Variability in the prevalence of depression among adults with chronic pain: UK Biobank analysis through clinical prediction models.

BACKGROUND: The prevalence of depression among people with chronic pain remains unclear due to the heterogeneity of study samples and definitions of depression. We aimed to identify sources of variation in the prevalence of depression among people with chronic pain and generate clinical prediction models to estimate the probability of depression among individuals with chronic pain. METHODS: Participants were from the UK Biobank. The primary outcome was a "lifetime" history of depression. The model's performance was evaluated using discrimination (optimism-corrected C statistic) and calibration (calibration plot). RESULTS: Analyses included 24,405 patients with chronic pain (mean age 64.1 years). Among participants with chronic widespread pain, the prevalence of having a "lifetime" history of depression was 45.7% and varied (25.0-66.7%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.66; good calibration on the calibration plot) included age, BMI, smoking status, physical activity, socioeconomic status, gender, history of asthma, history of heart failure, and history of peripheral artery disease. Among participants with chronic regional pain, the prevalence of having a "lifetime" history of depression was 30.2% and varied (21.4-70.6%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.65; good calibration on the calibration plot) included age, gender, nature of pain, smoking status, regular opioid use, history of asthma, pain location that bothers you most, and BMI. CONCLUSIONS: There was substantial variability in the prevalence of depression among patients with chronic pain. Clinically relevant factors were selected to develop prediction models. Clinicians can use these models to assess patients' treatment needs. These predictors are convenient to collect during daily practice, making it easy for busy clinicians to use them.

The causal association between maternal depression, anxiety, and infection in pregnancy and neurodevelopmental disorders among 410 461 children: a population study using quasi-negative control cohorts and sibling analysis.

BACKGROUND: To address if the long-standing association between maternal infection, depression/anxiety in pregnancy, and offspring neurodevelopmental disorder (NDD) is causal, we conducted two negative-control studies. METHODS: Four primary care cohorts of UK children (pregnancy, 1 and 2 years prior to pregnancy, and siblings) born between 1 January 1990 and 31 December 2017 were constructed. NDD included autism/autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy. Maternal exposures included depression/anxiety and/or infection. Maternal (age, smoking status, comorbidities, body mass index, NDD); child (gender, ethnicity, birth year); and area-level (region and level of deprivation) confounders were captured. The NDD incidence rate among (1) children exposed during or outside of pregnancy and (2) siblings discordant for exposure in pregnancy was compared using Cox-regression models, unadjusted and adjusted for confounders. RESULTS: The analysis included 410 461 children of 297 426 mothers and 2 793 018 person-years of follow-up with 8900 NDD cases (incidence rate = 3.2/1000 person years). After adjustments, depression and anxiety consistently associated with NDD (pregnancy-adjusted HR = 1.58, 95% CI 1.46-1.72; 1-year adj. HR = 1.49, 95% CI 1.39-1.60; 2-year adj. HR = 1.62, 95% CI 1.50-1.74); and to a lesser extent, of infection (pregnancy adj. HR = 1.16, 95% CI 1.10-1.22; 1-year adj. HR = 1.20, 95% CI 1.14-1.27; 2-year adj. HR = 1.19, 95% CI 1.12-1.25). NDD risk did not differ among siblings discordant for pregnancy exposure to mental illness HR = 0.97, 95% CI 0.77-1.21 or infection HR = 0.99, 95% CI 0.90-1.08. CONCLUSIONS: Maternal risk appears to be unspecific to pregnancy: our study provided no evidence of a specific, and therefore causal, link between in-utero exposure to infection, common mental illness, and later development of NDD.

Trends in prevalence of fractures among adults in the United States, 1999-2020: a population-based study.

