Introduction and Objective. The treatment of severe deformities often requiring aggressive techniques such as vertebral resection and osteotomies with high comorbidity. To mitigate this risk, several methods have been used to achieve a partial reduction of stiff curves. The objective of this study was to evaluate and quantify the effectiveness of the Perioperative Halo-Gravity Traction (HGT) in the Treatment of Severe Spinal Deformity in Children. Materials and Methods. A historical cohort of consecutive childs with severe spinal deformity who underwent to a perioperative HGT as a part of the treatment protocol. Minimum follow-up of 2 years. Demographic, clinical and radiological data, including time duration of perioperative HGT and Cobb angle in the coronal and sagittal plane. The radiological variables were measured before the placement of the halo, after placement of the halo, at the end of the period of traction, after surgery and in the final follow-up. Results. Seventeen males (57%) and twenty females (43%) were included in the final analysis. The mean age was 6.5 years (SD 4.8). The most frequent etiology for the spinal deformity was syndromic (13 patients). The average preoperative Cobb angle was 88º (range, 12–135). HGT was used in 17 cases prior to a primary surgery and in 20 cases prior to a revision surgery. After the HGT, an average correction of 34% of the deformity was achieved (p <0.05). After the surgery this correction improved. At 2-year follow-up there was a correction loss of 20% (p <0.05). There were 3 complications (8.1%): 2 pin infections and cervical subluxation. Conclusions. The application of HGT in cases of severe rigid deformity is useful allowing a correction of the preoperative deformity of 34%, facilitating surgery. Preoperative HGT seems to be a safe and effective intervention in pediatric patients with high degree deformity

Introduction and Objective. Pectus carinatum is a common congenital anterior chest wall deformity, characterized by outward protrusion of sternum and ribcage resulted from rib cartilage overgrowth. The protrusion may be symmetrical or asymmetrical. Pectus carinatum association with mitral valve diseases, Marfan's syndrome, and scoliosis enforces that poor connective tissue development as possible etiological factor. Despite the coexistence of pectus carinatum and scoliosis has attracted the attention of some researchers, the association between pectus carinatum and the other spinal deformities has not been studied comprehensively. The frequency of spinal deformity in patients with pectus carinatum and the mutual relationships of their subtypes are needed to be studied to determine the epidemiological character of the combined deformity and to plan patient evaluation and management. Our study aimed to investigate the association, define the incidence and evaluate the characteristics between different types of spinal deformities and Pectus carinatum. Materials and Methods. Radiological and physical examinations were performed for 117 pectus carinatum patients in Marmara university hospital/Turkey in the years between 2006 and 2013. The incidence of spinal deformity was calculated. Spinal deformities were classified as scoliosis, kyphosis, kyphoscoliosis, and spinal asymmetry, whereas pectus carinatum were subdivided into symmetric and asymmetric subgroups. The relationship between spinal deformities and the symmetrical-asymmetric subtype of pectus excavatum was statistically analyzed, Pearson chi-square test was used to compare the association of qualitative data. The significance level was accepted as p <0.05. Lastly, the angular values of the deformities of scoliosis and kyphosis patients were measured using the Cobb method. In this way, the magnitude of the deformity was given as a numerical value. Results. Spinal deformity was detected in 23 (17 symmetrical PE and 6 asymmetrical PE) of 117 pectus excavatum patients. Scoliosis and kyphosis were seen equally in symmetrical pectus carinatum, whereas scoliosis was seen in 33.3% and kyphosis in 50% in asymmetric pectus carinatum patients, respectively. However, there were no statistically significant differences in the distribution of scoliosis and kyphosis in patients with symmetrical and asymmetrical PE. Idiopathic scoliosis constituted the most common scoliosis group. Congenital kyphosis was not found in any kyphosis patient. The average Cobb angle of scoliosis patients was 32°, and the mean T2-T12 kyphosis angle of these patients was 55.5°, while the average kyphosis angle of those with kyphosis deformity was 71°. Conclusions. Patients with Pectus carinatum have a higher incidence of spinal deformities than the normal population. Such high concomitant incidence should be taken under consideration in evaluating and treating patients presenting with either deformity

