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In this paper, we review the methodology of one of the most comprehensive indices of gender equality, the Gender Equality Index by the European Institute for Gender Equality (EIGE). Building on Permanyer’s (J Eur Soc Policy, 25(4):414–430, 2015) critical analysis, we offer an extended critique of the EIGE’s current methodology, focusing on four interrelated issues: (a) the lack of transparency around the methodological decisions and the concomitant implicit theorising, (b) the continuing over-contribution of the ‘correcting coefficient’ to the index such that it predominantly captures achievement levels rather than gender gaps, (c) problems with the verification process and use of Principal Component Analysis, (d) issues arising from the aggregation and weighting of index components. Our analysis shows that in addition to the use of the correcting coefficient, other methodological choices (such as the use of ratios and geometric means) result in an unjustified penalisation of lower-GDP countries, reinforcing biased assumptions about gender equality progress in more affluent countries vis-á-vis lower-GDP countries in the sample. We call for greater transparency around theory, method and the relationship between the two while also proposing methodological improvements. These changes would bring the EIGE index closer to fulfilling its undoubted potential to provide a nuanced understanding of gender equality levels in the European Union and effectively inform policy development toward social change.

Purpose Physiotherapy interventions are prescribed as first-line treatment for people with sciatica; however, their effectiveness remains controversial. The purpose of this systematic review was to establish the short-, medium- and long-term effectiveness of physiotherapy interventions compared to control interventions for people with clinically diagnosed sciatica. Methods This systematic review was registered on PROSPERO CRD42018103900. Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), Embase, PEDro, PubMed, Scopus and grey literature were searched from inception to January 2021 without language restrictions. Inclusion criteria were randomised controlled trials evaluating physiotherapy interventions compared to a control intervention in people with clinical or imaging diagnosis of sciatica. Primary outcome measures were pain and disability. Study selection and data extraction were performed by two independent reviewers with consensus reached by discussion or third-party arbitration if required. Risk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias tool with third-party consensus if required. Meta-analyses and sensitivity analyses were performed with random effects models using Revman v5.4. Subgroup analyses were undertaken to examine the effectiveness of physiotherapy interventions compared to minimal (e.g. advice only) or substantial control interventions (e.g. surgery). Results Three thousand nine hundred and fifty eight records were identified, of which 18 trials were included, with a total number of 2699 participants. All trials had a high or unclear risk of bias. Meta-analysis of trials for the outcome of pain showed no difference in the short (SMD − 0.34 [95%CI − 1.05, 0.37] p = 0.34, I2 = 98%), medium (SMD 0.15 [95%CI − 0.09, 0.38], p = 0.22, I2 = 80%) or long term (SMD 0.09 [95%CI − 0.18, 0.36], p = 0.51, I2 = 82%). For disability there was no difference in the short (SMD − 0.00 [95%CI − 0.36, 0.35], p = 0.98, I2 = 92%, medium (SMD 0.25 [95%CI − 0.04, 0.55] p = 0.09, I2 = 87%), or long term (SMD 0.26 [95%CI − 0.16, 0.68] p = 0.22, I2 = 92%) between physiotherapy and control interventions. Subgroup analysis of studies comparing physiotherapy with minimal intervention favoured physiotherapy for pain at the long-term time points. Large confidence intervals and high heterogeneity indicate substantial uncertainly surrounding these estimates. Many trials evaluating physiotherapy intervention compared to substantial intervention did not use contemporary physiotherapy interventions. Conclusion Based on currently available, mostly high risk of bias and highly heterogeneous data, there is inadequate evidence to make clinical recommendations on the effectiveness of physiotherapy interventions for people with clinically diagnosed sciatica. Future studies should aim to reduce clinical heterogeneity and to use contemporary physiotherapy interventions.