BACKGROUND: Population data that examines recent national trends in the prevalence of fractures are lacking in the United States (US). MATERIALS AND METHODS: Analyses were based on 1999-2020 data from the National Health and Nutrition Examination Survey (NHANES). Primary outcomes included the prevalence of hip, wrist, and vertebral fractures among adults aged greater than or equal to 50 years. Changes in the prevalence over time were determined by joinpoint regression analysis. The authors also described the variation by fracture subtypes, sociodemographic characteristics, and their combination. RESULTS: For adults aged greater than or equal to 50 years in NHANES 2017-March 2020, the authors estimated that there was 2.6 million Americans with hip fractures, 14.6 million Americans with wrist fractures, and 5.2 million Americans with vertebral fractures. The prevalence of wrist fractures significantly increased from 8.7% (7.4-9.9%) in 1999-2000 to 12.8% (11.6-14.1%) in 2017-March 2020 among adults aged greater than or equal to 50 years ( P for trend=0.04); significant increases were also observed in fractures that occurred at age less than 50 years, non-Hispanic White, high family income groups, and several combination subgroups (e.g. fractures occurred at age <50 years among women). The prevalence of vertebral fractures increased from 2.2% (1.7-2.8%) in 1999-2000 to 4.6% (3.7-5.5%) in 2017-March 2020 among adults aged greater than or equal to 50 years ( P for trend=0.02); significant increases were also observed in 50-64 years, women, non-Hispanic White, high family income groups and several combination subgroups (e.g. fractures that occurred at age <50 years among women). The authors did not observe significant trend changes in the prevalence of hip fractures among adults aged greater than or equal to 50 years between 1999 and 2020. CONCLUSION: The estimated prevalence of wrist and vertebral fractures significantly increased among US adults aged greater than or equal to 50 years from 1999 to 2020, although hip fractures did not significantly change.

Optimal cut-offs of depression screening tools during the COVID-19 pandemic: a systematic review.

BACKGROUND: Studies have reported an increase in the prevalence of depression during the COVID-19 pandemic. The accuracy of screening tools may change with the prevalence and distribution of a disease in a population or sample: the "Spectrum Effect". METHODS: First, we selected commonly used screening tools and developed search strategies for the inclusion of original studies during the pandemic. Second, we searched PsycINFO, EMBASE, and MEDLINE from March 2020 to September 2022 to obtain original studies that investigated the accuracy of depression screening tools during the pandemic. We then searched these databases to identify meta-analyses summarizing the accuracy of these tools conducted before the pandemic and compared the optimal cut-offs for depression screening tools during the pandemic with those before. RESULT: Four original studies evaluating the optimal cut-offs for four screening tools (Beck Depression Inventory [BDI-II], Hospital Anxiety and Depression Scale-Depression [HADS-D], Patient Health Questionnaire-9 [PHQ-9], and Geriatric Depression Scale-4 [GDS-4]) were published during the pandemic. Four meta-analyses summarizing these tools before the pandemic. We found that the optimal cut-off of BDI-II was 14 during the pandemic (23.8% depression prevalence, screening patients with Type 2 diabetes) and 14.5 before the pandemic (17.6% depression prevalence, screening psychiatric, primary care, and healthy populations); HADS-D was 10 during the pandemic (23.8% depression prevalence, screening patients with type 2 diabetes) and 7 before the pandemic (15.0% depression prevalence, screening medically ill patients); PHQ-9 was 11 during the pandemic (14.5% depression prevalence, screening university students) and 8 before the pandemic (10.9% depression prevalence, screening the unrestricted population), and GDS-4 was 1.8 during the pandemic (29.0% depression prevalence, screening adults seen in a memory clinic setting) and 3 before the pandemic (18.5% depression prevalence, screening older adults). CONCLUSION: The optimal cut-off for different screening tools may be sensitive to changes in study populations and reference standards. And potential spectrum effects that should be considered in post-COVID time which aiming to improve diagnostic accuracy.

Representativeness in health research studies: an audit of Greater Manchester Clinical Research Network studies between 2016 and 2021.

BACKGROUND: There are increasing concerns that participants in health research in the UK are not representative of the UK population, risking widening health inequities. However, detailed information on the magnitude of the problem is limited. Therefore, we evaluated if the health research conducted in the Greater Manchester region was broadly representative of its diverse population. METHODS: We conducted an audit of all health  research studies conducted exclusively in Greater Manchester, using data from a national research network. Two researchers selected studies that were (1) an interventional or observational study of a health outcome; (2) 'closed' for recruitment between May 2016 and May 2021 and (3) human research. They extracted study information (dates, contacts, sample recruited, clinical speciality). Participant characteristics were sourced from published and unpublished manuscripts and requested directly from principal investigators and named study contacts. Data were extracted, summarised and compared to the Greater Manchester population for the following metrics: ethnicity, sex, age, deprivation and smoking status. A weighted mean age estimate was calculated to account for variation in age reporting. Too few studies provided patient-level deprivation data so, using the area code of the recruitment site, the area level multiple deprivation, health deprivation and disability index and decile was derived. These data were geo-mapped using QGIS 3.26. RESULTS: Overall, 145/153 (95%) studies met inclusion criteria and participant information was sourced for 85/145 (59%) studies, representing 21,797 participants. Participant information was incomplete for all metrics. Where ethnicity (N = 10,259) data were available and compared to Greater Manchester estimates there was evidence that ethnic minorities were under-represented (6% versus 16%). Most of the recruitment occurred in central Manchester (50%) and with NHS hospital settings (74%). CONCLUSIONS: Greater Manchester health research in 2016-2021 was centralised and under-represented ethnic minorities. We could not report which ethnic minority group was least represented because sourcing detailed participant information was challenging. Recommendations to improve the reporting of key participant characteristics with which to monitor representativeness in health research are discussed.