Intervertebral disc (IVD) degeneration is responsible for severe clinical symptoms including chronic back pain. Galectins are a family of carbohydrate-binding proteins, some of which can induce functional disease markers in IVD cells and other musculoskeletal diseases. Galectins −4 and −8 were shown to trigger disease-promoting activity in chondrocytes but their effects on IVD cells have not been investigated yet. This study elucidates the role of galectin-4 and −8 in IVD degeneration. Immunohistochemical evidence for the presence of galectin-4 and −8 in the IVD was comparatively provided in specimens of 36 patients with spondylochondrosis, spondylolisthesis, or spinal deformity. Confocal microscopy revealed co-localization of galectin-4 and −8 in chondrocyte clusters of degenerated cartilage. The immunohistochemical presence of galectin-4 correlated with histopathological and clinical degeneration scores of patients, whereas galectin-8 did not show significant correlations. The specimens were separated into annulus fibrosus (AF), nucleus pulposus (NP) and endplate, which was confirmed histologically. Separate cell cultures of AF and NP (n=20) were established and characterized using cell type-specific markers. Potential binding sites for galectins including sialylated N-glycans and LacdiNAc structures were determined in AF and NP cells using LC/ESI-MS-MS. To assess galectin functions, cell cultures were treated with recombinant galectin-4 or −8, in comparison to IL-1β, and analyzed using RT-qPCR and In-cell Western blot. In vitro, both galectins triggered the induction of functional disease markers (CXCL8 and MMP3) on mRNA level and activated the nuclear factor-kB pathway. NP cells were significantly more responsive to galectin-8 and Il-1β than AF cells. Phosphorylation of p-65 was time-dependently induced by both galectins in both cell types to a comparable extent. Taken together, this study provides evidence for a functional role of glycobiological processes in IVD degeneration and highlights galectin-4 and −8 as regulators of pro-inflammatory and degrative processes in AF and NP cells

Introduction. Unplanned reoperations (UROs) following corrective surgery for adult spinal deformity (ASD) present significant challenges for both patients and surgeons. Understanding the specific UROs types is crucial for improving patient outcomes and refining surgical strategies in ASD correction. Method. This retrospective analysis utilized data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database spanning from 2017 to 2021. Patient information was extracted using specific CPT codes related to posterior pedicle fixation. Result. In a cohort of 1088 patients undergoing posterior spinal deformity corrections, we examined various preoperative factors to discern their correlation with reoperation prevalence. Our analysis revealed no statistically significant differences in reoperation prevalence concerning gender (male: 4.0%, p=0.131) or ethnicity (Hispanic: 4.2%, p=0.192). Similarly, no notable associations were identified for diabetes mellitus, smoking status, dyspnea, history of severe COPD, hypertension, ASA classification, or functional health status before surgery, with reoperation prevalences ranging from 3.2% to 8.8% and p-values spanning from 0.146 to 0.744. Overall, the reoperation prevalence within the entire cohort stood at 5.2% (55 cases). In terms of the types of reoperations investigated, spinal-related procedures emerged as the most prevalent, accounting for 43.7% (24 cases), followed closely by wound site revisions at 23.6% (13 cases). Additionally, gastrointestinal-related procedures and various other miscellaneous interventions, such as uroscopy, demonstrated reoperation prevalences of 7.2% (4 cases) and 25.5% (14 cases), respectively. Conclusion. our findings highlight the diverse spectrum of reoperation procedures encountered following posterior spinal deformity corrections, with wound site revisions and spinal-related interventions being the most prevalent categories. These results emphasize the complexity of managing UROs in spinal surgery and the need for tailored approaches and infection/incision protocols to address the specific challenges associated with each type of reoperation