Abstract: Latin Gospel Harmonies have attracted comparatively little interest within broader biblical tradition. The oldest extant Latin harmony is Codex Fuldensis, and scholarship has tended to use this in conjunction with vernacular harmonies to try to reconstruct a lost Old Latin Vorlage rather than examine the surviving later manuscripts. After a brief account of the history of research, this chapter presents a gospel pericope (John 2:1–11) from fourteen Latin harmony manuscripts. This provides an impression of their textual variety, especially in later manuscripts. A comparison between earlier and later commentaries on Latin gospel harmonies show that the same traditions are utilized, which belong to the wider stream of medieval commentary tradition manifested in the Glossa ordinaria. Finally, an outline is given of the likely trajectory from the Fuldensis-type Vulgate harmony to vernacular harmonies via the glossed Latin harmony.

This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behaviour and biomarkers in preclinical models of focal neuropathic pain. We searched MEDLINE, EMBASE, Web of Science, PubMed, SCOPUS, CINAHL and Cochrane library from inception to November 2022 for preclinical studies evaluating the effect of exercise compared to control interventions on neuropathic pain behaviour after experimental sciatic nerve injury. If possible, data were meta-analysed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analysed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (SMD 0.53 (95% CI 0.31, 0.74), p= 0.0001, I2=0%, n=364), heat (0.32 (0.07,0.57), p=0.01, I2=0%, n=266) and cold hypersensitivity (0.51 (0.03, 1.0), p=0.04, I2=0%, n=90) compared to control interventions. No relationship was apparent between exercise duration or intensity and antinociception. Exercise modulated biomarkers related to different systems (e.g., immune system, neurotrophins). Whereas firm conclusions are prevented by the use of male animals only, variable reporting quality and unclear risk of bias in many studies, our results suggest that aerobic exercise is a promising tool in the management of focal neuropathic pain. Registration PROSPERO CRD42021231286. Perspective: This systematic review and meta-analysis demonstrates that aerobic exercise reduces neuropathic pain-related behavior in preclinical models of sciatic nerve injury. This effect is accompanied by changes in biomarkers associated with inflammation and neurotrophins among others. These results could help to develop exercise interventions for patients with neuropathic pain.

Background Trigger finger and carpal tunnel syndrome are the two most common non-traumatic connective tissue disorders of the hand. Both of these conditions frequently co-occur, often in patients with rheumatoid arthritis. However, this phenotypic association is poorly understood. Hypothesising that the co-occurrence of trigger finger and carpal tunnel syndrome might be explained by shared germline predisposition, we aimed to identify a specific genetic locus associated with both diseases. Methods In this genome-wide association study (GWAS), we identified 2908 patients with trigger finger and 436 579 controls from the UK Biobank prospective cohort. We conducted a case-control GWAS for trigger finger, followed by co-localisation analyses with carpal tunnel syndrome summary statistics. To identify putative causal variants and establish their biological relevance, we did fine-mapping analyses and expression quantitative trait loci (eQTL) analyses, using fibroblasts from healthy donors (n=79) and tenosynovium samples from patients with carpal tunnel syndrome (n=77). We conducted a Cox regression for time to trigger finger and carpal tunnel syndrome diagnosis against plasma IGF-1 concentrations in the UK Biobank cohort. Findings Phenome-wide analyses confirmed a marked association between carpal tunnel syndrome and trigger finger in the participants from UK Biobank (odds ratio [OR] 11·97, 95% CI 11·1–13·0; p−300). GWAS for trigger finger identified five independent loci, including one locus, DIRC3, that was co-localised with carpal tunnel syndrome and could be fine-mapped to rs62175241 (0·76, 0·68–0·84; p=5·03 × 10−13). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased DIRC3 and IGFBP5 expression. Increased plasma IGF-1 concentrations were associated with both carpal tunnel syndrome and trigger finger in participants from UK Biobank (hazard ratio >1·04, p Interpretation In this GWAS, the DIRC3 locus on chromosome 2 was significantly associated with both carpal tunnel syndrome and trigger finger, possibly explaining their co-occurrence. The disease-protective allele of rs62175241 was associated with increased expression of long non-coding RNA DIRC3 and its transcriptional target, IGBP5, an antagonist of IGF-1 signalling. These findings suggest a model in which IGF-1 is a driver of both carpal tunnel syndrome and trigger finger, and in which the DIRC3-IGFBP5 axis directly antagonises fibroblastic IGF-1 signalling.

