John Anker Henrik Zwart

• Streit, Fabian; Awasthi, Swapnil; Hall, Alisha S.M.; Braun, Alice; Niarchou, Maria & Marouli, Eirini [Show all 152 contributors for this article] (2026). Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders. Nature Genetics. ISSN 1061-4036. 58, p. 1831–1861. doi: 10.1038/s41588-026-02654-3. Full text in Research Archive Show summary

  Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

• Maamoen, Anniken; Bondjers, Kristina; Langerud, Anne Kathrine; Dyb, Grete Anita; Stensland, Synne Øien Blixt & Zwart, John Anker Henrik [Show all 12 contributors for this article] (2026). Turnover Intentions Among Intensive Care Healthcare Workers: Key Factors Influencing Decisions to Stay or Leave. Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 70(7). doi: 10.1111/aas.70296. Full text in Research Archive Show summary

  Background: Turnover among healthcare workers (HCWs) is highly prevalent in intensive care units (ICUs). Due to demanding workloads, stressful conditions, and increasing pressure to work more efficiently, this problem is likely to persist. Consequently, implementing proactive strategies to support HCWs retention is needed. This study aimed to examine associations between work environment factors and ICU HCWs’ intentions to quit. Methods: Based on data from a prospective, open‐cohort, multicenter study of hospital frontline workers conducted during the four main waves of the COVID‑19 pandemic in Norway, we analyzed self‐reported data from HCWs who completed the final survey, which included two outcomes relevant to turnover: (1) frequent thoughts of quitting and (2) intention to look for a new job. A work‐environment ‐factor tool assessing occupational risk and characteristics in emergencies (FORCE‐index). Hierarchical linear regression was used to examine associations between work environment factors and the two turnover outcomes. Results: Among 977 frontline HCWs (median age 45 years, 75% women, median 16 years of work experience), several work environment factors showed protective association with turnover intention. Across both outcomes, familiarity with colleagues and surroundings and social support from colleagues and immediate superiors were the most important protective factors, linked to fewer thoughts of quitting and a lower intention to seek a new job. For frequent thoughts of quitting, additional protective factors included better stress management, workload manageability, infection safety, and social safety. Younger age was a consistent risk factor for both outcomes, while working in the ICU and experiencing morally distressing situations were specifically associated with thoughts of quitting. Pandemic exposure variables were not significantly associated with either outcome. Conclusion: Turnover intention among ICU HCWs at four Norwegian university hospitals during the fourth time point of the COVID‑19 pandemic was associated with work environment factors. Work in the ICU, younger age, and morally distressing experiences were associated with frequent thoughts of quitting, whereas several work environment factors were protective. Familiarity and social support were also protective against actively looking for a new job, suggesting that strengthening these factors may be particularly important for reducing turnover intention and retaining HCWs in the ICU.

• Habiba, Samer; Danielsen, Elisabet; Ingebrigtsen, Tor; Johansen, Tonje Okkenhaug; Sundseth, Jarle & Myrseth, Erling [Show all 10 contributors for this article] (2026). Preoperative headache severity and the risk of unsuccessful outcomes after anterior surgery for degenerative cervical radiculopathy: a population-based study from the Norwegian Registry for Spine Surgery. Brain and Spine. 6. doi: 10.1016/j.bas.2026.106100. Full text in Research Archive
• Szczepanski, Tomasz Szymon; Nilsen, Kristian Bernhard; Dunker, Øystein; Reiner, Andrew Henry; Sand, Trond Halfdan & Tannemaat, Martijn [Show all 11 contributors for this article] (2026). Improving Indirect Methods for Calculating Reference Limits for Nerve Conduction Studies From Historical Data. Muscle and Nerve. ISSN 0148-639X. 74(2), p. 328–338. doi: 10.1002/mus.70281. Full text in Research Archive Show summary

  Introduction/Aims: High quality reference limits for nerve conduction studies (NCS) are essential for diagnosis of neuromuscular disorders. Examining healthy controls to calculate reference limits directly is expensive and time consuming. Indirect methods, including extrapolated norms (E-norms), extrapolated reference values (E-Ref), and multivariate extrapolated reference values (MeRef), use historical hospital data instead. These methods sort the historical measurements in increasing order, creating so called S-curves, and select normal measurements based on the shape of these S-curves. Current versions of these methods have several limitations, and we aimed to improve them by modifying how they select normal measurements. Methods: E-norms, E-Ref and MeRef were modified with new S-curve selection algorithms. The modified versions of the methods were used to calculate reference limits for common NCS measurements from a large historical database. The results were compared to reference limits calculated from 680 healthy subjects using Youden’s J statistic and z-score deviation. Results: The modified methods provided reference limits with Youden’s J > 0.8 and z-score deviation < 0.9 for most types of NCS measurements and similar or higher Youden’s J than the unmodified methods. In most cases, the methods required at least 500 measurements and fewer than 20% abnormal measurements for good performance. Discussion: Changing the S-curve selection algorithms improves E-norms, E-Ref, and MeRef. The modifications require a sufficient number and proportion of normal measurements in the historical database. When these prerequisites are met, a combination of indirect methods can be used when developing reference limits from historical patient data.

• Strom, Nora I.; Verhulst, Brad; Bacanu, Silviu Alin; Cheesman, Rosa Catherine Gillespie; Purves, Kirstin L. & Gedik, Hüseyin [Show all 135 contributors for this article] (2026). Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling. Nature Genetics. ISSN 1061-4036. 58(2), p. 275–288. doi: 10.1038/s41588-025-02485-8. Full text in Research Archive Show summary

  The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat–response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

• Habiba, Samer; Danielsen, Elisabet; Ingebrigtsen, Tor; Johansen, Tonje Okkenhaug; Sundseth, Jarle Østberg & Mikkelsen, Eirik [Show all 9 contributors for this article] (2026). Defining the minimal important change in headache after surgery for degenerative cervical radiculopathy: a population-based study from the Norwegian Registry for Spine Surgery. Journal of Neurosurgery : Spine. ISSN 1547-5654. p. 1-9–1-9. doi: 10.3171/2025.8.SPINE25546. Full text in Research Archive
• Shen, Jie; Valentim, Wander; Friligkou, Eleni; Overstreet, Cassie; Choi, Karmel W. & Koller, Dora [Show all 245 contributors for this article] (2025). Shared genetic architecture of posttraumatic stress disorder with cardiovascular imaging, risk, and diagnoses. Nature Communications. 16(1). doi: 10.1038/s41467-025-60487-w. Full text in Research Archive Show summary

  Patients with post-traumatic stress disorder face increased cardiovascular risk. This study examines shared genetic regions between post-traumatic stress disorder and 246 cardiovascular conditions across electronic health records, 82 cardiac imaging, and health behaviors defined by Life’s Essential 8. Post-traumatic stress disorder is genetically correlated with cardiovascular diagnoses in 33 regions, imaging traits in 4 regions, and health behaviors in 44 regions. Potentially shared causal variants between post-traumatic stress disorder and 17 cardiovascular conditions were observed in 11 regions. Subsequent observational analysis in AllofUS cohort showed post-traumatic stress disorder is associated with 13 diagnoses even after accounting for socioeconomic factors and depression. Genetically regulated proteome expression in brain and blood tissues identified 33 blood and 122 brain genes shared between the two conditions, revealing neuronal, immune, metabolic, and calcium-related mechanisms, with several genes as targets for existing drugs. These findings exhibit shared risk loci and genes are involved in tissue-specific mechanisms.

• Smit, Roelof A.J.; Wade, Kaitlin H.; Hui, Qin; Arias, Joshua D.; Yin, Xianyong & Christiansen, Malene R. [Show all 628 contributors for this article] (2025). Polygenic prediction of body mass index and obesity through the life course and across ancestries. Nature Medicine. ISSN 1078-8956. 31(9), p. 3151–3168. doi: 10.1038/s41591-025-03827-z. Full text in Research Archive Show summary

  Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.

• Zhang, Xinhe; Grove, Jakob; Gu, Yuanjun; Buus, Cornelia K.; Nielsen, Lea K. & Neufeld, Sharon A. S. [Show all 295 contributors for this article] (2025). Polygenic and developmental profiles of autism differ by age at diagnosis. Nature. ISSN 0028-0836. 646(8087), p. 1146–1155. doi: 10.1038/s41586-025-09542-6. Full text in Research Archive Show summary

  Abstract Although autism has historically been conceptualized as a condition that emerges in early childhood 1,2 , many autistic people are diagnosed later in life 3–5 . It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated ( r g  = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.

• Grotzinger, Andrew D.; Werme, Josefin; Peyrot, Wouter J.; Frei, Oleksandr; Leeuw, Christiaan de & Bicks, Lucy K. [Show all 72 contributors for this article] (2025). Mapping the genetic landscape across 14 psychiatric disorders. Nature. ISSN 0028-0836. 649(8096), p. 406–415. doi: 10.1038/s41586-025-09820-3. Full text in Research Archive Show summary

  Psychiatric disorders display high levels of comorbidity and genetic overlap, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder, genomic methods have revealed that the majority of genetic signal is shared. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.

• Argren, Maria Bengtson Argren; Engstrand, Helene; Husøy, Andreas Kattem; Kristoffersen, Espen Saxhaug; Toft, Mathias & Pripp, Are Hugo [Show all 8 contributors for this article] (2025). Prevalence of headache disorders in Norway: results from the population based PopHEAD study. The Journal of Headache and Pain. ISSN 1129-2369. 26(1). doi: 10.1186/s10194-025-02216-8. Full text in Research Archive Show summary

  Background Reliable and up-to-date prevalence estimates of headache disorders are essential for public health planning. Despite previous large-scale studies, there is a lack of validated and up-to-date population-representative prevalence estimates from Europe. Here, we aimed to estimate the one-year prevalence of the major headache disorders in Norway using a validated diagnostic tool. Methods PopHEAD is a population-based Norwegian cross-sectional study. A random sample of 28,753 individuals aged 18–70 years was invited to complete a digital version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, adapted and translated into Norwegian. Headache diagnoses were made using a standardized algorithm based on the International Classification of Headache Disorders (ICHD-3) criteria and validated by telephone interview in a sub-sample. Prevalence estimates were calculated as crude proportions with 95% confidence intervals and sequentially adjusted for age and sex, measurement error and selection bias. Associations with demographic variables were investigated. Results A total of 8,265 participants (3,344 men and 4,921 women; mean age 47.3 years) responded. The crude one-year prevalence was 29.6% for migraine (36.5% in women, 19.4% in men), 52.7% for tension-type headache (TTH) (51.4% in women, 54.6% in men), and 5.1% for probable medication-overuse headache (pMOH) (6.5% in women, 3.1% in men). After adjusting for age, sex, measurement error, and selection bias, the estimated prevalence was 20.3% for migraine, 47.9% for TTH, and 5.9% for pMOH. Migraine prevalence was highest among participants with low income and low education, while TTH prevalence was highest in participants with high socioeconomic status. pMOH prevalence was highest in participants aged 26–45 years and in participants with low education. Conclusion The PopHEAD study provides updated, validated and bias-adjusted prevalence estimates for migraine, TTH and pMOH in the Norwegian adult population. These data may inform health resource allocation for headache management in similar populations.

• Engstrand, Helene; Argren, Maria Bengtson Argren; Zwart, John Anker Henrik; Tronvik, Erling Andreas & Winsvold, Bendik Slagsvold (2025). The burden of high-frequency episodic migraine and chronic migraine in the population-based PopHEAD study. Cephalalgia. ISSN 0333-1024. 45(12). doi: 10.1177/03331024251406103. Full text in Research Archive Show summary

  Aim The diagnostic criteria for chronic migraine, which are based on the total number of monthly headache days, are the subject of ongoing debate. The present study aimed to investigate and compare the burden of disease and quality of life between high-frequency episodic migraine and chronic migraine, using data from the large population-based PopHEAD study. Methods PopHEAD is a population-based cross-sectional study in the Norwegian county of Vestfold and Telemark performed in 2023. Among 28,753 randomly selected adults (aged 18–70 years) invited to complete an electronic questionnaire, 8265 (28.7%) participants responded. The questionnaire was a modified version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation questionnaire, and migraine was classified using a diagnostic algorithm that has been validated by telephone interview in this population. High-frequency episodic migraine was classified according to newly proposed criteria, and chronic migraine according to International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria. Using linear regression for continuous variables and logistic regression for binary outcomes, we compared the disease burden and quality of life between participants classified with high-frequency episodic migraine and those with chronic migraine. The analysis was conducted in two steps: a primary analysis adjusted for age and sex, as well as a second analysis with an additional adjustment for monthly migraine days. Results Of the 8265 responders, 225 had high-frequency episodic migraine and 349 had chronic migraine. Compared to the high-frequency episodic migraine group, the chronic migraine group had more monthly migraine days (17.9 vs. 9.7, p  < 0.001) and headache days (20.8 vs. 9.9, p  < 0.001). The chronic migraine group also used more acute medication ( p  < 0.001). In analyses adjusted for age and sex, participants with chronic migraine reported greater disease burden across almost all measures, including work and social impairment, and had a lower quality of life ( p  < 0.01). With additional adjustment for monthly migraine days, no significant differences in disease burden were found between the two groups, except from days missed from household work ( p  = 0.03). Conclusions The higher disease burden observed in chronic migraine compared to high-frequency episodic migraine was fully explained by the higher number of monthly migraine days in the chronic migraine group. Our findings support previous suggestions to simplify the ICHD-3 criteria for chronic migraine by basing it solely on the number of monthly migraine days.

