Pathological Perspective Research Articles

Mature Placental Teratoma: A Case Report

Introduction: Placental teratoma is an uncommon, non-trophoblastic benign tumor. Since the first description of this type of tumor by Morvilli in 1925, only a few cases of this abnormality have been diagnosed and reported. Case presentation: We describe here a 35-year-old pregnant woman admitted for an elective cesarean section. The placenta and membranes were delivered spontaneously. After delivering the placenta, a tumor mass containing hair was detected between the extraplacental amnion and chorion. On gross examination, a singleton placenta weighing 173 g, measuring 15 × 11 cm in area and 5.5 cm thick, with an attached cord and membranes, was observed. Microscopic examination showed orthokeratinized stratified squamous epithelium with underlying hair follicles, telangiectatic vessels, and sebaceous glands accompanied by subcutaneous fat. The fat also contained fibrocollagenous bundles. In addition, interconnecting bone trabecula rimmed by osteoblasts and attached mature cartilage were also found. Conclusion: An awareness of placental teratoma from a pathological perspective is needed to include this anomaly in the differential diagnosis of benign placental nodules, obtain more information about this unusual lesion, and to conduct more studies on this prenatal abnormality.

Study on the Relationship between Lung Cancer Stromal Cells and Air Cavity Diffusion Based on an Image Acquisition System.

Objective The study aimed to investigate the role of tumor stromal cells in the pathogenesis of STAS, the relationship between air diffusion (STAS) and tumor stromal cells (TSCs) was studied, and the prognostic significance of TSC and STAS in patients with lung adenocarcinoma was evaluated. Methods A total of 150 patients with lung cancer diagnosed in the Affiliated Hospital of Jiangsu Province were selected. From the perspective of pathology, medical information technology was used to assist the diagnosis. The data of multiple magnetic resonance images were analyzed by three-dimensional space convolution (CNN), fuzzy neural network (FNN), transfinite learning machine (ELM), and binarization. Result After data fusion, the specificity and sensitivity of multiple magnetic resonance (MRI) data are significantly higher than those of single MRI data, and the more fusion times, the better the sensitivity and specificity. With the increase in the number of information and data fusion, the proportion of the significant effect and the comprehensive effective rate of patients are on the rise. Multiple MRI data fusion examination and analysis under medical information technology can improve the cure rate of patients, and the 1-year survival rate and the 3-year survival rate of patients have also gradually improved. Conclusion The MRI data fusion diagnosis method under the application of information technology can improve the sensitivity and specificity of the diagnosis results and comprehensively improve the clinical cure rate and the survival rate at different times of prognosis. In the context of the current big data information age, this multifeature fusion analysis technology is playing a more and more important role in medical treatment. The application of this method and technology not only improves the quality of life of patients but also processes multiple types of data at one time only by using the proposed medical assistant diagnosis model, which can save the diagnosis time to a certain extent. It has effectively realized the medical management and medical service quality and has important promotion significance.

It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer's and Lewy Body Disease Spectra.

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.

Role of Platelets in the Pathogenicity of Atherosclerosis and Thrombosis in Coronary Heart Diseases

Atherosclerosis is a chronic inflammatory process that results in coronary artery disease, peripheral artery disease and in many cases of stroke. It is a disease that involves multiple inflammatory cytokine which is regarded as the primary underlying cause of cardiovascular diseases (CVD). CVD is the leading cause of death in the developed and developing countries like Nigeria. From pathological perspective, the chronic inflammatory condition of atherosclerosis occurs due to interplay between platelets, monocytes, macrophages. Physiologically platelets play a significant role in coagulation and repair of endothelial injury. Pathologically, studies have shown that activated platelets release multiple inflammatory cytokines and chemokines that serve as positive mediators of atherosclerosis. This chemokine is (RANTES, P-selectin and PF-4). Activated platelet release p-selectin that mediate platelet adhesion and rolling to injured endothelial cell, RANTES trigger the recruitment of monocytes into the sub- endothelium and PF4 promote the differentiation of monocytes into macrophages in the intimal layer of the endothelium which engulf ox-LDL to form FOAM cells. Thus, the aim of this review is to understand and describe the role of activated platelets in atherosclerosis as well as therapeutic target of these platelet inflammatory chemokines which is the major mediator of atherosclerosis in human.

