Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

Prevalence and risk of psychiatric disorders in young people: prospective cohort study exploring the role of childhood trauma (the HUNT study).

BACKGROUND: Better knowledge about childhood trauma as a risk factor for psychiatric disorders in young people could help strengthen the timeliness and effectiveness of prevention and treatment efforts. AIMS: To estimate the prevalence and risk of psychiatric disorders in young people following exposure to childhood trauma, including interpersonal violence. METHOD: This prospective cohort study followed 8199 adolescents (age range 12-20 years) over 13-15 years, into young adulthood (age range 25-35 years). Data about childhood trauma exposure from adolescents participating in the Trøndelag Health Study (HUNT, 2006-2008) were linked to data about subsequent development of psychiatric disorders from the Norwegian Patient Registry (2008-2021). RESULTS: One in four (24.3%) adolescents were diagnosed with a psychiatric disorder by young adulthood. Regression analyses showed consistent and significant relationships between childhood exposure to both interpersonal violence and other potentially traumatic events, and subsequent psychiatric disorders and psychiatric comorbidity. The highest estimates were observed for childhood exposure to two or more types of interpersonal violence (polyvictimisation), and development of psychotic disorders (odds ratio 3.41, 95% CI 1.93-5.72), stress and adjustment disorders (odds ratio 4.20, 95% CI 3.05-5.71), personality disorders (odds ratio 3.98, 95% CI 2.70-5.76), alcohol-related disorders (odds ratio 3.28, 95% CI 2.06-5.04) and drug-related disorders (odds ratio 4.67, 95% CI 2.87-7.33). CONCLUSIONS: These findings emphasise the importance of integrating knowledge about childhood trauma as a potent risk factor for psychopathology into the planning and implementation of services for children, adolescents and young adults.

Relationship between migraine and epilepsy in a large population-based cohort: The HUNT Study.

BACKGROUND AND PURPOSE: Several studies have reported substantial comorbidity between epilepsy and migraine. Most of these were based on clinical cohorts or used unvalidated diagnostic instruments. Our study re-examined this association in a large general population cohort using validated diagnoses for both disorders. METHODS: A total of 65,407 participants (≥20 years old) from HUNT (the Trøndelag Health Study) were classified for migraine and nonmigraine headache using a validated questionnaire. Medical record review was used to validate and classify epilepsy in 364 participants (cases), who were compared with 63,298 participants without epilepsy (controls). The association between epilepsy and migraine was analysed using logistic regression adjusted for sex and age. RESULTS: Patients with epilepsy had no increased prevalence of migraine (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.68-1.33) or nonmigraine headache (OR = 1.18, 95% CI = 0.93-1.50) compared to controls. When stratified by headache frequency, epilepsy was associated with a higher prevalence of migraine with highly frequent headache (≥7 days/month; OR = 1.73, 95% CI = 1.08-2.78). CONCLUSIONS: Migraine was equally common in people with and without epilepsy. Patients with epilepsy who suffered from migraine were more prone to having highly frequent migraine.

Overweight and obesity as risk factors for chronic low back pain: a new follow-up in the HUNT Study.

