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OBJECTIVES: Body posture of patients with temporomandibular disorders (TMD) has been investigated using different methods, whereas outcome and conclusions were controversial. The present clinical trial aimed to investigate the effects of splint therapy on global body posture. MATERIALS AND METHODS: 24 subjects (20 females, 4 males; age 24.2 ± 4.0 years) with TMD symptoms were examined clinically (RDC/TMD) and subsequently, splint fabrication was initiated. Along with routine therapy, all subjects underwent three-dimensional pre- and post-treatment full body scans in standing and upright sitting posture using a Vitus Smart XXL 3D scanner. Each scan was acquired in triplicate and evaluated in duplicate, measuring twelve standing and nine sitting postural parameters. Influencing factors were analyzed using analysis of variance (ANOVA), and additional Bland-Altman analyses verified the significance of the ANOVA results. RESULTS: The increase of Forward Head angles and the decrease of Round Shoulders angles were consistent for both positions and sides. Forward Head angles were significantly influenced by limited mandibular mobility and myofascial pain. Round Shoulders angles showed a significant correlation with myofascial pain, joint noises and the absence of limited mandibular mobility. CONCLUSION: The influence of occlusal splints on global posture is limited and only small effects on cervicocranial parameters were found. In the present study, the average head position of post treatment measurements was more centered on the body's core, whereas the shoulders were tilted more anteriorly. CLINICAL RELEVANCE: Understanding the limited influence of occlusal splints on cervicocranial parameters underscores the need for multimodal treatment strategies for TMD patients.

Asunto(s)

Ferulas Oclusales , Postura , Trastornos de la Articulación Temporomandibular , Humanos , Femenino , Masculino , Postura/fisiología , Estudios Prospectivos , Trastornos de la Articulación Temporomandibular/terapia , Trastornos de la Articulación Temporomandibular/fisiopatología , Adulto , Imagenología Tridimensional , Resultado del Tratamiento

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The major histocompatibility complex (MHC) with its highly polymorphic HLA genes represents one of the most intensely studied genomic regions in the genome. MHC proteins play a key role in antigen-specific immunity and are associated with a wide range of complex diseases. Despite decades of research and many advances in the field, the characterization and interpretation of its genetic and genomic variability remain challenging. Here an overview is provided of the MHC, the nature of its exceptional variability, and the complex evolutionary processes assumed to drive this variability. Highlighted are also recent advances in the field that promise to improve our understanding of the variability in the MHC and in antigen-specific immunity more generally.

Asunto(s)

Evolución Molecular , Variación Genética , Antígenos HLA , Complejo Mayor de Histocompatibilidad , Humanos , Antígenos HLA/genética , Complejo Mayor de Histocompatibilidad/genética , Animales

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Positive treatment expectations demonstrably shape treatment outcomes regarding pain and disability in patients with chronic low back pain. However, knowledge about positive and negative treatment expectations as putative predictors of interindividual variability in treatment outcomes is sparse, and the role of other psychological variables of interest, especially of depression as a known predictor of long-term disability, is lacking. We present results of the first prospective study considering expectations in concert with depression in a sample of 200 patients with chronic low back pain undergoing an inpatient interdisciplinary multimodal pain therapy. We analyzed the characteristics of pain and disability, treatment expectation, and depression assessed at the beginning (T0), at the end of (T1), and at 3-month follow-up (T2) of interdisciplinary multimodal pain therapy. Treatment expectations did emerge as a significant predictor of changes in pain intensity and disability, respectively, showing that positive expectations were associated with better treatment outcomes. Mediation analyses revealed a partially mediating effect of treatment expectations on the relation between depression and pain outcomes. PERSPECTIVE: These results expand knowledge regarding the role of treatment expectations in individual treatment outcome trajectories in chronic pain patients, paving the way for much-needed efforts toward optimizing patient expectations and personalized approaches in clinical settings.