5-hydroxytryptamine in migraine: The puzzling role of ionotropic 5-HT3 receptor in the context of established therapeutic effect of metabotropic 5-HT1 subtypes.

5-hydroxytryptamine (5-HT; serotonin) is traditionally considered as a key mediator implicated in migraine. Multiple 5-HT receptor subtypes contribute to a variety of region-specific functional effects. The raphé nuclei control nociceptive inputs by releasing 5-HT in the brainstem, whereas dural mast cells provide the humoral source of 5-HT in the meninges. Triptans (5-HT1B/D agonists) and ditans (5-HT1F agonists) are the best established 5-HT anti-migraine agents. However, activation of meningeal afferents via ionotropic 5-HT3 receptors results in long-lasting excitatory drive suggesting a pro-nociceptive role for these receptors in migraine. Nevertheless, clinical data do not clearly support the applicability of currently available 5-HT3 antagonists to migraine treatment. The reasons for this might be the presence of 5-HT3 receptors on inhibitory interneurons dampening the excitatory drive, a lack of 5-HT3 A-E subunit-selective antagonists and gender/age-dependent effects. This review is focusing on the controversial role of 5-HT3 receptors in migraine pathology and related pharmacological perspectives of 5-HT ligands. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Story education: Assessing history education in light of narrative therapy

This paper discusses the obstructive dimension of specific declarative knowledge on historical thinking. Through considering the anthropological and social-psychological functions of stories, the author identifies potential difficulties individuals may face when trying to decipher, understand, and evaluate particular stories, as intended by historical thinking. By comparing the incapacity to cope with complex historic narratives with the effects of trauma, the paper discusses how approaches in narrative psychotherapy may add interesting insights to the domain of history education. The paper concludes that selection of declarative knowledge needs to be critically reviewed from a pathological perspective if historical thinking is set to be one of the main functions of history education.

Featured Cover

The cover image is based on the Special Issue HEREDITARY NEUROPATHIES: A PATHOLOGICAL PERSPECTIVE by Tiziana Cavallaro et al., https://doi.org/10.1111/jns.12467.

Hereditary neuropathies: A pathological perspective.

Hereditary neuropathies may result from mutations in genes expressed by Schwann cells or neurons that affect selectively the peripheral nervous system (PNS) or may represent a minor or major component of complex inherited diseases that involve also the central nervous system and/or other organs and tissues. The chapter is constantly expanding and reworking, thanks to advances of molecular genetics; next-generation sequencing is identifying a plethora of new genes and is revolutionizing the diagnostic approach. In the past, diagnostic sural nerve biopsies paved the way to the discovery and elucidation of major genes and molecular pathways associated to most frequent hereditary motor-sensory neuropathies. Nowadays, a sural nerve biopsy may prove useful in selected cases for the differential diagnosis of an acquired neuropathy when clinical examination, nerve conduction studies, and molecular tests are not sufficiently informative. Skin biopsy has emerged as a minimally invasive window on the PNS, which may provide biomarkers of progression and clues to the physiopathology and molecular pathology of inherited neuropathies. The aim of our review is to illustrate the pathological features of more frequent and paradigmatic hereditary neuropathies and to highlight their correlations with the roles of the involved genes and functional consequences of related molecular defects.