• Taso, Mirad; Sommernes, Jon Håvard; Sundseth, Jarle Østberg; Pripp, Are Hugo; Bjorland, Siri & Engebretsen, Kaia Beck [Show all 9 contributors for this article] (2025). Surgical versus Nonsurgical Treatment for Cervical Radiculopathy. NEJM Evidence. 4(4). doi: 10.1056/evidoa2400404. Full text in Research Archive Show summary

  Background Cervical radiculopathy is typically caused by disc herniation or spondylosis. Few trials have compared the efficacy of surgical versus nonsurgical treatment for these conditions. Methods We conducted two randomized clinical trials among 180 patients presenting to the Oslo University Hospital in Norway with disabling radicular arm pain and cervical disc herniation (trial 1; n=89) or spondylosis (trial 2; n=91) proven by magnetic resonance imaging or computerized tomography. Patients were randomly assigned in a 1:1 ratio to receive either surgical or nonsurgical treatment. Surgery involved anterior cervical discectomy and fusion. Nonsurgical treatment involved three sessions with physical medicine/rehabilitation physicians and three sessions with physiotherapists for functional and cognitive behavioral support. The primary outcome in both trials was the Neck Disability Index (NDI) score (range, 0 to 100; higher scores indicate greater disability; minimal important difference is 15) at 12 months, which was self-reported by the patients. Results Among the 87 patients in the disc herniation trial with 12-month data (surgical group, n=45; nonsurgical group, n=42), the mean difference in NDI adjusted for baseline was 7.4 (95% confidence interval [CI], 1.6 to 13.3; P=0.01) in favor of surgical treatment. Among the 88 patients in the spondylosis trial with 12-month data (surgical, n=44; nonsurgical, n=44), the mean difference in NDI adjusted for baseline was 2.3 (95% CI, −4.9 to 9.6; P=0.52). In the disc herniation trial, two patients in the nonsurgical group crossed over to have surgery. In the spondylosis trial, 11 patients in the nonsurgical group crossed over to have surgery. There were no serious adverse events. Conclusions In patients with cervical radiculopathy, we found a statistically significant difference for NDI at 12 months in favor of surgical versus nonsurgical treatment in the disc herniation trial, but no difference in the spondylosis trial. (Funded by the Southern and Eastern Norway Regional Health Authority; HSØ#2017057; ClinicalTrials.gov number, NCT03674619.)

• Spildrejorde, Mari Roberts; Dunker, Øystein; Allen, Sara Maria; Kvaløy, Marie Bu; Uglem, Martin & Hjelland, Ina Elen [Show all 13 contributors for this article] (2025). Genome-wide association study of neuropathic pain. Pain. ISSN 0304-3959. doi: 10.1097/j.pain.0000000000003848. Full text in Research Archive Show summary

  Neuropathic pain is a complex chronic condition with a multifactorial etiology that includes genetic susceptibility. However, the genetic basis of neuropathic pain remains poorly understood. We aimed to investigate genetic variants associated with the presence and intensity of neuropathic pain using genome-wide association analyses in the GeNeuP cohort, comprised of 1146 deeply phenotyped individuals with peripheral neuropathy from Norway. Genotyping was performed using the Illumina Global Screening Array, and analyses were conducted to test associations with the presence and intensity of neuropathic pain. No significant associations were detected at the genome-wide significance level (P < 5 × 10−8) for either the presence or intensity of neuropathic pain. However, at the subthreshold level (P < 10−6), 3 single nucleotide polymorphisms (annotated to the CHRDL1 and MCF2L gene and a long non-coding RNA) were associated with intensity of neuropathic pain. A targeted candidate gene analysis of 163 genes previously implicated in neuropathic pain and neuropathy did not yield significant associations. These results highlight the complexity of the genetic architecture underlying neuropathic pain and the challenges in identifying common variants with detectable effects. The identification of subthreshold associations of genes involved in synaptic plasticity is intriguing and merits further investigation. Larger studies with refined phenotyping will be essential to validate these signals and to advance understanding of the genetic contributors to neuropathic pain.

• Szczepanski, Tomasz Szymon; Omland, Petter Moe; Dunker, Øystein; Sand, Trond Halfdan; Tannemaat, Martijn & Reijntjes, Robert [Show all 11 contributors for this article] (2025). Deriving reference limits from historical data – A comparison of four novel methods. Clinical Neurophysiology. ISSN 1388-2457. 182. doi: 10.1016/j.clinph.2025.2111451. Full text in Research Archive Show summary

  Objective To compare four novel methods – extrapolated norms (E-norms), extrapolated reference values (E-Ref), multivariable extrapolated reference values (MeRef) and mixture model clustering (MMC) – for obtaining reference limits for nerve conduction studies (NCS) from historical data containing both normal and abnormal studies. Methods Reference limits for 29 commonly clinically used NCS measurements were calculated from a historical database containing measurements from 24 618 patients using E-norms, E-ref, MeRef and MMC. The resulting reference limits were compared to reference limits for NCS calculated from 680 healthy subjects using Youden’s J statistics. Results Except for distal latencies, E-norms produced reference limits with the highest Youden’s J statistics with higher sensitivity, but lower specificity. E-Ref, MeRef and MMC produced reference limits with high specificity, but lower sensitivity than E-norms. Conclusions There are substantial differences in the performance of E-norms, E-Ref, MeRef and MMC. A dynamic approach, where the methods used are changed based on the type of NCS measurement and the amount of historical data available, may yield the highest accuracy. Significance When combining the different novel methods, it is possible to create clinically useful reference limits using historical data.

• Hatzikotoulas, Konstantinos; Southam, Lorraine; Stefansdottir, Lilja; Boer, Cindy G.; McDonald, Merry-Lynn & Pett, J. Patrick [Show all 175 contributors for this article] (2025). Translational genomics of osteoarthritis in 1,962,069 individuals. Nature. ISSN 0028-0836. 641, p. 1217–1224. doi: 10.1038/s41586-025-08771-z. Full text in Research Archive Show summary

  Abstract Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes 1 . By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide 2 . As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.

• Stensland, Synne Øien Blixt; Bondjers, Kristina; Zwart, John Anker Henrik; Rosseland, Leiv Arne; Atar, Dan & Christensen, Jan Olav [Show all 11 contributors for this article] (2025). Development and psychometric validation of the frontline health workers’ occupational risk and characteristics in emergencies index (FORCE-index) – The covid Hospital cohort study. Public Health in Practice. 9. doi: 10.1016/j.puhip.2025.100582. Full text in Research Archive Show summary

  Objectives: A lack of tools for the systematic identification of frontline health workers' changing occupational risks, characteristics, and needs, poses a major barrier to supporting vital personnel to stay in practice through health emergencies and beyond. The current study reports on the development and psychometric evaluation of the Frontline health workers’ Occupational Risk and Characteristics in Emergencies index (FORCE-index). Study design: The Covid hospital study is a large, multisite, four-wave, open cohort study of frontline health workers responding to the first four waves of the COVID-19 pandemic (2020–2022). Methods: 2496 frontline health workers responded to questionnaires assessing various aspects of their work environment. Using exploratory factor analysis, we estimated the latent structure of the FORCE-index at the first and second waves. This structure was evaluated using confirmatory factor analysis at the third and fourth waves. The internal consistency of the instrument's subscales (e.g., factors) was evaluated using omega reliability, Cronbach's alpha coefficient, and mean inter-item correlation. Results: A nine-factor solution provided best fit to the data. These factors mapped onto the following aspects of the work environment; competency, stress management, familiarity, workload manageability, work performance, infection safety, personal protective equipment, social safety, and social support. Internal consistency for the full FORCE-index and the nine factors was satisfactory. Conclusions: The initial psychometric validation indicates that the FORCE-index is a valid measure which can be used by health authorities, services, and institutions to adequately and systematically assess central aspects of frontline health workers’ work environment that are commonly challenged in health emergencies.

• Martinsen, Amy; Børte, Sigrid; Spildrejorde, Mari Roberts; Brumpton, Ben Michael; Heuch, Ingrid & Zwart, John Anker Henrik [Show all 7 contributors for this article] (2025). Insights into Chronic Low Back Pain Etiology: Population-Based Genome-Wide Association Study Identifies 18 Risk Loci. Spine. ISSN 0362-2436. 50(13), p. 881–889. doi: 10.1097/BRS.0000000000005254. Full text in Research Archive Show summary

  Study Design. Genome-wide association study (GWAS) meta-analysis with downstream analyses. Objective. To explore the genetic architecture of chronic low back pain (cLBP) and identify underlying biological mechanisms that contribute to its development. Background. cLBP is prevalent and debilitating, with many cases having no identifiable biological cause. Current treatment options provide only limited relief, highlighting the need for a deeper understanding of the genetic and molecular factors involved in cLBP pathogenesis. Identifying these factors may lead to more effective, targeted therapies. Materials and Methods. We conducted a GWAS meta-analysis involving 325,078 participants from the UK Biobank and the HUNT population studies. This was followed by downstream analyses, including gene prioritization, tissue enrichment analysis, and functional gene set analysis. Genetic loci were examined for their association with cLBP, and gene sets were assessed for functional relevance. Results. Eighteen genetic loci associated with cLBP were identified corresponding to as many prioritized genes, including 8 novel genes not previously linked to the condition. Tissue enrichment analysis highlighted significant involvement of hippocampal brain tissue, suggesting central memory processes may contribute to cLBP. Functional gene set analysis identified 37 gene sets, many related to transcription factors involved in bone and cartilage maintenance. Literature on the prioritized genes suggested a potential role for neurological, cartilaginous, and inflammatory mechanisms, including genes implicated in the innervation of intervertebral discs, inflammatory cell death, and central sensitization. Comparison with previous GWASs indicated potential differences between individuals who seek medical care and those who do not. Conclusion. This study enhances our understanding of the genetic basis of cLBP, revealing distinct biological mechanisms and suggesting the existence of patient subgroups with differing treatment needs. These insights may pave the way for more tailored and effective treatment approaches in the future. Level of Evidence. Level III—observational study.

• Dagestad, Magnhild Hammersland; Vetti, Nils; Bråten, Lars Christian Haugli; Gjefsen, Elisabeth; Grøvle, Lars & Gervin, Kristina [Show all 14 contributors for this article] (2025). Modic Change Edema in Chronic Low Back Pain Treated with Infliximab or Placebo: The BackToBasic Trial. Spine. ISSN 0362-2436. 50(16), p. 1091–1101. doi: 10.1097/BRS.0000000000005391. Full text in Research Archive
• Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Zucknick, Manuela; Wigemyr, Monica & Bråten, Lars Christian Haugli [Show all 11 contributors for this article] (2025). Gene Expression Correlates with Disability and Pain Intensity in Patients with Chronic Low Back Pain and Modic Changes in a Sex-Specific Manner. International Journal of Molecular Sciences. ISSN 1661-6596. 26(2). doi: 10.3390/ijms26020800. Full text in Research Archive Show summary

  Chronic low back pain (cLBP) lacks clear physiological explanations, and the treatment options are of limited effect. We aimed to elucidate the underlying biology of cLBP in a subgroup of patients with Modic changes type I (suggestive of inflammatory vertebral bone marrow lesions) by correlating gene expression in blood with patient-reported outcomes on disability and pain intensity and explore sex differences. Patients were included from the placebo group of a clinical study on patients with cLBP and Modic changes. Blood was collected at the time of inclusion, after three months, and after one year, and gene expression was measured at all time points by high-throughput RNA sequencing. The patients reported disability using the Roland–Morris Disability Questionnaire, and pain intensity was assessed as a mean of three scores on a 0–10 numeric rating scale: current LBP, worst LBP within the last two weeks, and mean LBP within the last two weeks. The gene expression profiles were then correlated to the reported outcomes. Changes in gene expression over time correlated significantly with changes in both disability and pain. The findings showed distinct patterns in men and women, with negligible overlap in correlated genes between the sexes. The genes involved were enriched in immunological pathways, particularly T cell receptor complex and immune responses related to neutrophils. Several of the genes harbour polymorphisms that previously have been found to be associated with chronic pain. Taken together, our results indicate gender differences in the underlying biology of disability and pain intensity in patients with low back pain.