Asunto(s)

Dolor Crónico , Depresión , Dolor de la Región Lumbar , Humanos , Masculino , Femenino , Persona de Mediana Edad , Dolor de la Región Lumbar/terapia , Dolor de la Región Lumbar/psicología , Adulto , Dolor Crónico/terapia , Dolor Crónico/psicología , Depresión/terapia , Estudios Prospectivos , Anciano , Estudios de Seguimiento , Terapia Combinada , Resultado del Tratamiento , Manejo del Dolor

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Postoperative epidural fibrosis (EF) is still a major limitation to the success of spine surgery. Fibrotic adhesions in the epidural space, initiated via local trauma and inflammation, can induce difficult-to-treat pain and constitute the main cause of failed back surgery syndrome, which not uncommonly requires operative revision. Manifold agents and methods have been tested for EF relief in order to mitigate this longstanding health burden and its socioeconomic consequences. Although several promising strategies could be identified, few have thus far overcome the high translational hurdle, and there has been little change in standard clinical practice. Nonetheless, notable research progress in the field has put new exciting avenues on the horizon. In this review, we outline the etiology and pathogenesis of EF, portray its clinical and surgical presentation, and critically appraise current efforts and novel approaches toward enhanced prevention and treatment.

RESUMEN

INTRODUCTION: Revision shoulder arthroplasty can be challenging. One of the main considerations for surgeons is the type of implant that was placed in the initial surgery. Anatomic shoulder arthroplasty (ASA) is used for cases of osteoarthritis as well as for fractures of the humeral head. Hemiarthroplasty can be used for complex proximal humerus fractures. The purpose of this study is to determine whether there is a difference in clinical and radiographic outcomes between patients that failed primary fracture hemiarthroplasty (FHA), or ASA for osteoarthritis and then required reoperation with a conversion to reverse shoulder arthroplasty (RSA). METHODS: Patients with failed anatomic shoulder replacement, who had undergone conversion to RSA, were enrolled after a mean follow-up of 107 (85-157) months. Two different groups, one with failed ASA implanted for osteoarthritis and one with failed FHA, were created. At follow-up patients were assessed with standard radiographs and clinical outcome scores. RESULTS: Twenty-nine patients (f = 17, m = 12; 51%) suffered from a failed ASA (Group A), while the remaining 28 patients (f = 21, m = 74; 49%) had been revised due to a failed FHA (Group B). Patients of Group B had a poorer Constant score (Group A: 60 vs. Group B: 46; p = 0.02). Abduction (Group A: 115° vs. Group B: 89°; p = 0.02) was worse after conversion of a failed FHA to RSA in comparison to conversions of failed ASA. The mean bone loss of the lateral metaphysis was higher in patients with failed FHA (Group A: 5 mm vs. Group B: 20 mm; p = 0.0). CONCLUSION: The initial indication for anatomic shoulder arthroplasty influences the clinical and radiological outcome after conversion to RSA. Conversion of failed FHA to RSA is related to an increased metaphyseal bone loss, decreased range of motion and poorer clinical outcomes when compared to conversions of failed ASA implanted for osteoarthritis. LEVEL OF EVIDENCE: III Retrospective Cohort Comparison Study.

Asunto(s)

Artroplastía de Reemplazo de Hombro , Hemiartroplastia , Osteoartritis , Radiografía , Reoperación , Fracturas del Hombro , Articulación del Hombro , Humanos , Artroplastía de Reemplazo de Hombro/métodos , Hemiartroplastia/métodos , Masculino , Femenino , Anciano , Reoperación/estadística & datos numéricos , Reoperación/métodos , Osteoartritis/cirugía , Osteoartritis/diagnóstico por imagen , Fracturas del Hombro/cirugía , Fracturas del Hombro/diagnóstico por imagen , Articulación del Hombro/cirugía , Articulación del Hombro/diagnóstico por imagen , Articulación del Hombro/fisiopatología , Persona de Mediana Edad , Resultado del Tratamiento , Anciano de 80 o más Años , Rango del Movimiento Articular , Estudios de Seguimiento , Estudios Retrospectivos