Rhabdomyosarcoma in Ovary- Pathologist’s Diagnostic Dilemma

Abstract Introduction/Objective Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. However, rhabdomyosarcoma in the ovary is exceptionally unusual and presents a diagnostic challenge. We report one such case and its clinical and pathological perspective. Methods/Case Report 16-year-old female presented with an enlarging pelvic mass, abdominal distension, and pain. Imaging revealed a heterogeneous left ovarian mass, right axillary lymphadenopathy, and right-hand soft tissue mass. CA-125 was 1833.0 U/ml. Patient underwent left salphingo-oophorectomy, omentectomy, peritoneal and mesenteric biopsy for ovarian staging, incidental appendectomy, and right axillary lymph node excision with suspicion of ovarian epithelial tumor. Pathological evaluation revealed a 16-cm intact ovary with multiple solid and cystic nodules with areas of hemorrhage and necrosis. Microscopic examination of ovarian tumor showed a high-grade malignant tumor consisting of sheets of small round blue cells with severe cytologic atypia, increased mitoses, and features suggestive of rhabdoid morphology. The other specimens were positive for metastases. The tumor cells were immunopositive for Myogenin and MyoD1 while immunonegative for Cytokeratin AE1/AE3, SF-1, PLAP, SALL4, MelanA, and S-100. INI-1 and BRG-1 demonstrated intact nuclear expression. FISH testing identified rearrangement of the FOX01 gene at 13q14. Based on these findings, diagnosis of alveolar rhabdomyosarcoma was rendered. Currently, the patient is receiving rhabdomyosarcoma chemotherapy treatment and has responded well. Results (if a Case Study enter NA) NA Conclusion In cases with complex and urgent clinical presentation, where the existence of a primary tumor is unknown and where symptoms attributable to primary ovarian tumor dominate the clinical picture, rhabdomyosarcoma is rarely proposed in the differential diagnoses of small round blue cell tumors of the ovary. At present, the right-hand mass is under evaluation; thus, the true nature of the ovarian mass, primary or metastatic is unknown. Our case illustrates the importance of exact diagnoses, as treatment of rhabdomyosarcoma, is different from other ovarian tumors.

A Core Response to the CDX2 Homeoprotein During Development and in Pathologies.

Whether a gene involved in distinct tissue or cell functions exerts a core of common molecular activities is a relevant topic in evolutionary, developmental, and pathological perspectives. Here, we addressed this question by focusing on the transcription factor and regulator of chromatin accessibility encoded by the Cdx2 homeobox gene that plays important functions during embryonic development and in adult diseases. By integrating RNAseq data in mouse embryogenesis, we unveiled a core set of common genes whose expression is responsive to the CDX2 homeoprotein during trophectoderm formation, posterior body elongation and intestinal specification. ChIPseq data analysis also identified a set of common chromosomal regions targeted by CDX2 at these three developmental steps. The transcriptional core set of genes was then validated with transgenic mouse models of loss or gain of function of Cdx2. Finally, based on human cancer data, we highlight the relevance of these results by displaying a significant number of human orthologous genes to the core set of mouse CDX2-responsive genes exhibiting an altered expression along with CDX2 in human malignancies.

Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives.

Endometrial cancer is the most common gynecological cancer in developed countries, and its incidence has increased. The majority of patients with endometrial cancer have an early disease and favorable prognosis; however, a significant proportion of endometrial cancer, which mainly comprises high-grade or type II endometrial cancer such as serous, clear cell, and carcinosarcoma, shows advanced/recurrent disease and dismal prognosis. Novel therapeutic development is required for patients with aggressive endometrial cancers. Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2 (HER2) overexpression/gene amplification in 20%-40% of patients with type II endometrial cancer. Historically, HER2 targeted therapy has been developed for various major cancers, including breast and gastric cancer. Notably, recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change. Simultaneously, an optimized HER2 test for endometrial cancer as companion diagnostics should be established. In this review, we summarize the recent findings on endometrial cancer, current treatment, optimized HER2 testing, key clinical trials on HER2 targeted therapy, and future directions in aggressive endometrial cancer, including serous carcinoma and carcinosarcoma.

Why high intensity plaque is bright on MRI?

Although CT is an excellent imaging modality for detecting lipid pools and calcification in the atherosclerotic plaque, it cannot distinguish hemorrhage from fibrous tissue. MRI has a unique capability of identifying subacute hemorrhage as high signal intensity area on T1-weighted MRI. Non-contrast T1-weighted MRI has been used to demonstrate high intensity plaque (HIP) in the coronary arterial wall. HIP was shown to be an important feature of a vulnerable plaque that increases the risk of future cardiac events. However, due to the lack of histopathological analysis of in vivo tissue samples from patients with HIP, the pathological features of HIP are still unknown. In the current issue of American Heart Journal Plus, Ehara et al. investigated the association between the PMR on non-contrast T1-weighted MRI and coronary intraplaque hemorrhage by analyzing plaque specimen obtained by directional coronary atherectomy. An antibody against glycophorin A was used to identify sites of previous plaque hemorrhage. They found a strong positive correlation between PMR and glycophorin A score. The results in the current study by Ehara reinforce the importance and implications of non-contrast T1-weighted MRI for the evaluation of HIP from a pathological perspective. Recent technical advances in MRI such as goldenangle radial sampling, self-gating, compressed sensing with deep learning reconstruction, and simultaneous acquisition of anatomical reference images and T1 weighted images may substantially reduce the total imaging time of coronary plaque MRI.