• O'Connell, Kevin Sean; Koromina, Maria; Veen, Tracy van der; Boltz, Toni; David, Friederike S. & Yang, Jessica Mei Kay [Show all 313 contributors for this article] (2025). Genomics yields biological and phenotypic insights into bipolar disorder. Nature. ISSN 0028-0836. 639, p. 968–975. doi: 10.1038/s41586-024-08468-9. Full text in Research Archive Show summary

  Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

• Bondjers, Kristina; Hyland, Philip; Atar, Dan; Christensen, Jan Olav; Nilsen, Kristian Bernhard & Reitan, Solveig Klæbo [Show all 12 contributors for this article] (2025). Burnout trajectories among healthcare workers during a pandemic, and predictors of change. BMC Health Services Research. 25(1). doi: 10.1186/s12913-025-12802-w. Full text in Research Archive Show summary

  Background: While several cross-sectional studies have suggested high burnout levels among health-care workers (HCW) during the Covid-19 pandemic, fewer studies have examined longitudinal trajectories of burnout. Objectives: To examine (1) trajectories of change in levels of burnout among Norwegian HCW during a one-year period in the mid-phase of the Covid-19 pandemic (second, third, and fourth incidence rate peaks), and (2) how demographic and occupational variables, and pandemic-related experiences (e.g., own infection, severe infection in family, friend, or colleague, caring for deceased patient with Covid-19) were associated with such change. Methods: Burnout was measured by the Copenhagen Burnout Inventory. Latent growth curve modeling was used to estimate trajectories of burnout symptoms, and predictors of starting point and rate of change in burnout levels. Results: Starting points of burnout scores were, on average, low-to-moderate. Women, younger HCW, those living alone, and nurses had higher initial scores. Overall, burnout scores remained mostly unchanged across the study period. However, lower burnout scores at the initial assessment were associated with increasing scores over time. Being exposed to patients with Covid-19 and having a Covid-19 infection were associated with increased burnout over time. Conclusions: While burnout symptoms among frontline health workers remained stable across the peaks of the Covid-19 pandemic overall, the study identified higher risk of worsening symptoms over time among certain demographic (younger personnel, females, and nurses) and highly exposed individuals and groups. These findings may be helpful for identifying frontline workers at particular risk of burnout during future public health emergencies.

• Gjefsen, Elisabeth; Bråten, Lars Christian Haugli; Ponzi, Erica; Dagestad, Magnhild Hammersland; Marchand, Gunn Hege & Kadar, Thomas Istvan Edelsvärd [Show all 22 contributors for this article] (2025). Efficacy of a Tumor Necrosis Factor Inhibitor in Chronic Low-Back Pain With Modic Type 1 Changes: A Randomized Controlled Trial. Arthritis & Rheumatology. ISSN 2326-5191. 77(5), p. 615–623. doi: 10.1002/art.43073. Full text in Research Archive Show summary

  Objective: The efficacy of tumor necrosis factor inhibitors for treating chronic low-back pain with Modic changes is uncertain. This study investigated the superiority of infliximab over placebo in patients with Modic type 1 changes. Methods: In this multicenter, randomized, triple-blind, placebo-controlled trial, patients aged 18 to 65 years with moderate to severe chronic low-back pain and Modic type 1 changes were enrolled from five Norwegian public hospitals between January 2019 and October 2022. Participants were randomly assigned to four intravenous infusions of 5 mg/kg infliximab or placebo. The primary outcome was difference in change in the Oswestry Disability Index (ODI) score from baseline to five months. Secondary outcomes included changes in low-back pain intensity, disability, and health-related quality of life. A linear mixed model was used for efficacy analyses. Results: A total of 128 patients (mean age 43 years, 65.6% women) participated (64 in each group). All patients who received at least one dose of the allocated infusion were included in the primary analyses. The average ODI score (±SD) change was −7.0 (±9.7) in the group who received infliximab and −6.4 (±10.4) in the group who received placebo. The difference in the ODI score change between the two groups was 1.3 ODI points (95% confidence interval −2.1 to 4.6, P = 0.45). Analyses showed no effect of infliximab compared to placebo on secondary outcomes. Adverse event rates were similar between groups. Conclusion: Infliximab did not demonstrate superiority over placebo in reducing pain-related disability in patients with moderate to severe chronic low-back pain with Modic type 1 changes at five months.

• Adams, Mark J.; Streit, Fabian; Meng, Xiangrui; Awasthi, Swapnil; Adey, Brett N. & Choi, Karmel W. [Show all 51 contributors for this article] (2025). Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies. Cell. ISSN 0092-8674. 188(3), p. 640–652.e9. doi: 10.1016/j.cell.2024.12.002. Full text in Research Archive Show summary

  In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.

• Strom, Nora I.; Gerring, Zachary F.; Galimberti, Marco; Yu, Dongmei; Halvorsen, Matthew W. & Abdellaoui, Abdel [Show all 214 contributors for this article] (2025). Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder. Nature Genetics. ISSN 1061-4036. 57, p. 1389–1401. doi: 10.1038/s41588-025-02189-z. Full text in Research Archive Show summary

  Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

• Gheorghiu, Ana; Brunborg, Cathrine; Johannessen, Tom Børge; Helseth, Eirik; Zwart, John Anker Henrik & Wiedmann, Markus (2024). Life-style and metabolic factors do not affect risk for glioma: a prospective population-based study (The Cohort of Norway). Frontiers in Oncology. 14, p. 1–13. doi: 10.3389/fonc.2024.1471733. Full text in Research Archive Show summary

  Background: The identification of modifiable risk factors for intracranial glioma remains a significant challenge. While lifestyle factors and metabolic syndrome are well-established risk factors for various other cancers, their association with glioma risk remains unclear. Objectives: This study aims to conduct a comprehensive analysis of lifestyle factors and metabolic factors in relation to glioma risk. Methods: The Cohort of Norway (CONOR) is a prospective, population-based health survey encompassing anthropometric measurements, blood tests and health questionnaires. CONOR data were linked to the National Cancer Registry to identify incident glioma cases. Follow-up time was calculated in person-years from the baseline examination until the date of glioma diagnosis, death, or the end of the follow-up period. Cox proportional hazards regression was used to calculate hazard ratios (HR). Results: The study cohort included 160,938 women and men. Over 2.8 million person-years of follow-up, 319 intracranial gliomas were diagnosed. Lifestyle factors such as physical activity, alcohol consumption, smoking, and marital status were not associated with glioma risk. There was no increased glioma risk among participants with diabetes mellitus or hypertension. Furthermore, metabolic syndrome in both women and men was not associated with an elevated risk of glioma. Blood lipids, including total cholesterol, triglycerides, and HDL, were not linked to glioma risk. However, increasing LDL levels were associated with a decreased risk of glioma in men (HR per category 0.84; 95% CI 0.74-0.96), but not in women. Conclusion: This is the first comprehensive prospective cohort study to evaluate potentially modifiable risk factors for glioma. Our findings do not support previously suggested associations between smoking, alcohol consumption, or metabolic syndrome and glioma risk.

• Gheorghiu, Anamaria; Brunborg, Cathrine; Johannessen, Tom Børge; Helseth, Eirik; Zwart, John Anker Henrik & Wiedmann, Markus (2024). Lifestyle and metabolic factors affect risk for meningioma in women: a prospective population-based study (The Cohort of Norway). Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1428142. Full text in Research Archive Show summary

  Background: Meningioma is the most common primary brain tumor, with a clear preponderance in women. Obesity is considered a risk factor for the development of meningioma. Obesity is also the clinical hallmark of metabolic syndrome, characterized by glucose intolerance, dyslipidemia, and hypertension. Lifestyle and metabolic factors directly impact overweight and obesity and are therefore potential risk factors for meningioma development. The aim of this study is to assess lifestyle and metabolic factors for meningioma risk in women. Methods: The Cohort of Norway (CONOR) is a nationwide health survey, conducted between 1994 and 2003, including anthropometric measures, blood tests, and health questionnaires. Linkage to the National Cancer Registry enabled the identification of intracranial meningioma during follow-up until December 2018. Results: A total of 81,652 women were followed for a combined total of 1.5 million years, and 238 intracranial meningiomas were identified. Increasing levels of physical activity (HR 0.81; 95% CI 0.68–0.96; p trend <0.02) and parity (HR 0.83; 95% CI 0.71–0.97; p trend <0.03) were negatively associated with meningioma risk. Diabetes mellitus or glucose intolerance increased the risk for meningioma (HR 2.54; 95% CI 1.60–4.05). Overweight and obesity were not associated with meningioma risk, nor was metabolic syndrome. However, participants without metabolic dysfunction had a reduced meningioma risk, while participants with all five metabolic factors present had a 4-fold risk increase for meningioma (HR 4.28; 95% CI 1.34–13.68). Conclusion: Lifestyle factors seem to significantly influence meningioma risk. However, disentangling the complex associations and interactions between factors for meningioma risk will be a challenging task for future studies.

• Akerlund, Mikael; Baskozos, Georgios; Li, Wenqianglong; Themistocleous, Andreas C.; Pascal, Mathilde M.V. & Rayner, N. William [Show all 40 contributors for this article] (2024). Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort. Pain. ISSN 0304-3959. doi: 10.1097/j.pain.0000000000003463. Full text in Research Archive Show summary

  We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10−8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the “irritable” nociceptor profile to those with a “nonirritable” nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 × 10−8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.

• Argren, Maria Bengtson Argren; Engstrand, Helene; Husøy, Andreas Kattem; Zwart, John Anker Henrik & Winsvold, Bendik Kristoffer Slagsvold (2024). The PopHEAD study: a population-based, cross-sectional study on headache burden in Norway: methods and validation of questionnaire-based diagnoses. The Journal of Headache and Pain. ISSN 1129-2369. 25(1). doi: 10.1186/s10194-024-01901-4. Full text in Research Archive Show summary

  Background There is a lack of up-to-date information on the prevalence and burden of headache in Norway. Here we describe the methods and validation of the diagnostic tool of the PopHEAD study, a study designed to determine the prevalence and burden of migraine, tension-type headache, and medication-overuse headache. Method PopHEAD is a Norwegian population-based cross-sectional study conducted in Vestfold and Telemark County in 2023. A random sample of 28,753 individuals aged 18 to 70 was invited to participate. The study used a digital version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, translated into Norwegian using the Lifting The Burden translation protocol. A subsample of participants was contacted by telephone within four weeks for an interview with a headache neurologist blinded to the questionnaire responses. Headache disorders were diagnosed according to the criteria of the International Classification of Headache Disorders version 3. Validity was expressed by sensitivity, specificity and Cohen’s kappa (κ). Results In total, 8,265 (3,344 men and 4,921 women) responded. Most men (75.0%) and women (89.7%) reported having had a headache in the past year. Of 667 participants contacted for a telephone interview, 505 responded. The sensitivity and specificity of the questionnaire-based diagnoses were 97% and 72% for self-reported headache in the previous year (Cohen’s kappa κ = 0.72), 77% and 85% for migraine (κ = 0.61), 77% and 74% for tension-type headache (κ = 0.51), and 58% and 99% for medication-overuse headache (κ = 0.63), respectively. Conclusion The PopHEAD questionnaire is a valid tool for identifying individuals with lifetime headache, migraine, tension-type headache, and medication overuse headache.

• Glad, Kristin Alve; Wøien, Hilde; Stensland, Synne; Reitan, Solveig Klæbo; Zwart, John Anker Henrik & Atar, Dan [Show all 8 contributors for this article] (2024). Health care workers’ qualitative descriptions of ethically challenging situations evoking moral distress during Covid-19. Nursing Ethics. ISSN 0969-7330. 31(8), p. 1709–1721. doi: 10.1177/09697330241257567. Full text in Research Archive Show summary

  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.

• Stangeland, Helle Håve; Aakvaag, Helene Flood; Baumann-Larsen, Monica; Wentzel-Larsen, Tore; Ottesen, Akiah & Zwart, John Anker Henrik [Show all 9 contributors for this article] (2024). Prevalence and risk of psychiatric disorders in young people: Prospective cohort study exploring the role of childhood trauma (the HUNT study). British Journal of Psychiatry. ISSN 0007-1250. doi: 10.1192/bjp.2024.98. Full text in Research Archive Show summary

  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.

• Engstrand, Helene; Revdal, Eline; Argren, Maria Bengtson Argren; Hagen, Knut; Zwart, John Anker Henrik & Brodtkorb, Eylert [Show all 7 contributors for this article] (2024). Relationship between migraine and epilepsy in a large population-based cohort: The HUNT Study. European Journal of Neurology. ISSN 1351-5101. 31(12). doi: 10.1111/ene.16496. Full text in Research Archive Show summary

  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.