RESUMEN

RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Commentary on: Abadie V et al. IL­15, gluten and HLA­DQ8 drive tissue destruction in coeliac disease. Nature. 2020; 578: 600­604

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Enfermedad Celíaca , Animales , Ratones , Humanos , Enfermedad Celíaca/diagnóstico , Modelos Animales de Enfermedad

RESUMEN

Using high-throughput sequencing for precise genotyping of multi-locus gene families, such as the major histocompatibility complex (MHC), remains challenging, due to the complexity of the data and difficulties in distinguishing genuine from erroneous variants. Several dedicated genotyping pipelines for data from high-throughput sequencing, such as next-generation sequencing (NGS), have been developed to tackle the ensuing risk of artificially inflated diversity. Here, we thoroughly assess three such multi-locus genotyping pipelines for NGS data, the DOC method, AmpliSAS and ACACIA, using MHC class IIß data sets of three-spined stickleback gDNA, cDNA and "artificial" plasmid samples with known allelic diversity. We show that genotyping of gDNA and plasmid samples at optimal pipeline parameters was highly accurate and reproducible across methods. However, for cDNA data, the gDNA-optimal parameter configuration yielded decreased overall genotyping precision and consistency between pipelines. Further adjustments of key clustering parameters were required tο account for higher error rates and larger variation in sequencing depth per allele, highlighting the importance of template-specific pipeline optimization for reliable genotyping of multi-locus gene families. Through accurate paired gDNA-cDNA typing and MHC-II haplotype inference, we show that MHC-II allele-specific expression levels correlate negatively with allele number across haplotypes. Lastly, sibship-assisted cDNA-typing of MHC-I revealed novel variants linked in haplotype blocks, and a higher-than-previously-reported individual MHC-I allelic diversity. In conclusion, we provide novel genotyping protocols for the three-spined stickleback MHC-I and -II genes, and evaluate the performance of popular NGS-genotyping pipelines. We also show that fine-tuned genotyping of paired gDNA-cDNA samples facilitates amplification bias-corrected MHC allele expression analysis.

Asunto(s)

Técnicas de Genotipaje , Secuenciación de Nucleótidos de Alto Rendimiento , Genotipo , Alelos , Técnicas de Genotipaje/métodos , ADN Complementario , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Expresión Génica , Haplotipos

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Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.

Asunto(s)

Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II , Vigilancia Inmunológica , Pérdida de Heterocigocidad , Neoplasias Pulmonares , Humanos , Antígenos de Histocompatibilidad Clase II/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Macrófagos Alveolares/inmunología , Factores de Riesgo , Fumar/inmunología , Vigilancia Inmunológica/genética , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Polimorfismo de Nucleótido Simple

RESUMEN

Pure-tone audiograms often poorly predict elderly humans' ability to communicate in everyday complex acoustic scenes. Binaural processing is crucial for discriminating sound sources in such complex acoustic scenes. The compromised perception of communication signals presented above hearing threshold has been linked to both peripheral and central age-related changes in the auditory system. Investigating young and old Mongolian gerbils of both sexes, an established model for human hearing, we demonstrate age-related supra-threshold deficits in binaural hearing using behavioral, electrophysiological, anatomical, and imaging methods. Binaural processing ability was measured as the binaural masking level difference (BMLD), an established measure in human psychophysics. We tested gerbils behaviorally with "virtual headphones," recorded single-unit responses in the auditory midbrain and evaluated gross midbrain and cortical responses using positron emission tomography (PET) imaging. Furthermore, we obtained additional measures of auditory function based on auditory brainstem responses, auditory-nerve synapse counts, and evidence for central inhibitory processing revealed by PET. BMLD deteriorates already in middle-aged animals having normal audiometric thresholds and is even worse in old animals with hearing loss. The magnitude of auditory brainstem response measures related to auditory-nerve function and binaural processing in the auditory brainstem also deteriorate. Furthermore, central GABAergic inhibition is affected by age. Because the number of synapses in the apical turn of the inner ear was not reduced in middle-aged animals, we conclude that peripheral synaptopathy contributes little to binaural processing deficits. Exploratory analyses suggest increased hearing thresholds, altered binaural processing in the brainstem and changed central GABAergic inhibition as potential contributors.