BACKGROUND: Numerous studies have examined associations between overweight and obesity and risk of low back pain (LBP), but the exact magnitude of these associations is not yet clear. The purpose of this work was to assess such sex-specific associations in a community-based setting in Norway, taking into account potential relationships with other risk factors. METHODS: A cohort study was conducted combining data from two waves of the Trøndelag Health Study, HUNT3 (2006-2008) and HUNT4 (2017-2019). Separate analyses were performed of risk of chronic LBP in HUNT4 among 14,775 individuals without chronic LBP in HUNT3, and of recurrence or persistence in HUNT4 among 5034 individuals with chronic LBP in HUNT3. Relative risks were estimated in generalised linear models for overweight and obesity compared to normal weight. Body size classification was based on values of BMI computed from measurements of height and weight. Chronic LBP was defined as LBP persisting at least 3 months during last year. RESULTS: After adjustment for age, smoking, physical activity in leisure time and work activity, analysis of risk among women produced relative risks 1.11 (95% CI 1.00-1.23) for overweight, 1.36 (95% CI 1.20-1.54) for obesity class I and 1.68 (95% CI 1.42-2.00) for obesity classes II-III. Relative risks among men were 1.10 (95% CI 0.94-1.28) for overweight, 1.36 (95% CI 1.13-1.63) for obesity class I and 1.02 (95% CI 0.70-1.50) for obesity classes II-III, the last estimate being based on relatively few individuals. Analyses of recurrence or persistence indicated similar relationships but with smaller magnitude of relative risks and no drop in risk among obesity classes II-III in men. The change in BMI from HUNT3 to HUNT4 hardly differed between individuals with and without chronic LBP in HUNT3. CONCLUSIONS: Risk of chronic LBP increases with higher values of BMI in both sexes, although it is uncertain whether this applies to very obese men. Very obese women carry a particularly large risk. Probabilities of recurrence or persistence of chronic LBP among those already afflicted also increase with higher values of BMI. Adjustment for other factors does not influence relationships with overweight and obesity to any major extent.

Health care workers' qualitative descriptions of ethically challenging situations evoking moral distress during Covid-19.

Background: The high public demand for healthcare services during the COVID-19 pandemic and strict infection control measures, coupled with threat of severe illness and death, and limited resources, led to many healthcare workers (HCWs) experiencing ethically challenging situations (ECSs). Objective: To systematically explore first-hand accounts of ECS-evoking moral distress among HCWs during this public health emergency. Research design: This was an open cohort study. All participants were asked whether they had been in ECS-evoking moral distress during the pandemic. Those who had were asked to describe these situations. Answers were systematically analyzed according to three levels of root causes for ECSs, using thematic analysis. Participants and research context: In January 2022, 977 HCWs from four Norwegian university hospitals participated. Ethical considerations: The study received ethical approval from the Norwegian Ethical Review Authority (No. 130944). Results: In total, 508 participants (52%) reported that they had experienced ECS-evoking moral distress during the pandemic, whereof 323 provided a qualitative description. We found that while a few reported ECSs caused at the patient level, and some described situations at the unit/team level, the vast majority reported situations caused at the system level, predominantly related to resource scarcity, particularly poor staffing. Conclusion: Our findings strongly indicate that efforts to mitigate moral distress among HCWs should be targeted at the system level. More specifically, the study findings highlight resource limitations, particularly poor staffing, as a major cause of moral distress during the pandemic.

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity.

BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (ß=-4.82×10-3 per year [95% CI, -6.49×10-3 to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

Genome-wide analysis identifies impaired axonogenesis in chronic overlapping pain conditions.

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions. Whether chronic overlapping pain conditions represent a distinct pathophysiology from the occurrence of pain at only one site is unknown. Using genome-wide approaches, we compared genetic determinants of chronic single-site versus multisite pain in the UK Biobank. We found that different genetic signals underlie chronic single-site and multisite pain with much stronger genetic contributions for the latter. Among 23 loci associated with multisite pain, nine loci replicated in the HUNT cohort, with the DCC netrin 1 receptor (DCC) as the top gene. Functional genomics identified axonogenesis in brain tissues as the major contributing pathway to chronic multisite pain. Finally, multimodal structural brain imaging analysis showed that DCC is most strongly expressed in subcortical limbic regions and is associated with alterations in the uncinate fasciculus microstructure, suggesting that DCC-dependent axonogenesis may contribute to chronic overlapping pain conditions via corticolimbic circuits.

Problematic alcohol use in young adults exposed to childhood trauma: The Trøndelag Health (HUNT) Study.