The pelvic girdle and spine vertebral column work as a long chain influenced by pelvic tilt. Spinal deformities or other musculoskeletal conditions may cause patients to compensate with excessive pelvic tilt, producing alterations in the degree of lumbar lordosis and subsequently causing pain. The objective of this study is to assess the effect of open and closed chain anterior or posterior pelvic tilt on lumbar spine kinematics using an in vitro cadaveric spine model. Three human cadaveric spines with intact pelvis were suspended with the skull fixed in a metal frame. Optotrak 3D motion system tracked real-time coordinates of pin markers on the lumbar spine. A force-torque digital gage applied consistent force to standardize the acetabular or sacral axis’ anterior and posterior pelvic tilt during simulated open and closed chain movements, respectively. In closed chain PPT, significant differences in relative intervertebral compression existed between L1/L2 [-2.54 mm] and L5/S1 [-11.84 mm], and between L3/L4 [-2.78 mm] and L5/S1 [-11.84 mm] [p <.05]. In closed chain APT, significant differences in relative intervertebral decompression existed between spinal levels L1/L2 [2.87mm] and L5/S1[24.48 mm] and between L3/L4 [2.94 mm] and L5/S1 [24.48 mm] [p <.05]. In open chain APT, significant differences in relative intervertebral decompression existed between spinal levels L4/L5 [1.53mm] and L5/S1 [25.14 mm] and between L2/L3 [1.68 mm] and L5/S1 [25.14 mm] [p<.05 for both]. Displacement during closed chain PPT was significantly greater than during open chain PPT, whereas APT showed no significant differences. In PPT, open chain pelvic tilts did not produce as much lumbar intervertebral displacement compared to closed chain. In contrast, APT saw no significant differences between open and closed chain. Additionally, results illustrate the increase in lumbar lordosis during APT and the loss of lordosis during PPT

Introduction. Congenital scoliosis is a prevalent congenital spinal deformity, more frequently encountered than congenital lordosis or kyphosis. The prevailing belief is that most instances of congenital scoliosis are not hereditary but rather stem from issues in fetal spine development occurring between the 5th and 8th weeks of pregnancy. However, it has been linked to several genes in current literature. Our goal was to explore potential pathways through an exhaustive bioinformatics analysis of genes related to congenital scoliosis. Method. The literature from the 1970s to February 2024 was surveyed for genes associated with CS, and 63 genes were found to be associated with AIS out of 1743 results. These genes were analyzed using DAVID Bioinformatics. Result. Our pathway analysis has unveiled several significant associations with congenital scoliosis. Notably, “Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate” (P-Value:8.8E-3, Fold Enrichment: 20.6), “Central carbon metabolism in cancer” (P-Value:1.3E-3, Fold Enrichment: 10.3), and “Lysine degradation” (P-Value: 9.0E-3, Fold Enrichment: 9.1) emerge as statistically significant pathways. Additionally, “Endocrine resistance” (P-Value:4.4E-3, Fold Enrichment:7.4) and”EGFR tyrosine kinase inhibitor resistance” (P-Value: 1.7E-2, Fold Enrichment:7.3) pathways are noteworthy. These findings suggest a potential involvement of these pathways in the biological processes underlying congenital scoliosis. Furthermore, “Signaling pathways regulating pluripotency of stem cells” (P-Value:4.0E-4, Fold Enrichment:7.1), “Notch signaling pathway” (P-Value:6.7E-2, Fold Enrichment: 7.0), and “TGF-beta signaling pathway” (P-Value:6.2E-3, Fold Enrichment: 6.7) exhibit a less pronounced yet intriguing association that may warrant further investigation. Conclusion. In conclusion, our comprehensive analysis of the genetic etiology of congenital scoliosis has revealed significant associations with various pathways, shedding light on potential underlying biological mechanisms. While further research is needed to fully understand these associations and their implications, our findings provide a valuable starting point for future investigations into the management and treatment of congenital scoliosis