Asunto(s)

Sordera , Pérdida Auditiva , Masculino , Anciano , Persona de Mediana Edad , Femenino , Animales , Humanos , Gerbillinae , Audición/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Umbral Auditivo , Percepción Auditiva/fisiología , Estimulación Acústica

RESUMEN

The immune-fibrosis axis plays a critical role in cardiac remodeling after acute myocardial infarction. Imaging approaches to monitor temporal inflammation and fibroblast activation in mice have seen wide application in recent years. However, the repeatability of quantitative measurements remains challenging, particularly across multiple imaging centers. We aimed to determine reproducibility of quantitative inflammation and fibroblast activation images acquired at 2 facilities after myocardial infarction in mice. Methods: Mice underwent coronary artery ligation and sequential imaging with 68Ga-DOTA-ECL1i to assess chemokine receptor type 2 expression at 3 d after myocardial infarction and 68Ga-FAPI-46 to assess fibroblast activation protein expression at 7 d after myocardial infarction. Images were acquired at 1 center using either a local or a consensus protocol developed with the second center; the protocols differed in the duration of isoflurane anesthesia and the injected tracer dose. A second group of animals were scanned at the second site using the consensus protocol. Image analyses performed by each site and just by 1 site were also compared. Results: The uptake of 68Ga-DOTA-ECL1i in the infarct territory tended to be higher when the consensus protocol was used (P = 0.03). No difference was observed between protocol acquisitions for 68Ga-FAPI-46. Compared with the local protocol, the consensus protocol decreased variability between individual animals. When a matched consensus protocol was used, the 68Ga-DOTA-ECL1i infarct territory percentage injected dose per gram of tissue was higher on images acquired at site B than on those acquired at site A (P = 0.006). When normalized to body weight as SUV, this difference was mitigated. Both the percentage injected dose per gram of tissue and the SUV were comparable between sites for 68Ga-FAPI-46. Image analyses at the sites differed significantly, but this difference was mitigated when all images were analyzed at site A. Conclusion: The application of a standardized acquisition protocol may lower variability within datasets and facilitate comparison of molecular radiotracer distribution between preclinical imaging centers. Like clinical studies, multicenter preclinical studies should use centralized core-based image analysis to maximize reproducibility across sites.

Asunto(s)

Radioisótopos de Galio , Infarto del Miocardio , Ratones , Animales , Reproducibilidad de los Resultados , Infarto del Miocardio/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Inflamación , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos

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We demonstrate a methodology which both improves oxygen transport and reduces or eliminates bubble formation in a novel hyperbaric membrane oxygenator catheter model system. Angular oscillations were introduced to a bundle of hollow fiber membranes (HFMs) supplied with hyperbaric 100% oxygen at average gauge pressures up to 0.35 barg. Oscillating bundles enabled delivery of an oxygen flux of up to 400 mL min-1 m-2 in an aqueous solution, a doubling over a previous non-oscillating setup. Similarly, the addition of angular oscillations facilitated a five-fold reduction in pressure to achieve similar oxygen flux. The increased angular speed of oscillation improved flux, while the addition of angular micro-oscillation variations resulted in flux reductions of 7-20% compared to continuous macro-oscillation only, depending on mixing conditions. However, semi-quantitative visual observation demonstrated that angular oscillations reduced or eliminated the instance of oxygen bubble formation on the HFMs. The modeled mass transfer coefficients indicated a quasi linear relationship between rotational velocity and flux, suggesting that faster oscillation speeds could further improve oxygen mass transport allowing for HFM bundles to maintain high oxygen fluxes while eliminating bubble formation. This encourages further development of our compact oxygenating catheter that could be used intravascularly.