Problematic alcohol use (PAU) severely impacts the health, functioning, and long-term prospects of young people. Prior research indicates that childhood trauma exposure may be an important risk factor for PAU, but few longitudinal studies have looked at how specific trauma types influence this risk. The aim of this study was to investigate the association between childhood trauma exposure and PAU in a large, population-based cohort of young people. The study sample included 1,913 adolescents who participated in the Trøndelag Health Study (HUNT) between 2006 and 2008 (age range: 12-20) and completed follow-up 10 years later as young adults (age range: 22-32). The results revealed an increased risk of PAU in young adults exposed to childhood trauma, especially direct physical violence, OR = 2.38, [95% CI 1.56, 3.64]. Young adults who had witnessed violence, OR = 1.55, [95% CI 1.11, 2.17], or experienced an accident, disaster, or other traumatic event, OR = 1.60, [95% CI 1.19, 2.15], also had higher odds of PAU compared to those without such experiences. These associations remained consistent after adjusting for symptoms of headaches and pain as well as posttraumatic and general psychological distress as reported by the participants in adolescence. Future prevention efforts targeting PAU among adolescents and young adults should address violence and other trauma exposure as potential drivers of problematic drinking.

"I've kept going" - a multisite repeated cross-sectional study of healthcare workers' pride in personal performance during the COVID-19 pandemic.

BACKGROUND: For healthcare workers, working through a pandemic may include both challenges, such as coping with increased demands and a lack of control, and rewards, such as experiencing a sense of achievement and meaningfulness. In this study, we explore the accomplishments healthcare workers themselves are proud of achieving at work, in order to elucidate the positive aspects of working through a pandemic. METHODS: In June 2020 (T1), December 2020 (T2), and May 2021 (T3), healthcare workers (n = 1,996) at four Norwegian hospitals participated in a web-based survey assessing job strain, psychological health, and support during the pandemic. The survey included the open-ended question "During the past two weeks, what have you been feeling proud of achieving at work?". Responses (1,046) to this item were analyzed using conventional content analysis, which resulted in 13 subthemes under 6 themes. RESULTS: For some, pride was found in their professional identity and dedication to their work. Others took pride in specific achievements, such as juggling their own needs (e.g., health, private life) with those of the workplace, contributing to cohesion and collaboration, their ability to learn and adjust, in being a useful resource at work, and in their efforts towards developing the organization and workplace. IMPLICATIONS: The current findings shed light on what healthcare workers feel proud of achieving in their day-to-day work. Assessment of these factors provides insight on both positive and negative aspects of working clinically during a pandemic, and highlights specific targets for building sustainable and rewarding work environments for healthcare workers.

Menopausal hormone therapy, oral contraceptives and risk of chronic low back pain: the HUNT Study.

BACKGROUND: There are indications that use of menopausal hormone therapy (MHT) and oral contraceptives (OC) increases the risk of low back pain (LBP), with higher oestrogen levels involved in the underlying mechanisms. The purpose of the present study was to investigate associations between use of systemic MHT or OC and risk of chronic LBP in a large population-based data set. METHODS: Data were obtained from two surveys in the Trøndelag Health Study in Norway, HUNT2 (1995-1997) and HUNT3 (2006-2008). A cross-sectional study of association between use of systemic MHT and prevalence of chronic LBP comprised 12,974 women aged 40-69 years in HUNT2, with 4007 women reporting chronic LBP. A cohort study involving MHT comprised 6007 women without chronic LBP at baseline in HUNT2, and after 11 years 1245 women reported chronic LBP at follow-up in HUNT3. The cross-sectional study of association with use of OC included 23,593 women aged 20-69 years in HUNT2, with 6085 women reporting chronic LBP. The corresponding cohort study included 10,586 women without chronic LBP at baseline in HUNT2, of whom 2084 women reported chronic LBP in HUNT3. Risk of chronic LBP was examined in both study designs in generalised linear models with adjustment for potential confounders. RESULTS: In the cohort study, current users of systemic MHT at baseline showed a greater risk of chronic LBP (relative risk (RR) 1.30; 95% CI: 1.14-1.49; compared with never users). The risk increased according to duration of MHT use (P for linear trend = 0.003). Known users of systemic MHT based exclusively on oestrogen experienced the highest risk (RR 1.49; 95% CI: 1.16-1.91), but an increased risk was also seen among known users of oestrogen-progestin combination MHT (RR 1.35; 95% CI: 1.16-1.57). A slight increase in risk of chronic LBP was found in the cohort study among former users of OC (RR 1.17; 95% CI: 1.06-1.30; compared with never users). CONCLUSIONS: Long-lasting use of systemic MHT, in particular therapy based on oestrogen only, is associated with greater risk of chronic LBP. Having been a user of OC most likely entails a minor increase in risk.