• Bondjers, Kristina; Glad, Kristin Alve; Wøien, Hilde; Wentzel-Larsen, Tore; Atar, Dan & Reitan, Solveig Klæbo [Show all 10 contributors for this article] (2024). Moral distress and protective work environment for healthcare workers during public health emergencies. BMC Medical Ethics. 25(1). doi: 10.1186/s12910-024-01098-w. Full text in Research Archive Show summary

  Background Public health emergencies, such as the Covid-19 pandemic, put great pressure on healthcare workers (HCW) across the world, possibly increasing the risk of experiencing ethically challenging situations (ECS). Whereas experiencing ECS as a HCW in such situations is likely unavoidable, mitigation of their adverse effects (e.g., moral distress) is necessary to reduce the risk of long-term negative consequences. One possible route of mitigation of these effects is via work environmental factors. Objectives The current study aimed to examine: [1] risk factors associated with ECS among HCW [2], intensity of moral distress associated with ECS across various occupational factors (i.e., profession, degree of exposure to patients with Covid-19), and [3] the impact of work environmental factors on this association, in a sample of HCW during the pandemic. Methods We employed multiple logistic and linear regression to self-report data from 977 HCWs at four Norwegian hospitals responding to a survey at the fourth wave of the pandemic. Results About half of HCW in this study had experienced ECS during the pandemic, and levels of moral distress associated with such were higher than in previous studies using similar assessment methods. Younger age, female sex, geographical work area (mid-north of Norway), and profession (nurse) were all associated with higher odds (range of OR: 1.30–2.59) of experiencing ECS, as were direct contact with patients with Covid-19. Among those participants who reported that they had experienced ECS during the pandemic, moral distress levels when recalling those situations were moderate (Mean 5.7 on a 0–10 scale). Men reported somewhat lower intensity of moral distress (partial eta squared; ηp2 = 0.02). Reporting a manageable workload (ηp2 = 0.02), and greater opportunity to work according to best practice (ηp2 = 0.02), were associated with lower levels of moral distress. Conclusions Our findings suggest that moral distress could potentially be mitigated on an organizational level, particularly by focusing on ensuring a manageable workload, and an ability to work according to best practice. To build sustainable healthcare systems robust enough to withstand future public health emergencies, healthcare organizations should implement measures to facilitate these aspects of HCWs’ work environment.

• Heuch, Ingrid; Heuch, Ivar; Hagen, Knut & Zwart, John Anker Henrik (2024). Overweight and obesity as risk factors for chronic low back pain: a new follow-up in the HUNT Study. BMC Public Health. 24(1). doi: 10.1186/s12889-024-20011-z. Full text in Research Archive Show summary

  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.

• Fongang, Bernard; Sargurupremraj, Muralidharan; Jian, Xueqiu; Mishra, Aniket; Damotte, Vincent & Rojas, Itziar De [Show all 51 contributors for this article] (2024). A genome-wide association meta-analysis of all-cause and vascular dementia. Alzheimer's & Dementia. ISSN 1552-5260. 20(9), p. 5973–5995. doi: 10.1002/alz.14115. Full text in Research Archive Show summary

  INTRODUCTION: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. RESULTS: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). DISCUSSION: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: * We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). * Known genetic variants associated with AD were replicated for ACD and VaD. * Functional analyses identified novel loci for ACD and VaD. * Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.

• Nievergelt, Caroline M.; Maihofer, Adam X.; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W. & Coleman, Jonathan R. I. [Show all 235 contributors for this article] (2024). Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nature Genetics. ISSN 1061-4036. 56, p. 792–808. doi: 10.1038/s41588-024-01707-9. Full text in Research Archive Show summary

  Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

• Qu, Kang; Li, Ming-Xi; Yu, Peng; Palotie, Aarno; Pressman, Alice & Belin, Andrea C. [Show all 72 contributors for this article] (2024). HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study. Scientific Reports. 14(1). doi: 10.1038/s41598-024-61628-9. Full text in Research Archive Show summary

  Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

• Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Espeland, Ansgar; Zucknick, Manuela & Wigemyr, Monica [Show all 14 contributors for this article] (2023). Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes. Antibiotics. 12(7). doi: 10.3390/antibiotics12071217. Full text in Research Archive Show summary

  Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.

• Bakker, Mark K.; Kanning, Jos P.; Abraham, Gad; Martinsen, Amy; Winsvold, Bendik Kristoffer Slagsvold & Zwart, John Anker Henrik [Show all 22 contributors for this article] (2023). Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity. Stroke. ISSN 0039-2499. 54(3), p. 810–818. doi: 10.1161/STROKEAHA.122.040715. Full text in Research Archive Show summary

  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 (β=−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.

• Baumann, Monica; Storheim, Kjersti; Stangeland, Helle; Zwart, John Anker Henrik; Wentzel-Larsen, Tore & Skurtveit, Svetlana Ondrasova [Show all 8 contributors for this article] (2023). Childhood trauma and the use of opioids and other prescription analgesics in adolescence and young adulthood. The HUNT study. Pain. ISSN 0304-3959. 165(6), p. 1317–1326. doi: 10.1097/j.pain.0000000000003131. Full text in Research Archive
• Winsvold, Bendik Kristoffer Slagsvold; Harder, Aster V. E.; Ran, Caroline; Chalmer, Mona A.; Dalmasso, Maria Carolina & Ferkingstad, Egil [Show all 93 contributors for this article] (2023). Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor. Annals of Neurology. ISSN 0364-5134. 94(4), p. 713–726. doi: 10.1002/ana.26743. Full text in Research Archive Show summary

  Objective The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713–726

• Heuch, Ingrid; Heuch, Ivar; Hagen, Knut; Storheim, Kjersti & Zwart, John Anker Henrik (2023). Menopausal hormone therapy, oral contraceptives and risk of chronic low back pain: the HUNT Study. BMC Musculoskeletal Disorders. 24. doi: 10.1186/s12891-023-06184-5. Full text in Research Archive Show summary

  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.

• Baumann-Larsen, Monica; Dyb, Grete Anita; Wentzel-Larsen, Tore; Zwart, John Anker Henrik; Storheim, Kjersti & Stensland, Synne Øien Blixt (2023). Exposure to traumatic events and use of over-the-counter analgesics in adolescents: cross-sectional findings from the Young-HUNT study. BMJ Open. 13(3). doi: 10.1136/bmjopen-2022-066058. Full text in Research Archive Show summary

  Objective Frequent and increasing use of over-the- counter analgesics (OTCA) among adolescents is a public health concern. Prior research indicates that adolescents exposed to traumatic events may be at increased risk of suffering from headaches and musculoskeletal pain. In this study, we assessed the association between trauma exposure and use of OTCA for headaches and musculoskeletal pain. Design A cross-sectional population study among adolescents, self-reported data on trauma exposure, pain and use of OTCA. Setting and participants All 10 608 adolescents aged 13–19 years in a region of Norway were invited in this school-based survey, participation rate was 76%. Outcome measure Frequency of OTCA use for headache and musculoskeletal pain served as separate outcomes in ordinal logistic regression analyses. Results Trauma exposure was significantly and consistently related to higher frequency use of OTCA for headache and musculoskeletal pain, of which associations for bullying (OR 1.79, 95% CI 1.50 to 2.12, and OR 2.12, 95% CI 1.70 to 2.66), physical violence (OR 1.49, 95% CI 1.25 to 1.78 and OR 1.83, 95% CI 1.45 to 2.32) and sexual abuse (OR 1.83, 95% CI 1.55 to 2.18 and OR 1.53, 95% CI 1.18 to 1.90) were particularly strong. A dose–response relationship was found between interpersonal violence and OTCA use for headache (OR 1.46, 95% CI 1.29 to 1.66 for one type and OR 1.81, 95% CI 1.53 to 2.14 for two or more types) and musculoskeletal pain (OR 1.61, 95% CI 1.91 to 3.00 for one type and OR 2.39, 95% CI 1.91 to 3.00 for two or more types). The associations remained significant after adjustment for pain, although an attenuation in strength was observed. Conclusion Trauma exposed adolescents use OTCA for headaches and musculoskeletal pain more frequently than those not exposed. The higher frequency of pain conditions among trauma exposed only partially explained their more frequent OTCA use, indicating an increased risk relating to features beyond frequency of pain.

• Petersen, Anja Sofie; Barloese, Mads; Lund, Nunu; Pedersen, Adam Friis; Søborg, Marie-Louise Kulas & Chalmer, Mona Ameri [Show all 16 contributors for this article] (2023). Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response. European Journal of Neurology. ISSN 1351-5101. 30(5), p. 1425–1434. doi: 10.1111/ene.15736. Full text in Research Archive Show summary

  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.

• Stangeland, Helle; Aakvaag, Helene Flood; Baumann, Monica; Wentzel-Larsen, Tore; Storheim, Kjersti & Zwart, John Anker Henrik [Show all 8 contributors for this article] (2023). Problematic alcohol use in young adults exposed to childhood trauma: The Trøndelag Health (HUNT) Study. Journal of Traumatic Stress. ISSN 0894-9867. 36(5), p. 968–979. doi: 10.1002/jts.22965. Full text in Research Archive Show summary

  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 sam- ple 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 phys- ical 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 post- traumatic 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.

• Dhariwal, Achal; Bråten, Lars Christian Haugli; Sturød, Kjersti; Silva, Gabriela Salvadori Da; Bargheet, Ahmed & Åmdal, Heidi Aarø [Show all 11 contributors for this article] (2023). Differential response to prolonged amoxicillin treatment: long-term resilience of the microbiome versus long-lasting perturbations in the gut resistome. Gut microbes. ISSN 1949-0976. 15(1). doi: 10.1080/19490976.2022.2157200. Full text in Research Archive Show summary

  The collateral impact of antibiotics on the microbiome has attained increasing attention. However, the ecological consequences of long-term antibiotic exposure on the gut microbiome, including anti- biotic resistance, are still limited. Here, we investigated long-term exposure effects to amoxicillin on the human gut microbiome and resistome. Fecal samples were collected from 20 patients receiving 3-months of amoxicillin or placebo treatment as part of a Norwegian multicenter clinical trial on chronic low back pain (AIM study). Samples were collected at baseline, last day of treatment, and 9 months after antibiotic cessation. The abundance and diversity of microbial and resistome composi- tion were characterized using whole shotgun and functional metagenomic sequencing data. While the microbiome profiles of placebo subjects were stable over time, discernible changes in diversity and overall microbiome composition were observed after amoxicillin treatment. In particular, health- associated short-chain fatty acid producing species significantly decreased in proportion. However, these changes were short-lived as the microbiome showed overall recovery 9 months post-treatment. On the other hand, exposure to long-term amoxicillin was associated with an increase in total antimicrobial resistance gene load and diversity of antimicrobial resistance genes, with persistent changes even at 9 months post-treatment. Additionally, beta-lactam resistance was the most affected antibiotic class, suggesting a targeted response to amoxicillin, although changes at the gene level varied across individuals. Overall, our results suggest that the impact of prolonged amoxicillin exposure was more explicit and long-lasting in the fecal resistome than in microbiome composition. Such information is relevant for designing rational administration guidelines for antibiotic therapies.

• Gjefsen, Elisabeth; Gervin, Kristina; Bråten, Lars Christian Haugli; Goll, Guro Løvik; Aass, Hans Christian & Schistad, Elina Iordanova [Show all 13 contributors for this article] (2023). Longitudinal changes of serum cytokines in patients with chronic low back pain and Modic changes. Osteoarthritis and Cartilage. ISSN 1063-4584. 31(4), p. 543–547. doi: 10.1016/j.joca.2023.01.001. Full text in Research Archive Show summary

  Objectives: To explore serum cytokine levels over time in patients with chronic low back pain (cLBP) and Modic changes (MCs), difference in change between treatment groups in the Antibiotics in Modic Changes (AIM) study and associations between change in cytokines and low back pain. Methods: Serum concentrations of 39 cytokines were measured at baseline and 1 year from 73 partic- ipants in the AIM study; 30 randomized to placebo, 43 to Amoxicillin. Low back pain intensity was measured by numeric rating scale. Change in cytokine levels over time were assessed by paired t-tests. Difference in change in cytokine levels between treatment groups and associations between changes in LBP and cytokine levels were assessed by linear regression models. Networks of cytokine changes in each treatment groups were explored by Pearson's correlations. Results: Five cytokines changed from baseline to 1 year, (mean change, log transformed values with CI) C-X-C motif chemokine ligand (CXCL) 10 (IP-10) (0.11 (0.01e0.20)), CXCL13 (0.61 (0.00e0.12)), C-C motif chemokine ligand (CCL)26 (0.05 (0.01e0.1)), granulocyte macrophage-colony stimulating factor (GM- CSF) ( 0.12 ( 0.23 to 0.00)) and CXCL11 (0.12 (0.03e0.22)). Treatment group only influenced change in CCL21 (b 0.07 (0.01e0.12)), and IL-6 (b 0.17 ( 0.30 to 0.03)). Change in CXCL13 (b 2.43 (0.49e4.38)), CCL27 (b 3.07 (0.46e5.69)), IL-8 (b 1.83 (0.08e3.58)) and CCL19 (b 3.10 (0.86e5.43)) were associated with change in LBP. The correlation networks of cytokine changes demonstrate small differences between treatment groups. Conclusions: Cytokine levels are relatively stable over time in our sample, with little difference between treatment groups. Some cytokines may be associated with LBP intensity. The differences between the correlation networks suggest that long-term Amoxicillin-treatment may have longstanding effects to be further explored.