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Oxígeno , Oxigenadores , Catéteres , Diseño de Equipo , Oxigenadores de Membrana

RESUMEN

An essential process in transmission of the malaria parasite to the Anopheles vector is the conversion of mature gametocytes into gametes within the mosquito gut, where they egress from the red blood cell (RBC). During egress, male gametocytes undergo exflagellation, leading to the formation of eight haploid motile microgametes, while female gametes retain their spherical shape. Gametocyte egress depends on sequential disruption of the parasitophorous vacuole membrane and the host cell membrane. In other life cycle stages of the malaria parasite, phospholipases have been implicated in membrane disruption processes during egress, however their importance for gametocyte egress is relatively unknown. Here, we performed comprehensive functional analyses of six putative phospholipases for their role during development and egress of Plasmodium falciparum gametocytes. We localize two of them, the prodrug activation and resistance esterase (PF3D7_0709700) and the lysophospholipase 1 (PF3D7_1476700), to the parasite plasma membrane. Subsequently, we show that disruption of most of the studied phospholipase genes does neither affect gametocyte development nor egress. The exception is the putative patatin-like phospholipase 3 (PF3D7_0924000), whose gene deletion leads to a delay in male gametocyte exflagellation, indicating an important, albeit not essential, role of this enzyme in male gametogenesis.

Asunto(s)

Malaria , Plasmodium falciparum , Animales , Masculino , Femenino , Fosfolipasas/genética , Mosquitos Vectores , Eritrocitos/parasitología

Asunto(s)

Anestesia , Respiración Artificial , Humanos

RESUMEN

Background: The epidemiology of Mycobacterium tuberculosis complex (MTBC) lineage 5 (L5) infections in Ghana revealed a significantly increased prevalence in Ewes compared to other self-reported ethnic groups. In that context, we sought to investigate the early phase of tuberculosis (TB) infection using ex vivo infection of macrophages derived from the blood of Ewe and Akan ethnic group volunteers with MTBC L4 and L5 strains. Methods: The study participants consisted of 16 controls, among which self-reported Akan and Ewe ethnicity was equally represented, as well as 20 cured TB cases consisting of 11 Akans and 9 Ewes. Peripheral blood mononuclear cells were isolated from both healthy controls and cured TB cases. CD14+ monocytes were isolated and differentiated into monocyte-derived macrophages (MDMs) before infection with L4 or L5 endemic strains. The bacterial load was assessed after 2 hours (uptake) as well as 3 and 7 days post-infection. Results: We observed a higher capacity of MDMs from Ewes to phagocytose L4 strains (p < 0.001), translating into a higher bacillary load on day 7 (p < 0.001) compared to L5, despite the higher replication rate of L5 in Ewe MDMs (fold change: 1.4 vs. 1.2, p = 0.03) among the controls. On the contrary, within macrophages from Akans, we observed a significantly higher phagocytic uptake of L5 (p < 0.001) compared to L4, also translating into a higher load on day 7 (p = 0.04). However, the replication rate of L4 in Akan MDMs was higher than that of L5 (fold change: L4 = 1.2, L4 = 1.1, p = 0.04). Although there was no significant difference in the uptake of L4 and L5 among cured TB cases, there was a higher bacterial load of both L4 (p = 0.02) and L5 (p = 0.02) on day 7 in Ewe MDMs. Conclusion: Our results suggest that host ethnicity (driven by host genetic diversity), MTBC genetic diversity, and individual TB infection history are all acting together to modulate the outcome of macrophage infections by MTBC.