Anterior surgical treatment for cervical degenerative radiculopathy: a prediction model for non-success.

PURPOSE: By using data from the Norwegian Registry for Spine Surgery, we wanted to develop and validate prediction models for non-success in patients operated with anterior surgical techniques for cervical degenerative radiculopathy (CDR). METHODS: This is a multicentre longitudinal study of 2022 patients undergoing CDR surgery and followed for 12 months to find prognostic models for non-success in neck disability and arm pain using multivariable logistic regression analysis. Model performance was evaluated by area under the receiver operating characteristic curve (AUC) and a calibration test. Internal validation by bootstrapping re-sampling with 1000 repetitions was applied to correct for over-optimism. The clinical usefulness of the neck disability model was explored by developing a risk matrix for individual case examples. RESULTS: Thirty-eight percent of patients experienced non-success in neck disability and 35% in arm pain. Loss to follow-up was 35% for both groups. Predictors for non-success in neck disability were high physical demands in work, low level of education, pending litigation, previous neck surgery, long duration of arm pain, medium-to-high baseline disability score and presence of anxiety/depression. AUC was 0.78 (95% CI, 0.75, 0.82). For the arm pain model, all predictors for non-success in neck disability, except for anxiety/depression, were found to be significant in addition to foreign mother tongue, smoking and medium-to-high baseline arm pain. AUC was 0.68 (95% CI, 0.64, 0.72). CONCLUSION: The neck disability model showed high discriminative performance, whereas the arm pain model was shown to be acceptable. Based upon the models, individualized risk estimates can be made and applied in shared decision-making with patients referred for surgical assessment.

Killing pain?: a population-based registry study of the use of prescription analgesics, anxiolytics, and hypnotics among all children, adolescents and young adults in Norway from 2004 to 2019.

The ongoing opioid epidemic has been a global concern for years, increasingly due to its heavy toll on young people's lives and prospects. Few studies have investigated trends in use of the wider range of drugs prescribed to alleviate pain, psychological distress and insomnia in children, adolescents and young adults. Our aim was to study dispensation as a proxy for use of prescription analgesics, anxiolytics and hypnotics across age groups (0-29 years) and sex over the last 15 years in a large, representative general population. The study used data from a nationwide prescription database, which included information on all drugs dispensed from any pharmacy in Norway from 2004 through 2019. Age-specific trends revealed that the prevalence of use among children and adolescents up to age 14 was consistently low, with the exception of a substantial increase in use of melatonin from age 5. From age 15-29, adolescents and young adults used more prescription drugs with increasing age at all time points, especially analgesics and drugs with higher potential for misuse. Time trends also revealed that children from age 5 were increasingly dispensed melatonin over time, while adolescents from age 15 were increasingly dispensed analgesics, including opioids, gabapentinoids and paracetamol. In contrast, use of benzodiazepines and z-hypnotics slightly declined in young adults over time. Although trends were similar for both sexes, females used more prescription drugs than their male peers overall. The upsurge in use of prescription analgesics, anxiolytics and hypnotics among young people is alarming.Trial registration The study is part of the overarching Killing Pain project. The rationale behind the Killing Pain research was pre-registered through ClinicalTrials.gov on April 7, 2020. Registration number NCT04336605; https://clinicaltrials.gov/ct2/show/record/NCT04336605 .

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache.

OBJECTIVE: Identifying common genetic variants that confer genetic risk for cluster headache. METHODS: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. RESULTS: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2  = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. INTERPRETATION: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216.