• Bråten, Lars Christian Haugli; Gjefsen, Elisabeth; Gervin, Kristina; Pripp, Are Hugo; Skouen, Jan Sture & Schistad, Elina Iordanova [Show all 16 contributors for this article] (2023). Cytokine Patterns as Predictors of Antibiotic Treatment Effect in Chronic Low Back Pain with Modic Changes: Subgroup Analyses of a Randomized Trial (AIM Study). Journal of Pain Research. 16, p. 1713–1724. doi: 10.2147/JPR.S406079. Full text in Research Archive Show summary

  Objective: Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation. Design: We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (> 6 months) LBP with pain intensity ≥ 5 on a 0– 10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland–Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously. Results: The 78 patients were 25– 62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; − 2.0, 95% CI: − 5.2– 1.3, RMDQ points; p-value for interaction 0.54). Conclusion: Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes.

• Strømme, Sofie Hammernes; Guddal, Maren Hjelle; Fenstad, Anne Marie; Visnes, Håvard; Zwart, John Anker Henrik & Storheim, Kjersti [Show all 7 contributors for this article] (2023). Musculoskeletal pain is not clearly associated with the risk of anterior cruciate ligament reconstruction in adolescents. BMJ Open sport & exercise medicine. 9(2). doi: 10.1136/bmjsem-2022-001453. Full text in Research Archive Show summary

  Objectives: The purpose of this study was to investigate whether self-reported musculoskeletal pain (MSP) was associated with a future anterior cruciate ligament reconstruction (ACLR). Methods: In this population-based prospective cohort study, we included 8087 participants from the adolescent part of the Trøndelag Health Study (Young-HUNT) in Norway. The exposure was self-reported MSP from the Young-HUNT3 study (2006–2008), which was categorised into two MSP load groups (high MSP and low MSP) based on frequency and number of pain sites. The outcome was ACLRs recorded in the Norwegian Knee Ligament Register between 2006 and 2019. Logistic regression was used to investigate association between MSP load and ACLR, given as ORs with 95% CIs. All tests were two-sided and p values of ≤0.05 were considered statistically significant. Results: 8087 adolescents were included. We identified a total of 99 ACLRs, with 6 ACLRs (0.9%) in adolescents who reported high MSP load and 93 ACLRs (1.3%) among those who reported low MSP load. Adolescents reporting high MSP load had 23% lower odds of an ACLR (OR 0.77, 95% CI 0.31 to 1.91) compared with adolescents with low MSP load. However, the CIs were very wide. Conclusion: Self-reported high MSP load in adolescents was not associated with increased risk of future ACLR. Although the number of participants was high, the relatively few cases of ACLR mean that we cannot be conclusive about the presence or absence of an association.

• Baumann, Monica; Zwart, John Anker Henrik; Dyb, Grete Anita; Wentzel-Larsen, Tore; Stangeland, Helle & Storheim, Kjersti [Show all 7 contributors for this article] (2023). Killing pain? A prospective population-based study on trauma exposure in childhood as predictor for frequent use of over-the-counter analgesics in young adulthood. The HUNT study. Psychiatry Research. ISSN 0165-1781. 327, p. 1–8. doi: 10.1016/j.psychres.2023.115400. Full text in Research Archive Show summary

  Frequent and increasing use of over-the-counter analgesics (OTCA) is a public health concern. Pain conditions and psychological distress are related to frequent OTCA use, and as exposure to potentially traumatic events (PTE) in childhood appears to increase risk of experiencing such symptoms, we aimed to assess childhood PTEs and related symptoms in adolescence as predictors for frequent OTCA use in young adulthood. Prospective population survey data were used (n =2947, 59.1% female, 10–13 years follow-up). Exposure to PTEs, symptoms of post-traumatic stress, anxiety and depression, musculoskeletal pain and headache were assessed in adolescence (13–19 years). Use of OTCA was assessed in young adulthood (22–32 years) and use of OTCA to treat musculoskeletal pain and headache served as separate outcomes in ordinal logistic regression analyses. Overall, exposure to childhood PTEs, particularly direct interpersonal violence, was significantly and consistently related to more frequent use of OTCA to treat musculoskeletal pain and headaches in young adulthood. Adjusting for psychological symptoms and pain attenuated associations, indicating that these symptoms are of importance for the relationship between traumatic events and OTCA use. These findings emphasize the need to address symptomatology and underlying causes at an early age.

• Espeland, Ansgar; Kristoffersen, Per Martin; Bråten, Lars Christian Haugli; Grøvle, Lars; Grotle, Margreth & Haugen, Anne Julsrud [Show all 12 contributors for this article] (2023). Longitudinal Relationship Between Reduced Modic Change Edema and Disability and Pain in Patients With Chronic Low Back Pain. Spine. ISSN 0362-2436. 48(24), p. 1699–1708. doi: 10.1097/BRS.0000000000004837. Full text in Research Archive Show summary

  Study Design. Secondary analyses of a randomized trial [Antibiotics In Modic changes (MCs) study]. Objective. To assess whether or not reduced MC edema over time is related to reduced disability and pain in patients with chronic low back pain (LBP). Summary of Background Data. It is not clear whether or not reduced MC edema implies improved clinical outcomes. Patients and Methods. Linear regression was conducted separately in 2 subgroups with MC edema at baseline on short tau inversion recovery (STIR) or T1/T2-weighted magnetic resonance imaging, respectively. Independent variable: reduced edema (yes/no) at 1 year on STIR or T1/T2-series, respectively. Dependent variable: 1-year score on the Roland-Morris Disability Questionnaire (RMDQ), Oswestry Disability Index (ODI), or 0 to 10 numeric rating scale for LBP intensity, adjusted for the baseline score, age, smoking, body mass index, physical workload, and baseline edema on STIR (STIR analysis only). Post hoc, we, in addition, adjusted all analyses for baseline edema on STIR, treatment group (amoxicillin/placebo), and prior disc surgery—or for disc degeneration. Results. Among patients with MC edema on STIR at baseline (n = 162), reduced edema on STIR was not significantly related to the RMDQ (B: −1.0, 95% CI: −2.8, 0.8; P = 0.27), ODI (B:−1.4, 95% CI: −5.4, 2.6; P = 0.50), or LBP intensity scores (B: −0.05, 95% CI: −0.8, 0.7; P = 0.90) after 1 year. Among patients with MC edema on T1/T2-series at baseline (n = 116), reduced edema on T1/T2 (i.e., reduced volume of the type 1 part of MCs) was not significantly related to RMDQ (B: −1.7, 95% CI: −3.8, 0.3; P = 0.10) or ODI score (B: −2.3, 95% CI: −7.1, 2.5; P = 0.34) but was significantly related to LBP intensity at 1 year (B: −0.9, 95% CI: −1.8, −0.04; P = 0.04; correlation coefficient: 0.24). The post hoc analyses supported these results. Conclusion. Reduced MC edema over 1 year was not significantly associated with pain-related disability but was (on T1/T2-series) significantly but weakly related to reduced LBP intensity.

• Bondjers, Kristina; Lingaas, Ingebjørg; Stensland, Synne; Atar, Dan; Zwart, John Anker Henrik & Wøien, Hilde [Show all 7 contributors for this article] (2023). “I’ve kept going” – a multisite repeated cross-sectional study of healthcare workers’ pride in personal performance during the COVID-19 pandemic. BMC Health Services Research. 23(1). doi: 10.1186/s12913-023-09246-5. Full text in Research Archive Show summary

  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.

• Jacobsen, Kaya Kvarme; Børte, Sigrid; Laborie, Lene Bjerke; Kristiansen, Hege; Schäfer, Annette & Martinsen, Amy [Show all 30 contributors for this article] (2023). COL11A1 is associated with developmental dysplasia of the hip and secondary osteoarthritis in the HUNT study. Osteoarthritis and Cartilage Open. 6(1), p. 1–7. doi: 10.1016/j.ocarto.2023.100424. Full text in Research Archive Show summary

  Objective: Developmental dysplasia of the hip (DDH) is a congenital condition affecting 2-3% of all infants. DDH increases the risk of osteoarthritis, is the cause of 30% of all total hip arthroplasties (THAs) in adults <40 years of age and can result in loss of life quality. Our aim was to explore the genetic background of DDH in order to improve diagnosis, management and longterm outcome. Design: We used the large, ongoing, longitudinal Trøndelag Health Study (HUNT) database. Case definition was based on ICD-9/-10 diagnoses of DDH, or osteoarthritis secondary to DDH. Analyses were performed using SAIGE software, with covariates including sex, batch, birth year and principal components. We included only single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) 0.01, R2 0.8 and Hardy-Weinberg equilibrium (HWE) P-value 0.0001. Significance level was set at p < 5x10-8. Meta-analysis using data from DDH and primary osteoarthritis genome-wide association studies (GWASs) was done using METAL software. The study was approved by the regional ethical committee. Results: Analysis included 69,500 individuals, of which 408 cases, and 8,531,386 SNPs. Two SNPs near COL11A1 were significantly associated with DDH; rs713162 ( = -0.43, SE = 0.07, p = 8.4x10-9) and rs6577334 ( = -0.43, SE = 0.08, p = 8.9x10-9). COL11A1 has previously been associated with acetabular dysplasia and osteoarthritis. Meta-analysis supported previous GWAS findings of both DDH and primary osteoarthritis. Conclusions: This large, genome-wide case-control study indicates an association between COL11A1 and DDH and is an important contribution to investigating the etiology of DDH, with further research needed.

• Stangeland, Helle; Handal, Marte; Skurtveit, Svetlana Ondrasova; Aakvaag, Helene Flood; Dyb, Grete Anita & Wentzel-Larsen, Tore [Show all 10 contributors for this article] (2022). 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. European Child and Adolescent Psychiatry. ISSN 1018-8827. p. 1–12. doi: 10.1007/s00787-022-02066-8. Full text in Research Archive Show summary

  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.

• Yengo, Loïc; Vedantam, Sailaja; Marouli, Eirini; Sidorenko, Julia; Bartell, Eric & Sakaue, Saori [Show all 628 contributors for this article] (2022). A saturated map of common genetic variants associated with human height. Nature. ISSN 0028-0836. 610(7933), p. 704–712. doi: 10.1038/s41586-022-05275-y. Full text in Research Archive Show summary

  Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

• Hartley, April; Sanderson, Eleanor; Granell, Raquel; Paternoster, Lavinia; Zheng, Jie & Smith, George Davey [Show all 62 contributors for this article] (2022). Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index. International Journal of Epidemiology. ISSN 0300-5771. 51(4), p. 1254–1267. doi: 10.1093/ije/dyab251. Full text in Research Archive Show summary

  Objectives Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. Methods One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)–BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. Results 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10–5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10–9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. Conclusions These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.

• Bahrami, Shahram; Hindley, Guy Frederick Lanyon; Winsvold, Bendik K S; O'Connell, Kevin Sean; Frei, Oleksandr & Shadrin, Alexey [Show all 39 contributors for this article] (2022). Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools. Brain. ISSN 0006-8950. 145(1), p. 142–153. doi: 10.1093/brain/awab267. Full text in Research Archive Show summary

  Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

• Bråten, Lars Christian Haugli; Grøvle, Lars; Wigemyr, Monica; Wilhelmsen, Maja; Gjefsen, Elisabeth & Espeland, Ansgar [Show all 13 contributors for this article] (2022). Minimal important change was on the lower spectrum of previous estimates and responsiveness was sufficient for core outcomes in chronic low back pain. Journal of Clinical Epidemiology. ISSN 0895-4356. 151, p. 75–87. doi: 10.1016/j.jclinepi.2022.07.012. Full text in Research Archive Show summary

  Objectives: The objective of this study was to estimate the minimal important change (MIC) and responsiveness of core patient reported outcome measures for chronic low back pain (LBP) and Modic changes. Study Design and Setting: In the Antibiotics in Modic changes (AIM) trial we measured disability (RMDQ, ODI), LBP intensity (NRS) and health-related quality of life (EQ5D) electronically at baseline, three- and 12-month follow-up. MICs were estimated using Receiver Operating Curve (ROC) curve and Predictive modeling analyses against the global perceived effect. Credibility of the estimates was assessed by a standardized set of criteria. Responsiveness was assessed by a construct and criterion approach according to COSMIN guidelines. Results: The MIC estimates of RMDQ, ODI and NRS scores varied between a 15–40% reduction, depending on including “slightly improved” in the definition of MIC or not. The MIC estimates for EQ5D were lower. The credibility of the estimates was moderate. For responsiveness, five out of six hypotheses were confirmed and AUC was >0.7 for all PROMs. Conclusion: When evaluated in a clinical trial of patients with chronic LBP and Modic changes, MIC thresholds for all PROMs were on the lower spectrum of previous estimates, varying depending on the definition of MIC. Responsiveness was sufficient.

• Gheorghiu, Ana; Brunborg, Cathrine; Johannessen, Tom Børge; Helseth, Eirik; Zwart, John Anker Henrik & Wiedmann, Markus (2022). The impact of body mass index and height on risk for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in 1.7 million norwegian women and men: a prospective cohort study. Acta Oncologica. ISSN 0284-186X. 61(1), p. 1–6. doi: 10.1080/0284186X.2021.2009562. Full text in Research Archive Show summary

  Background Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves comprise a heterogenous group of pathology, dominantly represented by meningioma, nerve sheath tumours (NST) and glioma. Body height and body mass index (BMI) are risk factors for certain brain tumour subgroups, but no other study has specifically assessed height and BMI in relation to primary tumours of the spine and peripheral nerves in women and men. Methods In this prospective population-based cohort study height and weight were measured in 1.7 million adult Norwegian women and men at baseline. Incident cases of primary tumours arising from the spinal cord, spinal meninges, spinal and peripheral nerves during follow-up were identified by linkage to the National Cancer Registry. Tumour risk was assessed by Cox regression analyses in relation to height and BMI. Results During 49 million person-years of follow-up, 857 primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves were identified. Overweight and obesity were not associated with risk for all tumours or any tumour subgroup. Height was positively associated with risk for all tumours (HR per 10 cm increase: 1.30, 95% CI 1.16–1.46). The association between height and tumour risk varied between tumour subgroups: while height was not significantly associated with NST, height increased the risk for meningioma (HR 1.42, 95% CI 1.13–1.78) and glioma (HR 1.56, 95% CI 1.06–2.28). The strongest association between height and tumour risk was found for the glioma subgroup of ependymoma in women (HR 3.38, 95% CI 1.64–6.94). Conclusion This study could not identify overweight and obesity as risk factors for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in women or men. Increasing body height was associated with increased tumour risk overall, but not universal for all tumour subgroups. Importance of the study Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves have received little focus in epidemiologic studies, although the incidence and histo-pathological tumour subgroups differ significantly from primary brain tumours. Risk factors for these tumours have hardly been assessed in previous studies. Height, overweight and obesity are known risk factors for several cancers, including certain brain tumour subgroups, such as meningioma. This is the first study to report the association between height, overweight and obesity and primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves. This includes tumour subgroups of meningioma, nerve sheath tumour, glioma and the most common spinal glioma subgroup of ependymoma. While overweight and obesity were not associated with either of the tumour subgroups, an association between increasing body height and risk for spinal meningioma and glioma, including ependymoma, was found. Nerve sheath tumour risk was not associated with increasing body height.

• Bortsov, Andrey V.; Parisien, Marc; Khoury, Samar; Martinsen, Amy; Lie, Marie & Heuch, Ingrid [Show all 10 contributors for this article] (2022). Brain-specific genes contribute to chronic but not to acute back pain. Pain Reports. 7(5), p. 1–10. doi: 10.1097/PR9.0000000000001018. Full text in Research Archive Show summary

  Introduction: Back pain is the leading cause of disability worldwide. Although most back pain cases are acute, 20% of acute pain patients experience chronic back pain symptoms. It is unclear whether acute pain and chronic pain have similar or distinct underlying genetic mechanisms. Objectives: To characterize the molecular and cellular pathways contributing to acute and chronic pain states. Methods: Cross-sectional observational genome-wide association study. Results: A total of 375,158 individuals from the UK Biobank cohort were included in the discovery of genome-wide association study. Of those, 70,633 (19%) and 32,209 (9%) individuals met the definition of chronic and acute back pain, respectively. A total of 355 single nucleotide polymorphism grouped into 13 loci reached the genome-wide significance threshold (5x10-8) for chronic back pain, but none for acute. Of these, 7 loci were replicated in the Nord-Trøndelag Health Study (HUNT) cohort (19,760 chronic low back pain cases and 28,674 pain-free controls). Single nucleotide polymorphism heritability was 4.6% (P=1.4x10-78) for chronic back pain and 0.81% (P=1.4x10-8) for acute back pain. Similar differences in heritability estimates between acute and chronic back pain were found in the HUNT cohort: 3.4% (P=0.0011) and 0.6% (P=0.851), respectively. Pathway analyses, tissue-specific heritability enrichment analyses, and epigenetic characterization suggest a substantial genetic contribution to chronic but not acute back pain from the loci predominantly expressed in the central nervous system. Conclusion: Chronic back pain is substantially more heritable than acute back pain. This heritability is mostly attributed to genes expressed in the brain.

• Kristoffersen, Per Martin; Vetti, Nils; Grøvle, Lars; Brox, Jens Ivar; Bråten, Lars Christian Haugli & Grotle, Margreth [Show all 17 contributors for this article] (2022). Amoxicillin did not Reduce Modic Change Oedema in Patients with Chronic Low Back pain - subgroup Analyses of a Randomised Trial (the AIM study). Spine. ISSN 0362-2436. 48(3). doi: 10.1097/BRS.0000000000004513. Full text in Research Archive Show summary

  Study Design - Exploratory subgroup analyses of a randomised trial [Antibiotics in Modic changes (AIM) study]. Objective - The aim was to assess the effect of amoxicillin versus placebo in reducing Modic change (MC) edema in patients with chronic low back pain. Summary of Background Data - The AIM study showed a small, clinically insignificant effect of amoxicillin on pain-related disability in patients with chronic low back pain and MC type 1 (edema type) on magnetic resonance imaging (MRI). Materials and Methods - A total of 180 patients were randomised to receive 100 days of amoxicillin or placebo. MC edema was assessed on MRI at baseline and one-year follow-up. Per-protocol analyses were conducted in subgroups with MC edema on short tau inversion recovery (STIR) or T1/T2-weighted MRI at baseline. MC edema reductions (yes/no) in STIR and T1/T2 series were analyzed separately. The effect of amoxicillin in reducing MC edema was analyzed using logistic regression adjusted for prior disk surgery. To assess the effect of amoxicillin versus placebo within the group with the most abundant MC edema on STIR at baseline (“STIR3” group), we added age, STIR3 (yes/no), and STIR3×treatment group (interaction term) as independent variables and compared the marginal means (probabilities of edema reduction). Results - Compared to placebo, amoxicillin did not reduce MC edema on STIR (volume/intensity) in the total sample with edema on STIR at baseline (odds ratio 1.0, 95% CI: 0.5, 2.0; n=141) or within the STIR3 group (probability of edema reduction 0.69, 95% CI: 0.47, 0.92 with amoxicillin and 0.61, 95% CI: 0.43, 0.80 with placebo; n=41). Compared with placebo, amoxicillin did not reduce MC edema in T1/T2 series (volume of the type 1 part of MCs) (odds ratio: 1.0, 95% CI: 0.5, 2.3, n=104). Edema declined in >50% of patients in both treatment groups. Conclusions - From baseline to one-year follow-up, amoxicillin did not reduce MC edema compared with placebo.

• Dagestad, Magnhild Hammersland; Vetti, Nils; Kristoffersen, Per M; Zwart, John Anker Henrik; Storheim, Kjersti & Bakland, Gunnstein [Show all 12 contributors for this article] (2022). Apparent diffusion coefficient values in Modic changes – interobserver reproducibility and relation to Modic type. BMC Musculoskeletal Disorders. 23, p. 1–12. doi: 10.1186/s12891-022-05610-4. Full text in Research Archive Show summary

  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.

• Taso, Mirad; Sommernes, Jon Håvard; Bjorland, Siri; Zwart, John Anker Henrik; Engebretsen, Kaia Beck & Sundseth, Jarle Østberg [Show all 9 contributors for this article] (2022). What is success of treatment? Expected outcome scores in cervical radiculopathy patients were much higher than the previously reported cut-off values for success. European spine journal. ISSN 0940-6719. doi: 10.1007/s00586-022-07234-7. Full text in Research Archive Show summary

  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.

• Schulze, Daniel Gregor; Nilsen, Kristian Bernhard; Clemm, Thomas; Grotle, Margreth; Zwart, John Anker Henrik & Ulvestad, Bente [Show all 7 contributors for this article] (2022). Influence of ergonomic factors on peripheral neuropathy under HAV exposure. Occupational Medicine. ISSN 0962-7480. 73(1), p. 13–18. doi: 10.1093/occmed/kqac118. Full text in Research Archive Show summary

  Background: Hand-arm vibration (HAV) is a risk factor for carpal tunnel syndrome (CTS) and ulnar neuropathy at the elbow (UNE). It is unclear how ergonomic factors influence the relationship between HAV exposure and CTS and UNE. Aims: We aimed to assess the relationship between cumulative HAV exposure and CTS and UNE in workers exposed to HAV from two tools with different ergonomic profiles. Methods: We performed nerve conduction studies (NCSs) of the sensory and motor median and ulnar nerves and recorded symptoms indicating CTS and UNE in workers exposed to HAV from impact wrenches or from rock drills. Exposure was measured as cumulative lifetime exposure. We used linear regression adjusted for age and body mass index to assess linear relationships. Results: Sixty-five workers participated (33 rock drill and 32 impact wrench operators). We found inverse linear associations between cumulative HAV exposure and median nerve sensory conduction velocity in impact wrench operators and ulnar nerve motor conduction velocity in rock drill operators (beta of 0.63 and 0.75). Based on NCS findings and symptoms, seven impact wrench operators had CTS and one UNE, and four rock drill operators had CTS and six UNE. Conclusions: Our findings indicate that ergonomic factors influence the development of CTS and UNE under HAV exposure. The ergonomic profile seems to influence which type of neuropathy workers exposed to HAV will develop. Design of occupational exposure guidelines and future studies should be based on ergonomic profile and exposure characteristics for different tools and not merely HAV.

• Hautakangas, Heidi; Winsvold, Bendik K S; Ruotsalainen, Sanni; Bjornsdottir, Gyda; Harder, Aster V. E. & Kogelman, Lisette J. A. [Show all 50 contributors for this article] (2022). Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nature Genetics. ISSN 1061-4036. 54, p. 152–160. doi: 10.1038/s41588-021-00990-0. Full text in Research Archive Show summary

  Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

• Lie, Marie; Pedersen, Linda Margareth; Heuch, Ingrid; Winsvold, Bendik K S; Gjerstad, Johannes & Hasvik, Eivind Olay [Show all 11 contributors for this article] (2022). Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC. Frontiers in Genetics. 12(12). doi: 10.3389/fgene.2021.757632. Full text in Research Archive Show summary

  In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; SOX5, CCDC26/GSDMC and DCC. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (n = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.

• Mjåset, Christer; Solberg, Tore; Zwart, John Anker Henrik; Småstuen, Milada Cvancarova; Kolstad, Frode & Grotle, Margreth (2022). Anterior surgical treatment for cervical degenerative radiculopathy: a prediction model for non-success. Acta Neurochirurgica. ISSN 0001-6268. p. 1–13. doi: 10.1007/s00701-022-05440-2. Full text in Research Archive Show summary

  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).<p> <p>Methods This is a multicentre longitudinal study of 2022 patients undergoing CDR surgery and followed for 12 months to fnd 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. <p>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 signifcant in addition to foreign mother tongue, smoking and medium-to-high baseline arm pain. AUC was 0.68 (95% CI, 0.64, 0.72). <p>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.

• Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Espeland, Ansgar; Kristoffersen, Per Martin & Vetti, Nils [Show all 17 contributors for this article] (2022). Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement. Scientific Reports. 12(1), p. 1–12. doi: 10.1038/s41598-021-04189-5. Full text in Research Archive Show summary

  Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.

• Mishra, Aniket; Malik, Rainer; Hachiya, Tsuyoshi; Jürgenson, Tuuli; Namba, Shinichi & Posner, Daniel C. [Show all 203 contributors for this article] (2022). Stroke genetics informs drug discovery and risk prediction across ancestries. Nature. ISSN 0028-0836. 611(7934). doi: 10.1038/s41586-022-05165-3. Full text in Research Archive Show summary

  Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

• Heuch, Ingrid; Heuch, Ivar; Hagen, Knut; Storheim, Kjersti & Zwart, John Anker Henrik (2022). Does the risk of chronic low back pain depend on age at menarche or menopause? A population-based cross-sectional and cohort study: the Trøndelag Health Study. BMJ Open. 12, p. 1–11. doi: 10.1136/bmjopen-2021-055118. Full text in Research Archive Show summary

  Objective In most population-based studies of low back pain (LBP), women have a higher risk than men, possibly reflecting hormonal influences. The aim of this study was to explore associations between age at menarche and menopause and risk of chronic LBP. Design Population-based cross-sectional and cohort study designs. Setting The HUNT2 and HUNT3 medical surveys of the entire population of Nord-Trøndelag County in Norway. Main outcome measure Prevalence or risk of chronic LBP, defined as LBP persisting at least 3 months continuously during last year. Participants Associations between age at menarche and prevalence of chronic LBP were examined in cross-sectional data from HUNT2, comprising 27 697 women aged 20–69 years, with 7300 women reporting LBP. The corresponding cohort data included 11 659 women without LBP at baseline in HUNT2, with 2353 women reporting LBP at follow-up 11 years later in HUNT3. Cross-sectional data on age at menopause or premenopausal status included 11 332 women aged 40–69 years, with 3439 women reporting chronic LBP. Corresponding cohort data included 7893 women without LBP at baseline, of whom 1100 developed LBP. Methods Associations between age at menarche or menopause and risk of chronic LBP were examined by generalised linear modelling. Results A U-shaped association was indicated between age at menarche and risk of chronic LBP, both in the cross-sectional and cohort studies. Age at menarche ≤11 years was associated with an increased risk of chronic LBP, with a relative risk of 1.32 (95% CI 1.15 to 1.52), compared with age 14 years at menarche, after relevant adjustments. Corresponding cross-sectional crude absolute risks were 32% and 25%, respectively. No association was established between age at menopause and risk of LBP. Being premenopausal had no influence on risk. Conclusions In contrast to results for age at menopause, the association with age at menarche suggests that hormonal factors affect the risk of LBP.

• Mjåset, Christer; Zwart, John Anker Henrik; Kolstad, Frode; Solberg, Tore & Grotle, Margreth (2022). Clinical improvement after surgery for degenerative cervical myelopathy; A comparison of Patient-Reported Outcome Measures during 12-month follow-up. PLOS ONE. 17(3), p. 1–14. doi: 10.1371/journal.pone.0264954. Full text in Research Archive Show summary

  Object Although many patients report clinical improvement after surgery due to degenerative cervical myelopathy, the aim of intervention is to stop progression of spinal cord dysfunction. We wanted to provide estimates and assess achievement rates of Minimal Clinically Important Difference (MCID) at 3- and 12-month follow-up for Neck Disability Index (NDI), Numeric Rating Scale for arm pain (NRS-AP) and neck pain (NRS-NP), Euro-Qol (EQ-5D-3L), and European Myelopathy Score (EMS). Methods 614 degenerative cervical myelopathy patients undergoing surgery responded to Patient-Reported Outcome Measures (PROMs) prior to, 3 and 12 months after surgery. External criterion was the Global Perceived Effect Scale (1–7), defining MCID as “slightly better”, “much better” and “completely recovered”. MCID estimates with highest sensitivity and specificity were calculated by Receiver Operating Curves for change and percentage change scores in the whole sample and in anterior and posterior procedural groups. Results The NDI and NRS-NP percentage change scores were the most accurate PROMs with a MCID of 16%. The change score for NDI and percentage change scores for NDI, NRS-AP and NRS-NP were slightly higher in the anterior procedure group compared to the posterior procedure group, while remaining PROM estimates were similar across procedure type. The MCID achievement rates at 12-month follow-up ranged from 51% in EMS to 62% in NRS-NP. Conclusion The NDI and NRS-NP percentage change scores were the most accurate PROMs to measure clinical improvement after surgery for degenerative cervical myelopathy. We recommend using different cut-off estimates for anterior and posterior approach procedures. A MCID achievement rate of 60% or less must be interpreted in the perspective that the main goal of surgery for degenerative cervical myelopathy is to prevent worsening of the condition.

• Rahman, Shafiqur; Winsvold, Bendik K S; Chavez, Sergio; Børte, Sigrid; Tsepilov, Vakov & Sharapov, Sodbo Zh [Show all 32 contributors for this article] (2021). Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain. Annals of the Rheumatic Diseases. ISSN 0003-4967. 80(9), p. 1227–1235. doi: 10.1136/annrheumdis-2020-219624. Full text in Research Archive Show summary

  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 Ca 2+ 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.

• Gjefsen, Elisabeth; Gervin, Kristina; Goll, Guro Løvik; Bråten, Lars Christian Haugli; Wigemyr, Monica & Aass, Hans Christian Dalsbotten [Show all 13 contributors for this article] (2021). Macrophage migration inhibitory factor: A potential biomarker for chronic low back pain in patients with Modic changes. RMD Open. 7(2), p. 1–10. doi: 10.1136/rmdopen-2021-001726. Full text in Research Archive Show summary

  Background: Low back pain (LBP) is a leading cause of disability worldwide, but the aetiology remains poorly understood. Finding relevant biomarkers may lead to better understanding of disease mechanisms. Patients with vertebral endplate bone marrow lesions visualised on MRI as Modic changes (MCs) have been proposed as a distinct LBP phenotype, and inflammatory mediators may be involved in the development of MCs. Objectives: To identify possible serum biomarkers for LBP in patients with MCs. Methods: In this case control study serum levels of 40 cytokines were compared between patients with LBP and MC type 1 (n=46) or type 2 (n=37) and healthy controls (n=50). Results: Analyses identified significantly higher levels of six out of 40 cytokines in the MC type 1 group (MC1), and five in the MC type 2 group (MC2) compared with healthy controls. Six cytokines were moderately correlated with pain. Principal component analyses revealed clustering and separation of patients with LBP and controls, capturing 40.8% of the total variance, with 10 cytokines contributing to the separation. Macrophage migration inhibitory factor (MIF) alone accounted for 92% of the total contribution. Further, receiver operating characteristics analysis revealed that MIF showed an acceptable ability to distinguish between patients and controls (area under the curve=0.79). Conclusions: These results suggest that cytokines may play a role in LBP with MCs. The clinical significance of the findings is unknown. MIF strongly contributed to clustering of patients with LBP with MCs and controls and might be a biomarker for MCs. Ultimately, these results may guide future research on novel treatments for this patient group.

• Harder, Aster V.E.; Winsvold, Bendik K S; Noordam, Raymond; Vijfhuizen, Lisanne S.; Børte, Sigrid & Kogelman, Lisette J.A. [Show all 22 contributors for this article] (2021). Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache. Annals of Neurology. ISSN 0364-5134. 90(2), p. 203–216. doi: 10.1002/ana.26146. Full text in Research Archive Show summary

  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.

• Johansen, Tonje Okkenhaug; Sundseth, Jarle Østberg; Fredriksli, Oddrun; Andresen, Hege; Zwart, John-Anker & Kolstad, Frode [Show all 9 contributors for this article] (2021). Effect of Arthroplasty vs Fusion for Patients With Cervical Radiculopathy: A Randomized Clinical Trial. JAMA Network Open. 4(8). doi: 10.1001/jamanetworkopen.2021.19606. Full text in Research Archive Show summary

  Surgical treatment for cervical radiculopathy is increasing. Treatment with motion preserving anterior cervical disc arthroplasty was introduced to prevent symptomatic adjacent segment disease, and there is need to evaluate results of this treatment compared with standard anterior cervical discectomy and fusion. Objective To investigate clinical outcomes at 5 years for arthroplasty vs fusion in patients who underwent surgical treatment for cervical radiculopathy. Design, Setting, and Participants This multicenter, single-blinded, randomized clinical trial included patients aged 25 to 60 years with C6 or C7 radiculopathy referred to study sites’ outpatient clinics from 2008 to 2013. Data were analyzed from December 2019 to December 2020. Interventions Patients were randomly assigned to arthroplasty or fusion. Patients were blinded to which treatment they received. The surgical team was blinded until nerve root decompression was completed. Main Outcomes and Measures The primary end point was change in Neck Disability Index (NDI) score. Secondary outcomes were arm and neck pain, measured with numeric rating scales (NRS); quality of life, measured with the EuroQol-5D (EQ-5D); reoperation rates; and adjacent segment disease. Results Among 147 eligible patients, 4 (2.7%) declined to participate and 7 (4.8%) were excluded. A total of 136 patients were randomized (mean [SD] age, 44.1 [7.0] years; 73 (53.7%) women), with 68 patients randomized to arthroplasty and 68 patients randomized to fusion. A total of 114 patients (83.8%) completed the 5-year follow-up. In the arthroplasty group, the mean NDI score was 45.9 (95% CI, 43.3 to 48.4) points at baseline and 22.2 (95% CI, 18.0 to 26.3) points at 5 years follow-up, and in the fusion group, mean NDI score was 51.3 (95% CI, 48.1 to 54.4) points at baseline, and 21.3 (95% CI, 17.0 to 25.6) points at 5 years follow-up. The changes in mean NDI scores between baseline and 5 years were statistically significant for arthroplasty (mean change, 24.8 [95% CI, 19.8 to 29.9] points; P < .001) and fusion (mean change, 29.9 [95% CI, 24.0 to 35.9] points; P < .001), but the change in mean NDI scores was not significantly different between groups (difference, 5.1 [95% CI, −2.6 to 12.7] points; P = .19). There were no significant differences in changes in arm pain (mean [SE] change, 3.5 [0.5] vs 3.1 [0.4]; P = .47), neck pain (mean [SE] change, 3.0 [0.5] vs 3.4 [0.5]; P = .50), EQ-5D (mean [SE] change, 0.39 [0.4] vs 0.45 [0.6]; P = .46), patients requiring reoperation (10 patients [14.7%] vs 8 patients [11.8%]; P = .61), and adjacent segment disease (0 patients vs 1 patient [1.5%]; P = .32) between the arthroplasty and fusion groups. Conclusions and Relevance In this randomized clinical trial, patients treated with arthroplasty and fusion reported similar and substantial clinical improvement at 5 years. Trial Registration ClinicalTrials.gov Identifier: NCT00735176

• Freidin, Maxim B.; Tsepilov, Yakov A.; Stanaway, Ian B.; Meng, Weihua; Hayward, Caroline & Smith, Blair H. [Show all 36 contributors for this article] (2021). Sex- and age-specific genetic analysis of chronic back pain. Pain. ISSN 0304-3959. 162(4), p. 1176–1187. doi: 10.1097/j.pain.0000000000002100. Full text in Research Archive Show summary

  Sex differences for chronic back pain (cBP) have been reported, with females usually exhibiting greater morbidity, severity, and poorer response to treatment. Genetic factors acting in an age-specific manner have been implicated but never comprehensively explored. We performed sex- and age-stratified genome-wide association study and single nucleotide polymorphism-by-sex interaction analysis for cBP defined as “Back pain for 3+ months” in 202,077 males and 237,754 females of European ancestry from UK Biobank. Two and 7 nonoverlapping genome-wide significant loci were identified for males and females, respectively. A male-specific locus on chromosome 10 near SPOCK2 gene was replicated in 4 independent cohorts. Four loci demonstrated single nucleotide polymorphism-by-sex interaction, although none of them were formally replicated. Single nucleotide polymorphism-explained heritability was higher in females (0.079 vs 0.067, P = 0.006). There was a high, although not complete, genetic correlation between the sexes (r = 0.838 ± 0.041, different from 1 with P = 7.8E-05). Genetic correlation between the sexes for cBP decreased with age (0.858 ± 0.049 in younger people vs 0.544 ± 0.157 in older people; P = 4.3E-05). There was a stronger genetic correlation of cBP with self-reported diagnosis of intervertebral disk degeneration in males than in females (0.889 vs 0.638; P = 3.7E-06). Thus, the genetic component of cBP in the UK Biobank exhibits a mild sex- and age-dependency. This provides an insight into the possible causes of sex- and age-specificity in epidemiology and pathophysiology of cBP and chronic pain at other anatomical sites.

• Khoury, Samar; Parisien, Marc; Thompson, Scott J.; Vachon-Presseau, Etienne; Roy, Mathieu & Mitchell, Amy [Show all 32 contributors for this article] (2021). Genome-wide analysis identifies impaired axonogenesis in chronic overlapping pain conditions. Brain. ISSN 0006-8950. 145(3), p. 1111–1123. doi: 10.1093/brain/awab359. Full text in Research Archive Show summary

  Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions (COPC). Whether COPC represents 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 vs. 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, 9 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 COPC via cortico-limbic circuits. Keywords: chronic overlapping pain conditions, netrin, uncinate fasciculus

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• Zwart, John Anker Henrik (2026). The 15th National Research Conference - Musculoskeletal Health (MUSS). Full text in Research Archive
• Szczepanski, Tomasz Szymon; Omland, Petter Moe; Dunker, Øystein; Sand, Trond Halfdan; Tannemaat, Martijn & Reijntjes, Robert [Show all 11 contributors for this article] (2025). Deriving reference limits from historical data - A comparison of four novel methods. Full text in Research Archive
• Gjefsen, Elisabeth; Zwart, John Anker Henrik; Bråten, Lars Christian Haugli; Espeland, Ansgar; Goll, Guro Løvik & Storheim, Kjersti (2025). Reply: Correspondence to Efficacy of a Tumor necrosis Factor Inhibitor in Chronic Low‐Back Pain with Modic type 1 Changes: A Randomized Controlled Trial. Arthritis & Rheumatology. ISSN 2326-5191. doi: 10.1002/art.43309. Full text in Research Archive
• Rolfsen, Mads Peder; Gammelsrud, Karianne Wiger; Espeland, Ansgar; Bråten, Lars Christian Haugli; Mjønes, Sverre Markussen & Austevoll, Ivar Magne [Show all 15 contributors for this article] (2024). Bacterial growth in patients with low back pain and Modic changes: protocol of a multicentre, case-control biopsy study. BMJ Open. 14(5), p. 1–7. doi: 10.1136/bmjopen-2023-082244. Full text in Research Archive Show summary

  Introduction Bacterial infection and Modic changes (MCs) as causes of low back pain (LBP) are debated. Results diverged between two randomised controlled trials examining the effect of amoxicillin with and without clavulanic acid versus placebo on patients with chronic LBP (cLBP) and MCs. Previous biopsy studies have been criticised with regard to methods, few patients and controls, and insufficient measures to minimise perioperative contamination. In this study, we minimise contamination risk, include a control group and optimise statistical power. The main aim is to compare bacterial growth between patients with and without MCs. Methods and analysis This multicentre, case–control study examines disc and vertebral body biopsies of patients with cLBP. Cases have MCs at the level of tissue sampling, controls do not. Previously operated patients are included as a subgroup. Tissue is sampled before antibiotic prophylaxis with separate instruments. We will apply microbiological methods and histology on biopsies, and predefine criteria for significant bacterial growth, possible contamination and no growth. Microbiologists, surgeons and pathologist are blinded to allocation of case or control. Primary analysis assesses significant growth in MC1 versus controls and MC2 versus controls separately. Bacterial disc growth in previously operated patients, patients with large MCs and growth from the vertebral body in the fusion group are all considered exploratory analyses. Ethics and dissemination The Regional Committees for Medical and Health Research Ethics in Norway (REC South East, reference number 2015/697) has approved the study. Study participation requires written informed consent. The study is registered at ClinicalTrials.gov (NCT03406624). Results will be disseminated in peer-reviewed journals, scientific conferences and patient fora.

• Mjåset, Christer; Solberg, Tore; Zwart, John Anker Henrik; Småstuen, Milada Cvancarova; Kolstad, Frode & Grotle, Margreth (2024). Correction to: Anterior surgical treatment for cervical degenerative radiculopathy: a prediction model for non-success (Acta Neurochirurgica, (2022), 165, 1, (145-157), 10.1007/s00701-022-05440-2). Acta Neurochirurgica. ISSN 0001-6268. 166(1). doi: 10.1007/s00701-024-06045-7. Full text in Research Archive
• Mjåset, Christer; Zwart, John Anker Henrik; Goedmakers, Caroline M.W.; Smith, Timothy R.; Solberg, Tore & Grotle, Margreth (2024). Corrigendum to ‘Criteria for success after surgery for cervical radiculopathy—estimates for a substantial amount of improvement in core outcome measures’ by Christer Mjåset et al’ [The Spine Journal 20/9 (2020) 1413-1421, (S1529943020307701), (10.1016/j.spinee.2020.05.549)]. The spine journal. ISSN 1529-9430. doi: 10.1016/j.spinee.2024.02.024. Full text in Research Archive
• Stangeland, Helle; Aakvaag, Helene Flood; Baumann-Larsen, Monica; Wentzel-Larsen, Tore; Storheim, Kjersti & Zwart, John Anker Henrik [Show all 8 contributors for this article] (2023). Problematic alcohol use in young adults exposed to childhood trauma: The Trøndelag Health (HUNT) Study, poster at the ISTSS 39th annual meeting. Full text in Research Archive
• Stangeland, Helle; Aakvaag, Helene Flood; Baumann-Larsen, Monica; Wentzel-Larsen, Tore; Storheim, Kjersti & Zwart, John Anker Henrik [Show all 8 contributors for this article] (2023). Problematic alcohol use in young adults exposed to childhood trauma: The Trøndelag Health (HUNT) Study, poster på den 12. Nasjonale forskningskonferansen om muskelskjeletthelse 2023 (MUSS). Full text in Research Archive
• Stangeland, Helle; Handal, Marte; Skurtveit, Svetlana Ondrasova; Aakvaag, Helene Flood; Dyb, Grete Anita & Wentzel-Larsen, Tore [Show all 10 contributors for this article] (2022). Killing pain? A 15-year population-based registry study of the use of prescription analgesics, anxiolytics and hypnotics among young people in Norway, oral presentation. Full text in Research Archive
• Wøien, Hilde; Rosseland, Leiv Arne; Bondjers, Kristina; Lingaas, Ingebjørg; Dyb, Grete Anita & Zwart, John Anker Henrik [Show all 7 contributors for this article] (2022). Stress reactions and health problems in hospital personel during the Covid-19 pandemic; a longitudinal, multicenter study. Full text in Research Archive
• Mishra, Aniket; Malik, Rainer; Hachiya, Tsuyoshi; Jürgenson, Tuuli; Namba, Shinichi & Posner, Daniel C. [Show all 187 contributors for this article] (2022). Erratum: Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries (Nature (2022) 611 7934 (115-123)). Nature. ISSN 0028-0836. 612(7938), p. E7–E7. doi: 10.1038/s41586-022-05492-5. Full text in Research Archive
• Mishra, Aniket; Malik, Rainer; Hachiya, Tsuyoshi; Jürgenson, Tuuli; Namba, Shinichi & Posner, Daniel C. [Show all 57 contributors for this article] (2022). Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries. Nature. ISSN 0028-0836. doi: 10.1038/s41586-022-05492-5. Full text in Research Archive Show summary

  In the version of this article initially published, the name of the PRECISE4Q Consortium was misspelled as “PRECISEQ” and has now been amended in the HTML and PDF versions of the article. Further, data in the first column of Supplementary Table 55 were mistakenly shifted and have been corrected in the file accompanying the HTML version of the article

• Wightman, Douglas P.; Jansen, Iris E.; Savage, Jeanne E.; Shadrin, Alexey; Bahrami, Shahram & Holland, Dominic [Show all 114 contributors for this article] (2022). Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease (Nature Genetics, (2021), 53, 9, (1276-1282), 10.1038/s41588-021-00921-z). Nature Genetics. ISSN 1061-4036. 54(7), p. 1062–1062. doi: 10.1038/s41588-022-01126-8. Full text in Research Archive
• Wightman, Douglas P.; Jansen, Iris E.; Savage, Jeanne E.; Shadrin, Alexey A.; Bahrami, Shahram & Holland, Dominic [Show all 114 contributors for this article] (2021). Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease (Nature Genetics, (2021), 53, 9, (1276-1282), 10.1038/s41588-021-00921-z). Nature Genetics. ISSN 1061-4036. doi: 10.1038/s41588-021-00977-x. Full text in Research Archive
• Stangeland, Helle; Handal, Marte; Skurtveit, Svetlana Ondrasova; Aakvaag, Helene Flood; Dyb, Grete Anita & Wentzel-Larsen, Tore [Show all 10 contributors for this article] (2021). Killing pain? A population-based registry study of the use of prescription analgesics, anxiolytics, and hypnotics among children, adolescents and young adults in Norway from 2004-2019, poster på den 10. Nasjonale forskningskonferansen innen muskelskjeletthelse 2021 (MUSS). Full text in Research Archive
• Bondjers, Kristina; Stensland, Synne; Zwart, John Anker Henrik; Rosseland, Leiv Arne; Wøien, Hilde & Atar, Dan [Show all 11 contributors for this article] (2021). Hvordan gikk det? Støtte og stolthet gjennom pandemien - rapport fra en longitudinell studie av 2000 sykehuspersonell. Full text in Research Archive
• Johnsen, Marianne Bakke; Magnusson, Karin; Børte, Sigrid; Gabrielsen, Maiken Elvestad; Winsvold, Bendik K S & Skogholt, Anne Heidi [Show all 10 contributors for this article] (2021). Response to Letter to the Editor: ‘Comments on the paper presenting prediction models for incident hand OA in the HUNT study’. Osteoarthritis and Cartilage. ISSN 1063-4584. 29(2), p. 292–293. doi: 10.1016/j.joca.2020.10.012. Full text in Research Archive
• Nygaard, Gro Owren; Schikora-Rustad, Stine; Lie, Ingeborg Haugesag; Aase, Audun; Leiknes, Ingvild Jullum & König, Marton [Show all 15 contributors for this article] (2021). Humoral immune response to the influenza vaccine in multiple sclerosis patients treated with cladribine or rituximab. Full text in Research Archive
• Stensland, Synne; Bondjers, Kristina; Zwart, John Anker Henrik; Rosseland, Leiv Arne; Wøien, Hilde & Atar, Dan [Show all 11 contributors for this article] (2021). Did hospital personnel receive adequate help and support to reduce work-related stress during the Covid-19 pandemic? The Norwegian Study of Hospital Personnel. Full text in Research Archive
• Bondjers, Kristina; Lingaas, Ingebjørg; Stensland, Synne; Wøien, Hilde; Muller, Ashley Elizabeth & Atar, Dan [Show all 8 contributors for this article] (2021). Is it all bad? - sense of accomplishment among health-care workers during the Covid-19 pandemic. Full text in Research Archive
• Bondjers, Kristina; Stensland, Synne; Zwart, John Anker Henrik; Rosseland, Leiv Arne; Wøien, Hilde & Atar, Dan [Show all 11 contributors for this article] (2021). Psychological impact of the Covid-19 pandemic on healthcare workers. Full text in Research Archive
• Bondjers, Kristina; Stensland, Synne; Zwart, John Anker Henrik; Rosseland, Leiv Arne; Wøien, Hilde & Atar, Dan [Show all 11 contributors for this article] (2021). Hvordan gikk det? Støtte og stolthet gjennom pandemien - rapport fra en longitudinell studie av 2000 sykehuspersonell. Full text in Research Archive
• Gjefsen, Elisabeth & Zwart, John Anker Henrik (2025). Chronic low back pain; Modic changes and inflammation. Universitetet i Oslo. ISSN 9788234806537. Full text in Research Archive Show summary

  Chronic low back pain is a common and disabling condition. The condition has wide-ranging impacts on individuals, families, health and social care systems. Nonetheless, the underlying cause remains unclear for most cases. In some patients, changes in the vertebrae visible on MRI known as Modic changes have been suggested as a potential source of pain. Inflammation has been proposed as a potential underlying mechanism, but treatment options are limited, and evidence is sparse. This thesis aimed to investigate the effectiveness of a targeted anti-inflammatory treatment in patients with chronic low back pain with Modic changes, and to examine systemic inflammatory markers. The project included a randomized placebo-controlled trial and biochemical analysis of inflammatory cytokines in blood samples. To investigate whether targeted anti-inflammatory medication is a new treatment option for this patient group, the multi center randomized, triple-blind, placebo-controlled BackToBasic-trial was conducted. Participants were randomly assigned to receive the TNF-inhibiting drug infliximab or placebo. Outcomes were measured after 5 months, and included disability, pain, and quality of life. Results showed no significant difference between the treatment and placebo groups. Infliximab did not reduce pain or improve function. However, blood analyses revealed elevated levels of inflammatory proteins in this patient group compared to healthy controls and pointed to the cytokine MIF as a potential biomarker. Inflammatory markers remained stable over time, indicating a persistent inflammatory response. In conclusion, while infliximab proved ineffective for this patient group, the findings support the theory that inflammation may contribute to the pathogenesis of chronic low back pain with Modic changes. The relevance of TNF is questioned, and the results underscore the need for further studies into alternative inflammatory pathways and tailored treatments.

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