Spinal surgery deals with the treatment of different pathological conditions of the spine such as tumors, deformities, degenerative disease, infections and traumas. Research in the field of vertebral surgery can be divided into two main areas: 1) research lines transversal to the different branches; 2) specific research lines for the different branches. The transversal lines of research are represented by strategies for the reduction of complications, by the development of minimally invasive surgical techniques, by the development of surgical navigation systems and by the development of increasingly reliable systems for the control of intra-operative monitoring. Instead, specific lines of research are developed within the different branches. In the field of oncological pathology, the current research concerns the development of in vitro models for the study of metastases and research for the study of targeted treatment methods such as electrochemotherapy and mesenchymal stem cells for the treatment of aneurysmal bone cysts. Research in the field of spinal deformities is focused on the development of increasingly minimally invasive methods and systems which, combined with appropriate pharmacological treatments, help reduce trauma, stress and post-operative pain. Scaffolds based on blood clots are also being developed to promote vertebral fusion, a fundamental requirement for improving the outcome of vertebral arthrodesis performed for the treatment of degenerative disc disease. To improve the management and the medical and surgical treatment of vertebral infections, research has focused on the definition of multidisciplinary strategies aimed at identifying the best possible treatment path. Thus, flow-charts have been created which allow to manage the patient suffering from vertebral infection. In addition, dedicated silver-coated surgical instrumentation and bone substitutes have been developed that simultaneously guarantee mechanical stability and reduce the risk of further local infection. In the field of vertebral traumatology, the most recent research studies have focused on the development of methods for the biostimulation of the bone growth in order to obtain, when possible, healing without surgery. Methods have also been developed that allow the minimally invasive percutaneous treatment of fractures by means of vertebral augmentation with PMMA, or more recently with the use of silicone which from a biomechanical point of view has an elastic modulus more similar to that of bone. It is clear that scientific research has changed clinical practice both in terms of medical and surgical management of patients with spinal pathologies. The results obtained stimulate the basic research to achieve even more. For this reason, new lines of research have been undertaken which, in the oncology field, aim at developing increasingly specific therapies against target receptors. Research efforts are also being multiplied to achieve regeneration of the degenerated intervertebral disc and to develop implants with characteristics increasingly similar to those of bone in order to improve mechanical stability and durability over time. Photodynamic therapies are being developed for the treatment of infections in order to reduce the use of antibiotic therapies. Finally, innovative lines of research are being launched to treat and regenerate damaged nerve structures with the goal, still far from today, of making patients with spinal cord injuries to walk

Complex spinal deformities can cause pain, neurological symptoms and imbalance (sagittal and/or coronal), severely impairing patients’ quality of life and causing disability. Their treatment has always represented a tough challenge: prior to the introduction of modern internal fixation systems, the only option was an arthrodesis to prevent worsening of the deformity. Then, the introduction of pedicle screws allowed the surgeons to perform powerful corrective manoeuvres, distributing forces over multiple levels, to which eventually associate osteotomies. In treating flexible coronal deformities, in-ternal fixation and corrective manoeuvres may be sufficient: the combination of high density pedicle screws and direct vertebral rotation revolutionized surgical treatment of scoliosis. However, spinal osteotomies are needed for correcting complex rigid deformities; the type of osteot-omy must be chosen according to the aetiology, type and apex of the deformity. When dealing with large radius deformities, spread over multiple levels and without fusion, multiple posterior column os-teotomies such as Smith-Petersen and Ponte (asymmetric, when treating scoliosis) can be performed, dissipating the correction over many levels. Conversely, the management of a sharp, angulated de-formity that involves a few vertebral levels and/or with bony fusion, requires more aggressive 3 col-umn osteotomies such as Pedicle Subtraction Osteotomies (PSO), Bone Disc Bone Osteotomies (BDBO) or Vertebral Column Resection (VCR). Sometimes the deformity is so severe that cannot be corrected with only one osteotomy: in this scenario, multilevel osteotomies can be performed

Currently, between 17% of patients undergoing surgery for adult spinal deformity experience severe instrumentation related problems such as screw pullout or proximal junctional failure necessitating revision surgery. Cables may be used to reinforce pedicle screw fixation as an additive measure or may provide less rigid fixation at the construct end levels in order to prevent junctional level problems. The purpose of this study is to provide insight into the maximum expected load during flexion in UHMWPE cable in constructs intended for correction of adult spine deformity (degenerative scoliosis) in the PoSTuRe first-in-man clinical trial. Following the concept of toppinoff, a new construct is proposed with screw/cable fixation of rods at the lower levels and standalone UHMWPE cables at the upper level (T11). A parametric FE model of the instrumented thoracolumbar spine, which has been previously validated, was used to represent the construct. Pedicle screws are modeled by assigning a rigid tie constraint between the rod and the lamina of the corresponding spinal level. Cables are modeled using linear elastic line elements, fixing the rod to the lamina medially at the cranial laminar end and laterally at the caudal laminar end. A Youngs modulus was assigned such that the stiffness of the line element was the same as that of the cable. An 8 Nm flexion moment was applied to the cranial endplate. The maximum value of the force in the wire (80 N) is found at the T11 (upper) level. At the other levels, forces in the cable are very small because most of the force is carried by the screw (T12) or because the wires are force shielded by the contralateral and adjacent level pedicle screws (L2, L3). The model provides first estimates of the forces that can be expected in the UHMWPE cables in constructs for kyphosis correction during movement. It is expected that this approach can help in defining the number of wires for optimal treatment