What is success of treatment? Expected outcome scores in cervical radiculopathy patients were much higher than the previously reported cut-off values for success.

PURPOSE: Treatment success can be defined by asking a patient how they perceive their condition compared to prior to treatment, but it can also be defined by establishing success criteria in advance. We evaluated treatment outcome expectations in patients undergoing surgery or non-operative treatment for cervical radiculopathy. METHODS: The first 100 consecutive patients from an ongoing randomized controlled trial (NCT03674619) comparing the effectiveness of surgical and nonsurgical treatment for cervical radiculopathy were included. Patient-reported outcome measures and expected outcome and improvement were obtained before treatment. We compared these with previously published cut-off values for success. Arm pain, neck pain and headache were measured by a numeric rating scale. Neck disability index (NDI) was used to record pain-related disability. We applied Wilcoxon signed-rank test to compare the expected outcome scores for the two treatments. RESULTS: Patients reported mean NDI of 42.2 (95% CI 39.6-44.7) at baseline. The expected mean NDI one year after the treatment was 4 (95% CI 3.0-5.1). The expected mean reduction in NDI was 38.3 (95% CI 35.8-40.8). Calculated as a percentage change score, the patients expected a mean reduction of 91.2% (95% CI 89.2-93.2). Patient expectations were higher regarding surgical treatment for arm pain, neck pain and working ability, P < 0.001, but not for headache. CONCLUSIONS: The expected improvement after treatment of cervical radiculopathy was much higher than the previously reported cut-off values for success. Patients with cervical radiculopathy had higher expectations to surgical treatment.

Apparent diffusion coefficient values in Modic changes - interobserver reproducibility and relation to Modic type.

BACKGROUND: Modic Changes (MCs) in the vertebral bone marrow were related to back pain in some studies but have uncertain clinical relevance. Diffusion weighted MRI with apparent diffusion coefficient (ADC)-measurements can add information on bone marrow lesions. However, few have studied ADC measurements in MCs. Further studies require reproducible and valid measurements. We expect valid ADC values to be higher in MC type 1 (oedema type) vs type 3 (sclerotic type) vs type 2 (fatty type). Accordingly, the purpose of this study was to evaluate ADC values in MCs for interobserver reproducibility and relation to MC type. METHODS: We used ADC maps (b 50, 400, 800 s/mm2) from 1.5 T lumbar spine MRI of 90 chronic low back pain patients with MCs in the AIM (Antibiotics In Modic changes)-study. Two radiologists independently measured ADC in fixed-sized regions of interests. Variables were MC-ADC (ADC in MC), MC-ADC% (0% = vertebral body, 100% = cerebrospinal fluid) and MC-ADC-ratio (MC-ADC divided by vertebral body ADC). We calculated mean difference between observers ± limits of agreement (LoA) at separate endplates. The relation between ADC variables and MC type was assessed using linear mixed-effects models and by calculating the area under the receiver operating characteristic curve (AUC). RESULTS: The 90 patients (mean age 44 years; 54 women) had 224 MCs Th12-S1 comprising type 1 (n = 111), type 2 (n = 91) and type 3 MC groups (n = 22). All ADC variables had higher predicted mean for type 1 vs 3 vs 2 (p < 0.001 to 0.02): MC-ADC (10- 6 mm2/s) 1201/796/576, MC-ADC% 36/21/14, and MC-ADC-ratio 5.9/4.2/3.1. MC-ADC and MC-ADC% had moderate to high ability to discriminate between the MC type groups (AUC 0.73-0.91). MC-ADC-ratio had low to moderate ability (AUC 0.67-0.85). At L4-S1, widest/narrowest LoA were for MC-ADC 20 ± 407/12 ± 254, MC-ADC% 1.6 ± 18.8/1.4 ± 10.4, and MC-ADC-ratio 0.3 ± 4.3/0.2 ± 3.9. Difference between observers > 50% of their mean value was less frequent for MC-ADC (9% of MCs) vs MC-ADC% and MC-ADC-ratio (17-20%). CONCLUSIONS: The MC-ADC variable (highest mean ADC in the MC) had best interobserver reproducibility, discriminated between MC type groups, and may be used in further research. ADC values differed between MC types as expected from previously reported MC histology.

Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain.

BACKGROUND AND OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. METHODS: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. RESULTS: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca2+transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. CONCLUSIONS: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

Oedema on STIR modified the effect of amoxicillin as treatment for chronic low back pain with Modic changes-subgroup analysis of a randomized trial.

OBJECTIVE: To evaluate potential MRI-defined effect modifiers of amoxicillin treatment in patients with chronic low back pain and type 1 or 2 Modic changes (MCs) at the level of a previous lumbar disc herniation (index level). METHODS: In a prospective trial (AIM), 180 patients (25-64 years; mean age 45; 105 women) were randomised to receive amoxicillin or placebo for 3 months. Primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (0-24 scale) at 1 year. Mean RMDQ score difference between the groups at 1 year defined the treatment effect; 4 RMDQ points defined the minimal clinically important effect. Predefined baseline MRI features of MCs at the index level(s) were investigated as potential effect modifiers. The predefined primary hypothesis was a better effect of amoxicillin when short tau inversion recovery (STIR) shows more MC-related high signal. To evaluate this hypothesis, we pre-constructed a composite variable with three categories (STIR1/2/3). STIR3 implied MC-related STIR signal increases with volume ≥ 25% and height > 50% of vertebral body and maximum intensity increase ≥ 25% and presence on both sides of the disc. As pre-planned, interaction with treatment was analysed using ANCOVA in the per protocol population (n = 155). RESULTS: The STIR3 composite group (n = 41) and STIR signal volume ≥ 25% alone (n = 45) modified the treatment effect of amoxicillin. As hypothesised, STIR3 patients reported the largest effect (- 5.1 RMDQ points; 95% CI - 8.2 to - 1.9; p for interaction = 0.008). CONCLUSIONS: Predefined subgroups with abundant MC-related index-level oedema on STIR modified the effect of amoxicillin. This finding needs replication and further support. KEY POINTS: • In the primary analysis of the AIM trial, the effect of amoxicillin in patients with chronic low back pain and type 1 or 2 MCs did not reach the predefined cut-off for clinical importance. • In the present MRI subgroup analysis of AIM, predefined subgroups with abundant MC-related oedema on STIR reported an effect of amoxicillin. • This finding requires replication and further support.

Shift work, low-grade inflammation, and chronic pain: a 7-year prospective study.

OBJECTIVES: We investigated prospective associations of shift work with chronic pain and C-reactive protein (CRP), an indicator of inflammation. Furthermore, we elucidated CRP as a possible mediator and/or moderator of effects of shift work on pain. METHODS: Data from a 7 years follow-up study were analyzed (N = 2323). Shift work and chronic pain of "neck/shoulder", "arm/hand", "upper back", "low back", "hip/leg/feet", and "other regions" were measured by questionnaires. "Chronic widespread pain", "number of chronic pain sites", and "any chronic pain" were computed. CRP was measured in serum samples. Logistic and Poisson regressions were conducted. Mediation was assessed by casual mediation analyses and moderation by the Relative Excess Risk due to Interaction (RERI). RESULTS: Shift work was not associated with any chronic pain variable and no mediation was detected. CRP was associated with low back pain, hip/leg pain, and "number of pain sites", and also with the combination of shift work and CRP of 1-2.99 mg/L (compared to: no shiftwork and CRP < 1). Additionally, shiftwork and CRP 1-2.99 mg/L was associated with risk of "any chronic pain" (OR: 1.76, 95% CI: 1.12, 2.85), which was not associated with CRP alone. Moderation analyses suggested the risks for "any chronic pain" and "number of pain regions" increased when individuals with elevated CRP worked shifts-beyond what the separate effects of CRP and shift would suggest. CONCLUSIONS: We found no evidence of shift work in general affecting CRP or chronic pain. However, shift work and elevated CRP combined may influence chronic pain.