Neurological testing is essential for screening and diagnosing suspected peripheral neuropathies. Detecting changes in somatosensory and motor nerve function can also have direct implications for management decisions. Nevertheless, there is considerable variation in what is included in a bedside neurological examination, and how it is performed. Neurological examinations are often used as screening tools to detect neurological deficits, but not used to their full potential for monitoring progress or deterioration. Here, we advocate for better use of the neurological examination within a clinical reasoning framework. Constrained by the lack of research in this field, our viewpoint is based on neuroscientific principles. We highlight six challenges for clinicians when conducting neurological examinations, and propose ways to overcome these challenges in clinical practice. We challenge widely held ideas about how the results of neurological examinations for peripheral neuropathies are interpreted and how the examinations are performed in practice.

Nervenkompressionssyndrome („Engpass-Syndrome“) wie Karpaltunnelsyndrom, Radikulopathien oder radikularer Schmerz sind die haufigsten peripheren Nervenlasionen und auch die haufigste Ursache fur neuropathischen Schmerz. Trotz ihrer hohen Pravalenz stellen sie diagnostisch und therapeutisch weiterhin oft eine klinische Herausforderung dar. Die vorliegende Ubersicht bietet aktuelle Informationen zur Atiologie und Pathophysiologie von Nervenkompressionssyndromen; dafur wird die Evidenz aus praklinischen wie auch klinischen Studien zusammengefasst. Mogliche Mechanismen werden in den Kontext klinischer Befunde gestellt. Das aktuelle diagnostische Vorgehen wird erortert, diagnostische Fallstricke werden beleuchtet. Zuletzt fasst der Beitrag die Evidenz fur die nichtinvasive und chirurgische Therapie haufiger Nervenkompressionssyndrome zusammen und zeigt zukunftige Forschungsbereiche auf.

The role that inflammation plays in human nerve injury and neuropathic pain is incompletely understood. Previous studies highlight the role of inflammation in the generation and maintenance of neuropathic pain, but the emerging evidence from the preclinical literature for its role in the resolution of neuropathic pain remains to be explored in humans. Here, we use carpal tunnel syndrome (CTS) as a human model system of nerve injury and neuropathic pain to determine changes in serum cytokine protein levels and gene expression levels before (active stage of disease) and after carpal tunnel decompression surgery (recovery). Fifty-five patients with CTS were studied, and 21 healthy age-matched and gender-matched participants served as controls. In the active stage of the disease (CTS before surgery vs healthy controls), PTGES2 mRNA was decreased in patients (adjusted P = 0.013), while transforming growth factor-β and C-C motif chemokine ligand 5 protein levels were increased (adjusted P = 0.016 and P = 0.047, respectively). In the resolution phase (CTS before surgery vs after surgery), IL-9 mRNA was increased after surgery (adjusted P = 0.014) and expression of IL-6 mRNA and IL-4 protein levels were increased before surgery (adjusted P = 0.034 and P = 0.002, respectively). IL-9 mRNA expression negatively correlated with several (neuropathic) pain scores. By contrast, protein levels of IL-4 positively correlated with pain scores. In conclusion, we demonstrate specific dysregulation of systemic cytokine expression in both the active and resolution phases of nerve injury and neuropathic pain. IL-9 represents an interesting candidate associated with resolution of nerve injury and neuropathic pain.

Gender equality indices are increasingly influential tools used for governance and knowledge production. This article evaluates the adequacy of the seventeen existing multi-dimensional gender equality indices and shows that all but one neglect unpaid reproductive labor to varying degrees. The empirical analysis offers three lessons for these indices’ improvement. First, that it is possible to measure the gendered division of unpaid reproductive labor using gender equality indices. Second, that data availability need not compromise the coherence of the indices’ frameworks. Finally, that indices can reduce the overbearing emphasis on quantitative indicators in governance by complementing their findings with qualitative analyses.

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up,” in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting., Neuron, 110 (16)

Although many planning systems are based on a combination of traditional land-use planning and strategic spatial planning, the interplay between the two approaches remains insufficiently investigat...

Central sensitization is a physiological mechanism associated with enhanced sensitivity and pain responses. At present, central sensitization cannot be determined directly in humans, but certain signs and symptoms may be suggestive of it. Although central sensitization has received increasing attention in the clinical literature, there is a risk that certain distinctions are being lost. This paper summarizes current knowledge of the physiology of central sensitization and its possible manifestations in patients, in order to inform a debate about the relevance of central sensitization for physical therapists. It poses 6 challenges associated with the application of central sensitization concepts in clinical practice and makes suggestions for assessment, treatment, and use of terminology. Physical therapists are asked to be mindful of central sensitization and consider potential top-down as well as bottom-up drivers, in the context of a person-centered biopsychosocial approach.

Supplemental Digital Content is Available in the Text. The severity more than the presence of neuropathic pain is related to the extent of neuropathy and a compromise of emotional well-being in entrapment neuropathies., It currently remains unclear why some patients with entrapment neuropathies develop neuropathic pain (neuP), whereas others have non-neuP, presumably of nociceptive character. Studying patients with carpal tunnel syndrome (CTS), this cross-sectional cohort study investigated changes in somatosensory structure and function as well as emotional well-being specific to the presence and severity of neuP. Patients with CTS (n = 108) were subgrouped by the DN4 questionnaire into those without and with neuP. The latter group was further subdivided into mild and moderate/severe neuP using a pain visual analogue scale. N = 32 participants served as healthy controls. All participants underwent a clinical examination, quantitative sensory testing, electrodiagnostic testing (EDT), and skin biopsy to determine the structural integrity of dermal and intraepidermal nerve fibres. Patients also completed questionnaires evaluating symptom severity and functional deficits, pain distribution, sleep quality, and emotional well-being. The overall prevalence of neuP in patients with CTS was 80%, of which 63% had mild neuP. Symptom severity and functional deficits as well as somatosensory dysfunction was more pronounced with the presence and increasing severity of neuP. No difference was identified among patient groups for EDT and nerve fibre integrity on biopsies. The severity of neuP was accompanied by more pronounced deficits in emotional well-being and sleep quality. Intriguingly, extraterritorial spread of symptoms was more prevalent in patients with moderate/severe neuP, indicating the presence of central mechanisms. NeuP is common in patients with CTS, and its severity is related to the extent of somatosensory dysfunction and a compromise of emotional well-being.

Question: In people with carpal tunnel syndrome who are waitlisted for surgical consultation, does a therapist-led care pathway involving education, splinting and exercises reduce the need for surgery and improve patient outcomes? Design: A multicentre, randomised controlled trial with concealed allocation, blinded assessment and intention-to-treat analysis. Participants: One hundred and five people with electrodiagnostically confirmed carpal tunnel syndrome on a waitlist for surgical consultation and recruited from four public hospitals in Australia. Interventions: The experimental group (n = 52) received a one-off group session of education, splinting, and nerve and tendon gliding exercises. The control group (n = 53) continued on the waitlist without additional care. Outcome Measures: The primary outcome measures were conversion to surgery by 24 weeks, the global rating of change (GROC) scale and patient satisfaction. Secondary outcomes included symptom severity and functional limitation. Results: At 24 weeks, conversion to surgery was 59% in the experimental group and 80% in the control group (risk difference −0.21, 95% CI −0.38 to −0.03). More participants in the experimental group identified as improved at 6 weeks (20% vs 4%; risk difference 0.15, 95% CI 0.03 to 0.28) but not at 24 weeks (24% vs 10%; risk difference 0.14, 95% CI −0.01 to 0.29). The intervention was also estimated to be beneficial on some measures of satisfaction, symptom severity and functional limitation. The study’s estimates of the benefits came with some uncertainty, which makes it unclear whether the wider population of people awaiting carpal tunnel surgery would consider that the benefits make the intervention worthwhile. No serious adverse effects were reported. Conclusions: A therapist-led pathway reduced conversion to carpal tunnel surgery and increased perceived improvement and satisfaction in people who were already on a waitlist for surgical consultation. Registration: ACTRN12613001095752.

Tackling gender inequality is a key focus for both civil society and government policy in Great Britain (GB). Yet, there is currently no consensus on how to conceptualize or operationalize gender inequalities, nor any detailed measurement of gender inequalities at the subnational level, despite high levels of regional inequality. This is a barrier to the development and evaluation of gender equality programs and policies, and to holding the government accountable. To address this gap, we propose a framework for a subnational index of gender inequalities in GB based on a review of relevant indices, theoretical models, and policy. This framework was further developed in a workshop with stakeholders. We also scope the data currently available from survey and administrative sources to capture the proposed framework, highlighting gaps in our ability to comprehensively measure gender inequalities at the subnational level in GB.

IntroductionSciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with ‘sciatica’) will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica.Methods and analysisWe will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence.Ethics and disseminationThe FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts.Trial registration numberISRCTN18170726; Pre-results.

Objective: Carpal tunnel syndrome (CTS) is the most common focal nerve injury. People with CTS may show alterations in central processing of nociceptive information. It remains unclear whether the central sensitization inventory (CSI) is capable of detecting such altered central pain processing. Methods: Thirty healthy volunteers were matched with 30 people with unilateral CTS from the orthopaedic waitlist. Changes to central pain processing were established through psychophysical sensory testing (bilateral pressure pain thresholds (PPT), conditioned pain modulation, temporal summation) and pain distribution on body charts. Patients also completed pain severity and function questionnaires, psychological questionnaires and the CSI. Results: Compared to healthy volunteers, patients with CTS have lower PPTs over the carpal tunnel bilaterally (t = −4.06, p < 0.0001 ipsilateral and t = −4.58, p < 0.0001 contralateral) and reduced conditioned pain modulation efficacy (t = −7.31, p Conclusion: Patients with CTS show signs of altered central pain mechanisms. The CSI seems unsuitable to detect changes in central pain processing but is rather associated with psychological factors in people with focal nerve injuries.

State-of-the-art in vitro test systems for nanomaterial toxicity assessment are based on dyes and several staining steps which can be affected by nanomaterial interference. Digital holographic microscopy (DHM), an interferometry-based variant of quantitative phase imaging (QPI), facilitates reliable proliferation quantification of native cell populations and the extraction of morphological features in a fast and label- and interference-free manner by biophysical parameters. DHM therefore has been identified as versatile tool for cytotoxicity testing in biomedical nanotechnology. In a comparative study performed at two collaborating laboratories, we investigated the interlaboratory variability and performance of DHM in nanomaterial toxicity testing, utilizing complementary standard operating procedures (SOPs). Two identical custom-built off-axis DHM systems, developed for usage in biomedical laboratories, equipped with stage-top incubation chambers were applied at different locations in Europe. Temporal dry mass development, 12-h dry mass increments and morphology changes of A549 human lung epithelial cell populations upon incubation with two variants of poly(alkyl cyanoacrylate) (PACA) nanoparticles were observed in comparison to digitonin and cell culture medium controls. Digitonin as cytotoxicity control, as well as empty and cabazitaxel-loaded PACA nanocarriers, similarly impacted 12-h dry mass development and increments as well as morphology of A549 cells at both participating laboratories. The obtained DHM data reflected the cytotoxic potential of the tested nanomaterials and are in agreement with corresponding literature on biophysical and chemical assays. Our results confirm DHM as label-free cytotoxicity assay for polymeric nanocarriers as well as the repeatability and reproducibility of the technology. In summary, the evaluated DHM assay could be efficiently implemented at different locations and facilitates interlaboratory in vitro toxicity testing of nanoparticles with prospects for application in regulatory science. Graphical abstract

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease and an altered skin microbiota with an increase of Staphylococcus aureus has been reported. However, the role of fungi remains poorly investigated.We aimed to improve the understanding of the fungal skin microbiota, the mycobiota, in AD in relation to the bacterial colonization.Skin swabs of 16 AD patients and 16 healthy controls (HC) from four different skin sites, that is antecubital crease, dorsal neck, glabella and vertex from multiple time points were analysed by DNA sequencing of the internal transcribed spacer region 1 (ITS1) and 16S rRNA gene for fungi and bacteria, respectively.Malassezia spp. were the predominant fungi in all subjects but with a decreased dominance in severe AD patients in favour of non-Malassezia fungi, for example Candida spp. For bacteria, a decrease of Cutibacterium spp. in AD patients in favour of Staphylococcus spp., particularly S. aureus, was observed. Further, both bacterial and fungal community compositions of severe AD patients significantly differed from mild-to-moderate AD patients and HC with the latter two having overall similar microbiota showing some distinctions in bacterial communities.We conclude that severe AD is associated with a pronounced dysbiosis of the microbiota with increased fungal diversity. Potentially infectious agents, for example Staphylococcus and Candida, were increased in severe AD.

