This special issue comprised 7 articles from leaders in the field that focus on "big pain data", the large datasets and the associated methods for data analysis that are currently emerging in pain ...research. This collection of articles highlights the power and potential as well as points of caution that multi-disciplinary research utilising big data and their associated methods and interpretations present for pain research.
Carpal tunnel syndrome (CTS) is a common and disabling condition of the hand caused by entrapment of the median nerve at the level of the wrist. It is the commonest entrapment neuropathy, with ...estimates of prevalence ranging between 5-10%. Here, we undertake a genome-wide association study (GWAS) of an entrapment neuropathy, using 12,312 CTS cases and 389,344 controls identified in UK Biobank. We discover 16 susceptibility loci for CTS with p < 5 × 10
. We identify likely causal genes in the pathogenesis of CTS, including ADAMTS17, ADAMTS10 and EFEMP1, and using RNA sequencing demonstrate expression of these genes in surgically resected tenosynovium from CTS patients. We perform Mendelian randomisation and demonstrate a causal relationship between short stature and higher risk of CTS. We suggest that variants within genes implicated in growth and extracellular matrix architecture contribute to the genetic predisposition to CTS by altering the environment through which the median nerve transits.
Epidemiological models used to inform government policies aimed to reduce the contagion of COVID-19, assume that the reproduction number is reduced through Non-Pharmaceutical Interventions (NPIs) ...leading to physical distancing. Available data in the UK show an increase in physical distancing before the NPIs were implemented and a fall soon after implementation. We aimed to estimate the effect of people's behaviour on the epidemic curve and the effect of NPIs taking into account this behavioural component. We have estimated the effects of confirmed daily cases on physical distancing and we used this insight to design a behavioural SEIR model (BeSEIR), simulated different scenaria regarding NPIs and compared the results to the standard SEIR. Taking into account behavioural insights improves the description of the contagion dynamics of the epidemic significantly. The BeSEIR predictions regarding the number of infections without NPIs were several orders of magnitude less than the SEIR. However, the BeSEIR prediction showed that early measures would still have an important influence in the reduction of infections. The BeSEIR model shows that even with no intervention the percentage of the cumulative infections within a year will not be enough for the epidemic to resolve due to a herd immunity effect. On the other hand, a standard SEIR model significantly overestimates the effectiveness of measures. Without taking into account the behavioural component, the epidemic is predicted to be resolved much sooner than when taking it into account and the effectiveness of measures are significantly overestimated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Growth-associated protein 43 (GAP-43) has long been used as a marker for nerve regeneration following nerve injury, with numerous in vitro and animal studies showing its upregulation in regenerating ...neurons. In humans, expression of GAP-43 has predominantly been examined in skin biopsies from patients with peripheral neuropathies; with several studies showing a reduction in GAP-43 immunoreactive cutaneous nerve fibres. However, it remains elusive whether cutaneous GAP-43 is a valid marker for human nerve regeneration. Here, we present a cohort of 22 patients with electrodiagnostically confirmed carpal tunnel syndrome (CTS), used as a model system for focal nerve injury and neural regeneration after decompression surgery. We evaluate GAP-43 immunoreactivity and RNA expression levels in finger skin biopsies taken before and 6 months after surgery, relative to healthy controls. We further classify patients as 'regenerators' or 'non-regenerators' based on post-surgical epidermal re-innervation. We demonstrate that patients with CTS have lower GAP-43 positive intra-epidermal nerve fibre density (IENFD) before surgery than healthy controls. However, this difference disappears when normalising for total IENFD. Of note, we found surgery did not change GAP-43 expression in IENF, with no differences both in patients who were classified as regenerators and non-regenerators. We also did not identify pre-post surgical differences in cutaneous GAP-43 gene expression or associations with regeneration. These findings suggest cutaneous GAP-43 may not be a compelling marker for nerve regeneration in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dorsal root ganglion (DRG) neurons provide connectivity between peripheral tissues and the spinal cord. Transcriptional plasticity within DRG sensory neurons after peripheral nerve injury contributes ...to nerve repair but also leads to maladaptive plasticity, including the development of neuropathic pain. This study presents tissue and neuron-specific expression profiling of both known and novel long noncoding RNAs (LncRNAs) in the rodent DRG after nerve injury. We have identified a large number of novel LncRNAs expressed within the rodent DRG, a minority of which were syntenically conserved between the mouse, rat, and human, and including, both intergenic and antisense LncRNAs. We have also identified neuron type-specific LncRNAs in the mouse DRG and LncRNAs that are expressed in human IPS cell-derived sensory neurons. We show significant plasticity in LncRNA expression after nerve injury, which in mice is strain and gender dependent. This resource is publicly available and will aid future studies of DRG neuron identity and the transcriptional landscape in both the naive and injured DRG. We present our work regarding novel antisense and intergenic LncRNAs as an online searchable database, accessible from PainNetworks (http://www.painnetworks.org/). We have also integrated all annotated gene expression data in PainNetworks, so they can be examined in the context of their protein interactions.