Background. After surgical correction of thoracic scoliosis, an improvement in the cardio-respiratory adaptation to exercise would be expected because of the correction of the rib cage associated with the spinal deformity. This work intended to evaluate the physiologic responses to incremental exercise in patients undergoing surgical correction of adolescent idiopathic scoliosis (AIS). The hypothesis of this study was that the exercise limitations described in patients with AIS could be related with the physical deconditioning instead of being linked to the severity of the vertebral deformity. Methods. Cross-sectional study of the exercise tolerance in a series of patients with AIS type Lenke 1A, before and 2 years after surgical correction. Twenty patients with AIS and 10 healthy adolescents aged between 12 and 17 years old were evaluated. The average magnitude of the curves was 60.3±12.9 Cobb. Cardio-respiratory function was assessed before surgery and at 2-year follow-up by maximal exercise tolerance test on treadmill following a Bruce standard protocol. Maximal oxygen uptake (VO2), VCO2, expiratory volume (VE), and VE/VO2 ratio were registered. Results. Before surgery, AIS patients showed lower values than healthy controls in all cardio-respiratory parameters. The most important restrictions were the VO2max in ml/kg/min. (30.3±5.4 vs 49.9±7.5), VE (43.2±10.3 vs 82.3±10.7) and VE/CO2 ratio (25.0±3.9 vs 29.6±4.2). Contrary to expectations, two years after surgery most of these parameters decreased but differences with preoperative data were no statistically significant. Besides the great correction of the deformity (coronal plane, 71.5%; axial rotation, 49.3%), the cardio-respiratory tolerance to the exercise was not modified by surgery. Conclusions. Patients with moderate-severe AIS showed a limited tolerance to maximal exercise that does not change 2 years after surgery. This findings suggests that the reduced cardio-pulmonary function during exercise is not strictly associated to the spinal deformity, since great corrections of the spinal curves does not improve functional ventilatory parameters. In addition, the results point out a severe exercise deconditioning in AIS patients. Level of evidence. Level IV

The surgical treatment of spinal deformities and degenerative or oncological vertebral diseases is becoming more common. However, this kind of surgery is complex and associated to a high rate of early and late complications. We retrospectively collected all the major complications observed in the perioperative and post-operative period for surgeries performed at our Division of Spine Surgery in the 2010–2012 period,. 285 surgeries were registered in 2010, 324 in 2011 and 308 in 2012. All the complications observed during the procedure and the follow-up period were recorded and classified according to the type (mechanical complications, neurological complications, infection, hematoma, cerebrospinal fluid fistula, systemic complications, death related to the surgery). In 2010, on 285 surgeries 47 patients (16.5 %) had 69 complications (24.2%): 25.7% for the treatment of oncological diseases, 23% for the treatment of degenerative diseases, 27% for the treatment of pathologies of traumatic origin, 11% for the treatment of spondylodiscitis (infectious diseases). In 2011, on 324 surgeries 35 patients (10.8 %) had 54 complications (16.7%): 16.3% for the treatment of oncological diseases, 16.3% for the treatment of degenerative diseases, 20% for the treatment of pathologies of traumatic origin, 28.6% for the treatment of spondylodiscitis. In 2012, on 308 surgeries, 25 patients (8.1 %) had 36 complications (11.7%): 14.4% for the treatment of oncological diseases, 7.2% for the treatment of degenerative diseases, 16.7% for the treatment of pathologies of traumatic origin, 20% for the treatment of spondylodiscitis. On 917 spinal surgeries performed from January 2010 to December 2012, 159 complications (17.3%) were recorded, with a prevalence of mechanical complications and infections. We are also prospectively collecting complications related to 2013–2015, in order to have a larger amount of data and try to detect potential risk factors to be taken into consideration in the decision-making process for complex spinal surgery