The purpose of this systematic review was to evaluate the effects of physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain (PNP). The search was performed in Pubmed, Web of Science, EMBASE, Cochrane, Cinhal, Psycinfo, Scopus, Medline, and Science Direct. Studies evaluating any type of physiotherapy intervention for PNP (systemic or traumatic) were included. Eighty-one articles were included in this review. The most common PNP model was chronic constriction injury, and the most frequently studied biomarkers were related to neuro-immune processes. Exercise therapy and Electro-acupuncture were the 2 most frequently studied physiotherapy interventions while acupuncture and joint mobilization were less frequently examined. Most physiotherapeutic interventions modulated the expression of biomarkers related to neuropathic pain. Whereas the results seem promising; they have to be considered with caution due to the high risk of bias of included studies and high heterogeneity of the type and anatomical localization of biomarkers reported. The review protocol is registered on PROSPERO (CRD42019142878). Perspective This article presents the current evidence about physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain. Existing findings are reviewed, and relevant data are provided on the effectiveness of each physiotherapeutic modality, as well as its certainty of evidence and clinical applicability. post-print 761 KB

Purpose Proprioceptive deficits are common in low back pain. The multifidus muscle undergoes substantial structural change after back injury, but whether muscle spindles are affected is unclear. This study investigated whether muscle spindles of the multifidus muscle are changed by intervertebral disc (IVD) degeneration in a large animal model. Methods IVD degeneration was induced by partial thickness annulus fibrosus lesion to the L3-4 IVD in nine sheep. Multifidus muscle tissue at L4 was harvested at six months after lesion, and from six age-/sex-matched naïve control animals. Muscle spindles were identified in Van Gieson’s-stained sections by morphology. The number, location and cross-sectional area (CSA) of spindles, the number, type and CSA of intrafusal fibers, and thickness of the spindle capsule were measured. Immunofluorescence assays examined Collagen I and III expression. Results Multifidus muscle spindles were located centrally in the muscle and generally near connective tissue. There were no differences in the number or location of muscle spindles after IVD degeneration and only changes in the CSA of nuclear chain fibers. The thickness of connective tissue surrounding the muscle spindle was increased as was the expression of Collagen I and III. Conclusion Changes to the connective tissue and collagen expression of the muscle spindle capsule are likely to impact their mechanical properties. Changes in capsule stiffness may impact the transmission of length change to muscle spindles and thus transduction of sensory information. This change in muscle spindle structure may explain some of the proprioceptive deficits identified with low back pain.

Trigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.

Objective This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN). Methods This is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator. Results The behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves. Conclusion This study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use. Impact These findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potenzial mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.Nervenkompressionssyndrome („Engpass-Syndrome“) wie Karpaltunnelsyndrom, Radikulopathien oder radikulärer Schmerz sind die häufigsten peripheren Nervenläsionen und auch die häufigste Ursache für neuropathischen Schmerz. Trotz ihrer hohen Prävalenz stellen sie diagnostisch und therapeutisch weiterhin oft eine klinische Herausforderung dar. Die vorliegende Übersicht bietet aktuelle Informationen zur Ätiologie und Pathophysiologie von Nervenkompressionssyndromen; dafür wird die Evidenz aus präklinischen wie auch klinischen Studien zusammengefasst. Mögliche Mechanismen werden in den Kontext klinischer Befunde gestellt. Das aktuelle diagnostische Vorgehen wird erörtert, diagnostische Fallstricke werden beleuchtet. Zuletzt fasst der Beitrag die Evidenz für die nichtinvasive und chirurgische Therapie häufiger Nervenkompressionssyndrome zusammen und zeigt zukünftige Forschungsbereiche auf.