In silico identification of variations in microRNAs with a potential impact on dairy traits using whole ruminant genome SNP datasets

MicroRNAs are small noncoding RNAs that have important roles in the lactation process and milk biosynthesis. Some polymorphisms have been studied in various livestock species from the perspective of pathology or production traits. To target variants that could be the causal variants of dairy traits, genetic variants of microRNAs expressed in the mammary gland or present in milk and localized in dairy quantitative trait loci (QTLs) were investigated in bovine, caprine, and ovine species. In this study, a total of 59,124 (out of 28 millions), 13,427 (out of 87 millions), and 4761 (out of 38 millions) genetic variants in microRNAs expressed in the mammary gland or present in milk were identified in bovine, caprine, and ovine species, respectively. A total of 4679 of these detected bovine genetic variants are located in dairy QTLs. In caprine species, 127 genetic variants are localized in dairy QTLs. In ovine species, no genetic variant was identified in dairy QTLs. This study leads to the detection of microRNA genetic variants of interest in the context of dairy production, taking advantage of whole genome data to identify microRNA genetic variants expressed in the mammary gland and localized in dairy QTLs.

A critical assessment of the potential vertical transmission hypotheses: Implications for research on the early-life infection with COVID-19.

The risk of potential vertical transmission in SARS-CoV-2 infected pregnant women is currently a topic of debate. To explore the correlation between the two, we searched PubMed, Embase®, and Web of Science for studies on vertical transmission of COVID-19. The quality of the studies was evaluated by the Cochrane risk of bias tool. Detailed information of each included case including methods of delivery, protection measures for mothers and neonates at birth, types of specimens, inspection time, results of testing and feeding patterns was collected to assess the possibility of vertical transmission. The results showed that of the 390 neonates reported in 36 studies, 23 were infected with SARS-CoV-2 by potential vertical transmission. From the perspective of virology and pathology, vertical transmission of SARS-CoV-2 was possible via uterus or breastmilk. Some reported potential vertically transmitted neonates could be attributed to horizontal transmission. It is extremely vital to fully elucidate the potential routes of transmission of SARS-CoV-2, implicating clinical practice and nursing to reduce the risk of not only horizontal transmission but also vertical transmission, thus protecting neonates from COVID-19 infection.

A pathological perspective to painful inguinal hernia: Report of two cases.

IntroductionPreoperative inguinal pain (painful inguinal hernia) is a well-known factor associated with chronic postoperative inguinal pain (CPIP). However, it remains unclear what preventive measures should be taken in such patients.Case presentationWe report two patients with painful inguinal hernia who underwent pragmatic ilioinguinal nerve neurectomy during open anterior repair. The nerve was compressed by bulky spermatic cord lipoma in case 1 and by the hernia sac presenting over a few decades in case 2. Hematoxylin and eosin staining of the resected nerves revealed mucoid degeneration. Toluidine blue staining of resin-embedded nerve sections demonstrated that fully-myelinated axons had significantly decreased in case 1 and almost disappeared in case 2, indicating the development of massive demyelination of the ilioinguinal nerve in both cases.DiscussionIn cases where the injured nerve is left in situ, CPIP may occur since demyelinating neuropathy sometimes becomes irreversible.ConclusionPlanned nerve resection via open anterior inguinal hernia repair may be an option to prevent CPIP in patients with painful inguinal hernia.

WHO/ISUP grading of clear cell renal cell carcinoma and papillary renal cell carcinoma; validation of grading on the digital pathology platform and perspectives on reproducibility of grade