INTRODUCTION. Over 85% of patients with multiple myeloma (MM) have bone disease, mostly affecting thoraco-lumbar vertebrae. Vertebral fractures can lead to pain and large spinal deformities requiring application of vertebroplasty (PVP). PVP could be enhanced by use of Coblation technique to remove lesions from compromised MM vertebrae prior to cement injection (C-PVP). METHODS. 28 cadaveric MM vertebrae, were initially fractured (IF) up to 75% of its original height on a testing machine, with rate of 1mm/min. Loading point was located at 25% of AP-diameter, from anterior. Two augmentation procedure groups were investigated: PVP and C-PVP. All vertebrae were augmented with 15% of PMMA cement. At the end of each injection the perceived injection force (PIF) was graded on a 5-point scale (1 very easy to 5 almost impossible). Augmented MM vertebrae were re-fractured, following the same protocol as for IF. Failure load (FL) was defined as 0.1% offset evaluated from load displacement curves. RESULTS. Mean initial FL was 2.5kN (STD=1.8kN) and 2.7kN (STD=1.8kN) for PVP and C-PVP, respectively. Mean augmented FL was 3.5kN (STD=3.1kN) and 4.2kN (STD=2.3kN)for PVP and C-PVP, respectively. Only the effect of augmentation was significant(p=0.006). Median PIF on the RIGHT side of vertebrae was 3.0 in PVP group and 2.5 in C-PVP (p=0.054). On the LEFT side it was 3.5 in PVP group and 3.0 in C-PVP (p=0.028). DISCUSSION. Results suggest that Coblation did not compromise strength of augmented MM vertebrae. The PIF was lower for C-PVP, as compared to PVP group, probably due to removal of lesion tissue

Summary Statement. Patients with adolescent idiopathic scoliosis show clear signs of abnormal motor coordination between the long superficial paraspinal muscles and the deep rotators. These findings suggest an abnormal behavior of the deep rotator muscles at the concave side. Introduction. An imbalance between the myoelectric activity of the muscles of the convexity and the concavity has been described in patients with adolescent idiopathic scoliosis (AIS). These findings are based on EMG patterns recorded with surface electrodes that do not distinguish between deep and superficial muscles. This work was aimed at analyzing the coupled behavior of the superficial and deep paraspinal muscles in subjects with AIS at both sides of the curve. Material. A total of 16 females (mean age, 16.2±4.3 years) with AIS between 20 and 35° Cobb (mean, 32.8±11.9°) underwent electromyography of the paraspinal muscles by direct intramuscular disposable concentric electrodes (Dantec DCN. TM. ) of 25mm and 37mm in length, and 0.46 mm. in diameter. A total of 4 electrodes were inserted at the apex on both sides of the curve (2 in deep rotator muscle and 2 in the long paraspinal superficial muscles). Myoelectrical activity was recorded simultaneously in the four muscle groups in different positions: standing, flexion, extension, right and left lateralizations, and rotations toward the side of the concavity and convexity. A 4-channel Keypoint® electromyography device (Medtronic, Denmark) was used. The recorded signals were analyzed in a laptop with Windows. ®. 7 Intel Core i3 64bit with Matlab. ®. R2012a. The following parameters were analyzed: Signal power, Mean and Median frecuency, and the Dimitrov spectral index, a marker of muscle fatigue. In addition, the signal power in each task was normalised by the signal power in standing position. The records were compared with those obtained in 4 healthy subjects, matched in age, without spinal deformity. Results. The signal amplitude in different subjects and tests ranged from tens of microvolts up to two milivolts. Most of the energy of the EMG signal was concentrated below 500 Hz in power spectrum density chart. In standing position, the activity of the deep muscle was greater than that of the long superficial paraspinal muscles, with higher activation in the convex side (63% of cases). Increased activity of the deep muscles as compared to the surperficial layers was also evident during flexion of the spine, with a higher activity of the deep muscles of the concavity. The 4 muscle groups showed low activity during spine extension movements, though the deep rotator activity was always greater than the superficial paraspinal muscles. In rotation exercises, the most active muscles were found the contralateral with a clear inhibition of the deep muscles of the concavity in the rotation to that side. This did not apply for rotation through the convex side. It was also noticeable that in the case of deep muscles, both sides of the spine require high activation when performing left flexion. Conclusions. Patients with AIS show clear signs of abnormal motor coordination between the superficial paraspinal muscles and the deep rotators. These findings do not clearly define whether this mismatch is primary or secondary to the presence of the deformity although they suggest an abnormal behavior of deep rotator muscles that could have etiopathogenic relevance