To improve the treatment of painful Diabetic Peripheral Neuropathy (DPN) and associated co-morbidities, a better understanding of the pathophysiology and risk factors for painful DPN is required. ...Using harmonised cohorts (N = 1230) we have built models that classify painful versus painless DPN using quality of life (EQ5D), lifestyle (smoking, alcohol consumption), demographics (age, gender), personality and psychology traits (anxiety, depression, personality traits), biochemical (HbA1c) and clinical variables (BMI, hospital stay and trauma at young age) as predictors.
The Random Forest, Adaptive Regression Splines and Naive Bayes machine learning models were trained for classifying painful/painless DPN. Their performance was estimated using cross-validation in large cross-sectional cohorts (N = 935) and externally validated in a large population-based cohort (N = 295). Variables were ranked for importance using model specific metrics and marginal effects of predictors were aggregated and assessed at the global level. Model selection was carried out using the Mathews Correlation Coefficient (MCC) and model performance was quantified in the validation set using MCC, the area under the precision/recall curve (AUPRC) and accuracy.
Random Forest (MCC = 0.28, AUPRC = 0.76) and Adaptive Regression Splines (MCC = 0.29, AUPRC = 0.77) were the best performing models and showed the smallest reduction in performance between the training and validation dataset. EQ5D index, the 10-item personality dimensions, HbA1c, Depression and Anxiety t-scores, age and Body Mass Index were consistently amongst the most powerful predictors in classifying painful vs painless DPN.
Machine learning models trained on large cross-sectional cohorts were able to accurately classify painful or painless DPN on an independent population-based dataset. Painful DPN is associated with more depression, anxiety and certain personality traits. It is also associated with poorer self-reported quality of life, younger age, poor glucose control and high Body Mass Index (BMI). The models showed good performance in realistic conditions in the presence of missing values and noisy datasets. These models can be used either in the clinical context to assist patient stratification based on the risk of painful DPN or return broad risk categories based on user input. Model's performance and calibration suggest that in both cases they could potentially improve diagnosis and outcomes by changing modifiable factors like BMI and HbA1c control and institute earlier preventive or supportive measures like psychological interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Publications related to pain research have increased significantly in recent years. The abundance of new evidence creates challenges staying up to date with the latest information. A comprehensive ...understanding of the literature is important for both clinicians and investigators involved in pain research. One commonly used method to combine and analyse data in health care research is meta-analysis. The primary aim of a meta-analysis is to quantitatively synthesise the results of multiple studies focused on the same research question. Meta-analysis is a powerful tool that can be used to advance pain research. However, there are inherent challenges when combining data from multiple sources. There are also numerous models and statistical considerations when undertaking a meta-analysis. This review aims to discuss the planning and preparation for completing a meta-analysis, review commonly used meta-analysis models, and evaluate the clinical implications of meta-analysis in pain research.