BackgroundThere are recognised potential pitfalls in digital diagnosis in urological pathology, including the grading of dysplasia. The World Health Organisation/International Society of Urological Pathology (WHO/ISUP) grading system for renal cell carcinoma (RCC) is prognostically important in clear cell RCC (CCRCC) and papillary RCC (PRCC), and is included in risk stratification scores for CCRCC, thus impacting on patient management. To date there are no systematic studies examining the concordance of WHO/ISUP grading between digital pathology (DP) and glass slide (GS) images. We present a validation study examining intraobserver agreement in WHO/ISUP grade of CCRCC and PRCC.MethodsFifty CCRCCs and 10 PRCCs were graded (WHO/ISUP system) by three specialist uropathologists on three separate occasions (DP once then two GS assessments; GS1 and GS2) separated by wash-out periods of at least two-weeks. The grade was recorded for each assessment, and compared using Cohen’s and Fleiss’s kappa.ResultsThere was 65 to 78% concordance of WHO/ISUP grading on DP and GS1. Furthermore, for the individual pathologists, the comparative kappa scores for DP versus GS1, and GS1 versus GS2, were 0.70 and 0.70, 0.57 and 0.73, and 0.71 and 0.74, and with no apparent tendency to upgrade or downgrade on DP versus GS. The interobserver kappa agreement was less, at 0.58 on DP and 0.45 on GS.ConclusionOur results demonstrate that the assessment of WHO/ISUP grade on DP is noninferior to that on GS. There is an apparent slight improvement in agreement between pathologists on RCC grade when assessed on DP, which may warrant further study.

EBV-positive B-cell lymphomas and lymphoproliferative disorders: Review from the perspective of immune escape and immunodeficiency.

BackgroundEpstein‐Barr virus (EBV) is detected in a variety of B‐cell lymphomas (BCLs) and B‐cell lymphoproliferative disorders (B‐LPDs). Immunodeficiency has been considered to play a key role in the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV+ BCLs and B‐LPDs. The PD‐1/PD‐L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T‐cell function. We now consider PD‐L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism.MethodsWe reviewed articles of EBV+ BCLs and B‐LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD‐L1 IHC.ResultsBased on PD‐L1 IHC, we consider that EBV+ BCL and B‐LPD can be classified into three types: “immunodeficiency”, “immune escape”, and “immunodeficiency + immune escape” type. The immunodeficiency type includes EBV+ diffuse large BCL (DLBCL) of the elderly, EBV+ sporadic Burkitt lymphoma, EBV+ mucocutaneous ulcer, and methotrexate (MTX)‐associated B‐LPD. The immune escape type includes EBV+ classic Hodgkin lymphoma (CHL) and EBV+ DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX‐associated LPD and a minor subset of EBV+ DLBCL of the elderly.ConclusionsRecently, good results have been reported for immune check‐point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD‐L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency.

Diagnostic Approach to Congenital Cystic Masses of the Neck from a Clinical and Pathological Perspective

Background: neck cysts are frequently encountered in pediatric medicine and can present a diagnostic dilemma for clinicians and pathologists. Several clinical items enable to subclassify neck cyst as age at presentation, anatomical location, including compartments and fascia of the neck, and radiological presentation. Summary: this review will briefly describe the clinical, imaging, pathological and management features of (I) congenital and developmental pathologies, including thyroglossal duct cyst, branchial cleft cysts, dermoid cyst, thymic cyst, and ectopic thymus; (II) vascular malformations, including lymphangioma. Key Messages: pathologists should be familiar with the diagnostic features and clinicopathologic entities of these neck lesions in order to correctly diagnose them and to provide proper clinical management.

Neural network analysis of neutron and x-ray reflectivity data: pathological cases, performance and perspectives

Neutron and x-ray reflectometry (NR and XRR) are powerful techniques to investigate the structural, morphological and even magnetic properties of solid and liquid thin films. While neutrons and x-rays behave similarly in many ways and can be described by the same general theory, they fundamentally differ in certain specific aspects. These aspects can be exploited to investigate different properties of a system, depending on which particular questions need to be answered. Having demonstrated the general applicability of neural networks to analyze XRR and NR data before (Greco et al 2019 J. Appl. Cryst. 52 1342), this study discusses challenges arising from certain pathological cases as well as performance issues and perspectives. These cases include a low signal-to-noise ratio, a high background signal (e.g. from incoherent scattering), as well as a potential lack of a total reflection edge (TRE). By dynamically modifying the training data after every mini batch, a fully-connected neural network was trained to determine thin film parameters from reflectivity curves. We show that noise and background intensity pose no significant problem as long as they do not affect the TRE. However, for curves without strong features the prediction accuracy is diminished. Furthermore, we compare the prediction accuracy for different scattering length density combinations. The results are demonstrated using simulated data of a single-layer system while also discussing challenges for multi-component systems.

Does the Interaction between Local and Systemic Inflammation Provide a Link from Psychology and Lifestyle to Tissue Health in Musculoskeletal Conditions?

Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions.