstrate low to moderate effect sizes on outcomes with conflicting results concerning effects on RTW. Possible gains for the individual and society might be accomplished with improvements of routines and contents of IPRP. It is thus problematic that IPRP is somewhat heterogenous as this can constitute problems establishing strategies for improvements. As a comparison,
The results obtained by the SQRP show that the subgroup of patients with a relatively better clinical picture before IPRP had worse IPRP results than those with a more severe clinical picture [70]. The patient group with the more difficult clinical picture is most improved by IPRP but not so much that they reach the subgroup with a better clinical picture. Both circumstances indicate a need for the development of IPRP so that IPRP better matches the clinical picture. For example, individual treatments, short interventions, small group activities with different content to be selected for individual patients, individual treatments with the team as a backup, and closer communication with primary care to ensure that recommendations can improve the lives of patients without going through extensive IPRPs, which might be more appropriate for the less severe subgroups [15]. In the long run, this could mean that different IPRPs are available in clinical settings. In addition, the activated, mainly unknown, neurobiological pain mechanisms might not be sufficiently targeted by the various interventions in IPRP.
Early interventions might also improve results. The association between prominent pain extent (i.e., widespread pain) and pain duration supports the concept of early intervention as clinically important and an opportunity to possibly change prognosis with conceivable gains for the individual and society. Early interventions with psychological risk factor screening combined with protocols for active collaboration between caregivers and key stakeholders have been demonstrated to positively impact return to work [136].
Poorer results of IPRP in socially more challenged populations might suggest that equal care is not delivered. For example, IPRP in Sweden may not meet the needs of patients outside Europe. It has been suggested that in particularly non-Western backgrounds might be associated with other attitudes towards self-management interventions, passive symptom-focused management strategies, as well as pharmacological treatments [137], which could influence IPRP outcomes. Selection to participation in IPRP and outcomes might also be disadvantaged by different biases of professionals towards non-European patients and/or insufficient knowledge about immigration and other cultures. Lower socio-economic groups may differ from health professionals in culture, beliefs, and communication style, resulting in disadvantages and possibly feelings of inferiority. Carr and Moffet provocatively suggest that CBT interventions designed by middle-class health professionals are more suitable for middle-class patients [130]. Also, a common goal of IPRP is increased physical functioning; however, exercise and sports activities are less likely to be adopted by people in lower socio-economic groups than by people in higher socio-economic groups [138, 139, 140].
This raises important questions concerning fairness and equality. The combination of sex, education, and country of birth needs to be considered in the assessment of chronic pain patients and is important to consider when optimising the content and delivery of IPRP in clinical practice. IPRPs need to be adapted and educational elements fitted to meet different learning styles using techniques to increase retention of new information as described in textbooks, such as ‘Explain pain supercharged’ [141]. In addition, Carr and Moffet suggest that a useful starting point when considering how to improve treatments is the knowledge that people in socially-deprived areas endure higher levels of stress and lower perceived control [130]. Techniques are suggested to reduce stress and learned helplessness and include involving patients in shared decision-making of treatment, increased social support, incorporating individual coaching where the individual can learn to take more control, and additional validation where IPRPs are supplemented by phone calls between sessions. When attendance is challenged, audio and video material could be provided for patients unable to attend.
The patient group with chronic/persistent pain conditions referred to specialist care in Sweden are heterogenous and different subgroups exist. The clinical presentations show clear associations with the extent of pain spreading, BMI, and socio-demographic variables. IPRP is an evidence-based intervention for chronic pain patients who suffer from substantial consequences of their chronic pain condition regarding function, social, and/or psychological well-being. The intervention is complex and is delivered by an interdisciplinary team of professionals in close collaboration with the patient. Observational analyses of IPRP in clinical settings agree with the evidence presented in SRs and MAs. However, results differ amongst subgroups and benefits are not present for all patients. Interestingly, those with the most severe clinical presentation, according to registry data, an assessment benefit most from IPRP. Also, socio-economic factors can influence results and need to be addressed to warrant more equal opportunities for improvement in IPRP.
Units offering IPRPs differ in their strategies, services, and resources, both in intensity and duration, as well as in the degree of individual interventions opposed to group treatment. This diversity should be addressed by researchers and incorporated in studies by looking into the impact of referral flow, traditions, and the heterogeneity of the patients assessed. Methods other than randomised studies, such as emulated trials, repeated measured for patients (patients as controls) should be refined to enhance the potential gaining of analysing real-life information in registries.
There is thus room for enhancement of IPRP possibly by a more structured use of registries. Furthermore, pain registries should expand to cover a variety of clinical efforts designed to meet the individual needs of people with chronic pain and to deliver information about the effectiveness of these measures.
The authors declare no conflict of interest.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. 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Women are diagnosed with PTSD approximately twice as often as men. In this review, we outline the evidence of gender differences related to PTSD, and the factors of resilience and susceptibility differ between men and women.",book:{id:"5472",slug:"gender-differences-in-different-contexts",title:"Gender Differences in Different Contexts",fullTitle:"Gender Differences in Different Contexts"},signatures:"Jingchu Hu, Biao Feng, Yonghui Zhu, Wenqing Wang, Jiawei Xie\nand Xifu Zheng",authors:[{id:"190985",title:"Dr.",name:"Xifu",middleName:null,surname:"Zheng",slug:"xifu-zheng",fullName:"Xifu Zheng"},{id:"194981",title:"BSc.",name:"Yonghui",middleName:null,surname:"Zhu",slug:"yonghui-zhu",fullName:"Yonghui Zhu"},{id:"194982",title:"MSc.",name:"Wenqing",middleName:null,surname:"Wang",slug:"wenqing-wang",fullName:"Wenqing Wang"},{id:"194985",title:"Dr.",name:"Jingchu",middleName:null,surname:"Hu",slug:"jingchu-hu",fullName:"Jingchu Hu"},{id:"194986",title:"MSc.",name:"Biao",middleName:null,surname:"Feng",slug:"biao-feng",fullName:"Biao Feng"},{id:"194987",title:"Ph.D. Student",name:"Jiawei",middleName:null,surname:"Xie",slug:"jiawei-xie",fullName:"Jiawei Xie"}]},{id:"52472",doi:"10.5772/65410",title:"Gender and Health",slug:"gender-and-health",totalDownloads:3432,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Research has found differences between women and men in some health indicators. 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Also, differences in self-rated health vary depending on other psychosocial and demographic variables. The present study reviews the main differences in women’s and men’s health as well as the most relevant factors that may account for them.",book:{id:"5472",slug:"gender-differences-in-different-contexts",title:"Gender Differences in Different Contexts",fullTitle:"Gender Differences in Different Contexts"},signatures:"María Pilar Matud",authors:[{id:"189729",title:"Prof.",name:"M. Pilar",middleName:null,surname:"Matud",slug:"m.-pilar-matud",fullName:"M. Pilar Matud"}]},{id:"52503",doi:"10.5772/65457",title:"Gender and Leadership",slug:"gender-and-leadership",totalDownloads:4127,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"The topic of leadership has been addressed and applied for millennia. Yet, it is only within the past 80 years that leadership has been a topic of serious discussion. It is important to understand variables relevant to effective leadership. Gender is one such variable that must be examined with regard to optimizing leadership effectiveness. The topic of gender and leadership deserves serious and thoughtful consideration and discussion because of professional, political, cultural, and personal realities of the twenty‐first century. Women and men have been, are, and should be leaders. Gender must be considered to determine how each leader can reach maximum potential and effectiveness. The FourCe‐PITO conceptual framework of leadership is designed to help guide leadership development and education. The present chapter uses this conceptual framework of leadership to discuss how consideration of gender may affect and optimize leadership development and effectiveness. 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I am giving examples from my developmental psychology research where the split-sample analysis by gender showed amazing and often unexpected effects.",book:{id:"5472",slug:"gender-differences-in-different-contexts",title:"Gender Differences in Different Contexts",fullTitle:"Gender Differences in Different Contexts"},signatures:"Chris Lange-Küttner",authors:[{id:"190245",title:"Prof.",name:"Chris",middleName:null,surname:"Lange-Küttner",slug:"chris-lange-kuttner",fullName:"Chris Lange-Küttner"}]},{id:"53721",doi:"10.5772/66093",title:"Professional Women's Experience of Autonomy and Independence in Sindh-Pakistan",slug:"professional-women-s-experience-of-autonomy-and-independence-in-sindh-pakistan",totalDownloads:1644,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"This chapter summarises the part of findings of my doctoral studies at the University of Sussex, Brighton, UK. In this case study, there are elements of both qualitative and quantitative approaches; the former is the principal approach to this research while the latter works as complementary. Participants of the research were divided into two categories: academic and non‐academic. Forty semi‐structured interviews (20 from each category) and 100 survey questionnaire (50 from each category) were collected. This research argues that existing concepts of ‘autonomy’ and ‘independence’ may not be useful indices/indicators for measuring the social status or position of women in Sindhi society, due to variations in understanding or the meanings attributed to these concepts across the globe. Findings argue that these professional women perceived concepts of ‘autonomy’, ‘independence’ and ‘individuality’ categorically different than those of Westernised understandings. This research asserts that Sindhi society, similarly to that of Tamil society, emphasises social groups rather than individuals. Hence, ‘collective identities’ are the essence of Sindhi society; however, individuals find their autonomy, independence and individuality in the context of ‘others’, which means to be more responsible for group's interests.",book:{id:"5472",slug:"gender-differences-in-different-contexts",title:"Gender Differences in Different Contexts",fullTitle:"Gender Differences in Different Contexts"},signatures:"Mukesh Kumar Khatwani",authors:[{id:"196384",title:"Dr.",name:"Mukesh",middleName:"Kumar",surname:"Khatwani",slug:"mukesh-khatwani",fullName:"Mukesh Khatwani"}]}],mostDownloadedChaptersLast30Days:[{id:"52503",title:"Gender and Leadership",slug:"gender-and-leadership",totalDownloads:4125,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"The topic of leadership has been addressed and applied for millennia. Yet, it is only within the past 80 years that leadership has been a topic of serious discussion. It is important to understand variables relevant to effective leadership. 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In this review, we outline the evidence of gender differences related to PTSD, and the factors of resilience and susceptibility differ between men and women.",book:{id:"5472",slug:"gender-differences-in-different-contexts",title:"Gender Differences in Different Contexts",fullTitle:"Gender Differences in Different Contexts"},signatures:"Jingchu Hu, Biao Feng, Yonghui Zhu, Wenqing Wang, Jiawei Xie\nand Xifu Zheng",authors:[{id:"190985",title:"Dr.",name:"Xifu",middleName:null,surname:"Zheng",slug:"xifu-zheng",fullName:"Xifu Zheng"},{id:"194981",title:"BSc.",name:"Yonghui",middleName:null,surname:"Zhu",slug:"yonghui-zhu",fullName:"Yonghui Zhu"},{id:"194982",title:"MSc.",name:"Wenqing",middleName:null,surname:"Wang",slug:"wenqing-wang",fullName:"Wenqing Wang"},{id:"194985",title:"Dr.",name:"Jingchu",middleName:null,surname:"Hu",slug:"jingchu-hu",fullName:"Jingchu Hu"},{id:"194986",title:"MSc.",name:"Biao",middleName:null,surname:"Feng",slug:"biao-feng",fullName:"Biao Feng"},{id:"194987",title:"Ph.D. Student",name:"Jiawei",middleName:null,surname:"Xie",slug:"jiawei-xie",fullName:"Jiawei Xie"}]},{id:"52472",title:"Gender and Health",slug:"gender-and-health",totalDownloads:3430,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Research has found differences between women and men in some health indicators. Women’s life expectancy is higher than men’s, but research on differences in morbidity has proved less consistent than on the differences in mortality. These differences vary in terms of the type of health indicator used, the life cycle period analyzed, and even the country where research is conducted. Generally, men have more life-threatening chronic diseases at younger ages, including coronary heart disease, as well as more externalizing mental health problems and substance use disorders. Women present higher rates of chronic debilitating conditions such as arthritis, frequent or severe headaches, gallbladder conditions, and also more internalizing mental problems such as affective and anxiety disorders. Results of research on the differences between women and men in self-rated health have also highlighted the complexity of gender differences in health. Although several studies have shown that women have poorer self-rated health than men, this is not the case in all countries. Also, differences in self-rated health vary depending on other psychosocial and demographic variables. The present study reviews the main differences in women’s and men’s health as well as the most relevant factors that may account for them.",book:{id:"5472",slug:"gender-differences-in-different-contexts",title:"Gender Differences in Different Contexts",fullTitle:"Gender Differences in Different Contexts"},signatures:"María Pilar Matud",authors:[{id:"189729",title:"Prof.",name:"M. Pilar",middleName:null,surname:"Matud",slug:"m.-pilar-matud",fullName:"M. Pilar Matud"}]},{id:"53212",title:"Broken Dreams—Balancing Self and Family Well-Being: The Experiences of Women Immigrants to Hamilton, ON",slug:"broken-dreams-balancing-self-and-family-well-being-the-experiences-of-women-immigrants-to-hamilton-o",totalDownloads:1512,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter presents the preliminary analysis of a study conducted in Hamilton, ON. It explores the intersection of women’s immigration, integration and mental health. Their perceptions of what is needed from them in relation to the various challenges/changes that moving to a new country entails is a particular focus of this research. To begin with, the term “women immigrant” (WI) is used, rather than immigrant women as commonly used—as the participants were women long before they became immigrants. 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Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. 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Currently, he is a professor of Orthodontics. He holds a Certificate of Advanced Study type A in Technology of Biomaterials used in Dentistry (1995); Certificate of Advanced Study type B in Dento-Facial Orthopaedics (1997) from the Faculty of Dental Surgery, University Denis Diderot-Paris VII, France; Diploma of Advanced Study (DESA) in Biocompatibility of Biomaterials from the Faculty of Medicine and Pharmacy of Casablanca (2002); Certificate of Clinical Occlusodontics from the Faculty of Dentistry of Casablanca (2004); University Diploma of Biostatistics and Perceptual Health Measurement from the Faculty of Medicine and Pharmacy of Casablanca (2011); and a University Diploma of Pedagogy of Odontological Sciences from the Faculty of Dentistry of Casablanca (2013). 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He is an academic staff member of the Department of Reproduction and Artificial Insemination, Selçuk University, Turkey. He manages several studies on sperms and embryos and is an editorial board member for several international journals. His studies include sperm cryobiology, in vitro fertilization, and embryo production in animals.",institutionString:"Selçuk University, Faculty of Veterinary Medicine",institution:null},{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/90846/images/system/90846.jpg",biography:"Yusuf Bozkurt has a BSc, MSc, and Ph.D. from Ankara University, Turkey. He is currently a Professor of Biotechnology of Reproduction in the field of Aquaculture, İskenderun Technical University, Turkey. His research interests include reproductive biology and biotechnology with an emphasis on cryo-conservation. He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular Economy, Contingency Planning and Response to Disasters, Ecosystem Services, Integrated Urban Water Management, Nature-based Solutions, Sustainable Urban Development, Urban Green Spaces",scope:"