Abstract
Introduction:
Previous epidemiological studies of neuropathic pain have reported a range of prevalences and factors associated with the disorder.
Objectives:
This study aimed to verify these ...characteristics in a large UK cohort.
Methods:
A cross-sectional analysis was conducted of 148,828 UK Biobank participants who completed a detailed questionnaire on chronic pain. The
Douleur Neuropathique en Quatre Questions
(DN4) was used to distinguish between neuropathic pain (NeuP) and non-neuropathic pain (non-NeuP) in participants with pain of at least 3 months' duration. Participants were also identified with less than 3 months' pain or without pain (NoCP). Multivariable regression was used to identify factors associated with NeuP compared with non-NeuP and NoCP, respectively.
Results:
Chronic pain was present in 76,095 participants (51.1%). The overall prevalence of NeuP was 9.2%. Neuropathic pain was significantly associated with worse health-related quality of life, having a manual or personal service type occupation, and younger age compared with NoCP. As expected, NeuP was associated with diabetes and neuropathy, but also other pains (pelvic, postsurgical, and migraine) and musculoskeletal disorders (rheumatoid arthritis, osteoarthritis, and fibromyalgia). In addition, NeuP was associated with pain in the limbs and greater pain intensity and higher body mass index compared with non-NeuP. Female sex was associated with NeuP when compared with NoCP, whereas male sex was associated with NeuP when compared with non-NeuP.
Conclusion:
This is the largest epidemiological study of neuropathic pain to date. The results confirm that the disorder is common in a population of middle- to older-aged people with mixed aetiologies and is associated with a higher health impact than non-neuropathic pain.
Loss-of-function mutations in NaV1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal ...approach, we investigated how NaV1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous NaV1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some NaV1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.
Display omitted
•Patients with CIP due to NaV1.7 mutations have a functional absence of nociceptors•Lack of nociceptive drive is reflected in a reduced cortical response to capsaicin•Patient iPSC nociceptors show reduced excitability, especially to ramp stimuli•Gene-edited iPSC nociceptors represent a valuable analgesic drug screening platform
Gene mutations associated with painless phenotypes offer great insight for analgesic development. Using a multi-modal approach, McDermott et al. show that mutations in the voltage-gated sodium channel NaV1.7 cause congenital insensitivity to pain due to a lack of functional nociceptors.
PurposeNeuropathic pain is a common disorder of the somatosensory system that affects 7%–10% of the general population. The disorder places a large social and economic burden on patients as well as ...healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.ParticipantsDOLORisk Dundee has been constructed by rephenotyping two pre-existing Scottish population cohorts for neuropathic pain using a standardised ‘core’ study protocol: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) (n=5236) consisting of predominantly type 2 diabetics from the Tayside region, and Generation Scotland: Scottish Family Health Study (GS:SFHS; n=20 221). Rephenotyping was conducted in two phases: a baseline postal survey and a combined postal and online follow-up survey. DOLORisk Dundee consists of 9155 participants (GoDARTS=1915; GS:SFHS=7240) who responded to the baseline survey, of which 6338 (69.2%; GoDARTS=1046; GS:SFHS=5292) also responded to the follow-up survey (18 months later).Findings to dateAt baseline, the proportion of those with chronic neuropathic pain (Douleur Neuropathique en 4 Questions questionnaire score ≥3, duration ≥3 months) was 30.5% in GoDARTS and 14.2% in Generation Scotland. Electronic record linkage enables large scale genetic association studies to be conducted and risk models have been constructed for neuropathic pain.Future plansThe cohort is being maintained by an access committee, through which collaborations are encouraged. Details of how to do this will be available on the study website (http://dolorisk.eu/). Further follow-up surveys of the cohort are planned and funding applications are being prepared to this effect. This will be conducted in harmony with similar pain rephenotyping of UK Biobank.
PDF