Asunto(s)

Tuberculosis Latente , Mycobacterium tuberculosis , Humanos , Animales , Femenino , Ovinos , Etnicidad , Ghana/epidemiología , Autoinforme , Leucocitos Mononucleares , Macrófagos

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BACKGROUND: Implant infections caused by biofilm forming bacteria are a major threat in orthopedic surgery. Delivering antibiotics directly to an implant affected by a bacterial biofilm via superparamagnetic nanoporous silica nanoparticles could present a promising approach. Nevertheless, short blood circulation half-life because of rapid interactions of nanoparticles with the host's immune system hinder them from being clinically used. The aim of this study was to determine the temporal in vivo resolution of magnetic nanoporous silica nanoparticle (MNPSNP) distribution and the effect of PEGylation and clodronate application using PET/CT imaging and gamma counting in an implant mouse model. METHODS: PEGylated and non-PEGylated MNPSNPs were radiolabeled with gallium-68 (68Ga), implementing the chelator tris(hydroxypyridinone). 36 mice were included in the study, 24 mice received a magnetic implant subcutaneously on the left and a titanium implant on the right hind leg. MNPSNP pharmacokinetics and implant accumulation was analyzed in dependence on PEGylation and additional clodronate application. Subsequently gamma counting was performed for further final analysis. RESULTS: The pharmacokinetics and biodistribution of all radiolabeled nanoparticles could clearly be visualized and followed by dynamic PET/CT imaging. Both variants of 68Ga-labeled MNPSNP accumulated mainly in liver and spleen. PEGylation of the nanoparticles already resulted in lower liver uptakes. Combination with macrophage depletion led to a highly significant effect whereas macrophage depletion alone could not reveal significant differences. Although MNPSNP accumulation around implants was low in comparison to the inner organs in PET/CT imaging, gamma counting displayed a significantly higher %I.D./g for the tissue surrounding the magnetic implants compared to the titanium control. Additional PEGylation and/or macrophage depletion revealed no significant differences regarding nanoparticle accumulation at the implantation site. CONCLUSION: Tracking of 68Ga-labeled nanoparticles in a mouse model in the first critical hours post-injection by PET/CT imaging provided a better understanding of MNPSNP distribution, elimination and accumulation. Although PEGylation increases circulation time, nanoparticle accumulation at the implantation site was still insufficient for infection treatment and additional efforts are needed to increase local accumulation.

Asunto(s)

Nanoporos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Animales , Ratones , Ácido Clodrónico , Radioisótopos de Galio , Distribución Tisular , Titanio , Modelos Animales de Enfermedad , Fenómenos Magnéticos

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In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The "PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain" (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18-55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs.

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Dolor de la Región Lumbar , Masculino , Humanos , Femenino , Dolor de la Región Lumbar/diagnóstico por imagen , Inteligencia Artificial , Estudios Transversales , Estudios Prospectivos , Columna Vertebral

RESUMEN

Genome sequencing enables answering fundamental questions about the genetic basis of adaptation, population structure and epigenetic mechanisms. Yet, we usually need a suitable reference genome for mapping population-level resequencing data. In some model systems, multiple reference genomes are available, giving the challenging task of determining which reference genome best suits the data. Here, we compared the use of two different reference genomes for the three-spined stickleback (Gasterosteus aculeatus), one novel genome derived from a European gynogenetic individual and the published reference genome of a North American individual. Specifically, we investigated the impact of using a local reference versus one generated from a distinct lineage on several common population genomics analyses. Through mapping genome resequencing data of 60 sticklebacks from across Europe and North America, we demonstrate that genetic distance among samples and the reference genomes impacts downstream analyses. Using a local reference genome increased mapping efficiency and genotyping accuracy, effectively retaining more and better data. Despite comparable distributions of the metrics generated across the genome using SNP data (i.e. π, Tajima's D and FST ), window-based statistics using different references resulted in different outlier genes and enriched gene functions. A marker-based analysis of DNA methylation distributions had a comparably high overlap in outlier genes and functions, yet with distinct differences depending on the reference genome. Overall, our results highlight how using a local reference genome decreases reference bias to increase confidence in downstream analyses of the data. Such results have significant implications in all reference-genome-based population genomic analyses.

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Metagenómica , Smegmamorpha , Animales , Genoma/genética , Mapeo Cromosómico , Genómica/métodos , Análisis de Secuencia de ADN/métodos , Smegmamorpha/genética