Prevalence, incidence, and re-occurrence risk of musculoskeletal pain in older adults in the United Kingdom: a population-based study.

Background: Throughout the literature, pain burden has been assessed by asking different questions, often cross-sectionally, different populations of interest. We know little about pain re-occurrence and how to translate knowledge between pain questions within the population of interest. We aimed to estimate the burden of musculoskeletal pain by estimating prevalence, incidence rates, and re-occurrence risk of back, hand, hip, knee, and foot pain using different questions from UK population-based samples and predict the number of affected individuals in the UK in 2030. Methods: We used two UK population-representative studies, with two eight-year-apart follow-ups and two pain questions assessing recent pain episodes and often troubled pain when walking. We estimated prevalence, 8-year incidence rates, and 8-year pain re-occurrence risk for women and men aged 50 years and older and the relation between the two pain questions. Results: Among UK individuals older than 50 years, the prevalence of musculoskeletal pain episode was 20%-50%, and the incidence was 20-40/1,000 person-years, while the prevalence of pain when walking was 10%-25%, and the incidence was 6-12/1,000 person-years. The most prevalent musculoskeletal pain types were back and knee pain; of five women experiencing back or knee pain episodes, three are expected to be often troubled by pain. Hip and foot pain had similar estimates in both questions. Hand pain peaked in women aged 50-65 years. Women had higher prevalence and incidence rates, but men had higher 8-year re-occurrence risk of all types of musculoskeletal pain. Reporting a pain episode was associated with two times higher risk, but often troubled by pain when walking was associated with four to seven times times higher risk of the same pain in 8 years. Women and men with a body mass index (BMI) of ≥27 kg/m2 were twice as likely to experience musculoskeletal pain than those with BMI<27 kg/m2. In 2030, we expect 2-7 million people older than 50 years in the United Kingdom to seek site-specific musculoskeletal pain-focused healthcare. Conclusions: In individuals older than 50 years, the experience of musculoskeletal pain at least doubles the chance of experiencing it again. Women report musculoskeletal pain more often, but men report more persistent pain. Musculoskeletal pain presents a significant burden to public health.

Trends in antipsychotic prescribing to children and adolescents in England: cohort study using 2000-19 primary care data.

BACKGROUND: The prescription of antipsychotics to children and adolescents has been increasing worldwide. We described up-to-date trends in antipsychotic prescribing and identified likely indications in a contemporary English cohort. METHODS: We used a large primary care database, the Clinical Practice Research Datalink (CPRD) Aurum database, and we included all children and adolescents aged 3-18 years in the database and registered in England between Jan 1, 2000, and Dec 31, 2019, excluding those whose gender was recorded as indeterminate. Participants were followed up until the earliest of Dec 31, 2019, June 30 of the year they turned 18 years, their death, when they transferred from the primary care practice, or when the practice left the database. Data were not collected on ethnicity. We recorded antipsychotic prescriptions using the date a prescription was issued. As CPRD prescriptions are not linked to indications, we developed an algorithm to ascertain the most likely indication associated with participants' first antipsychotic prescription using clinical codes. We reported prescribing trends as annual period prevalence and the rate of first antipsychotic prescription, and we used joinpoint regression analysis to identify changes in the outcome trend. We stratified prevalence estimates by age group, gender, and Index of Multiple Deprivation quintiles, we reported frequencies of likely indications associated with incident prescriptions, and we explored clinical preference for typical versus atypical antipsychotics within deprivation quintiles. FINDINGS: Between Jan 1, 2000, and Dec 31, 2019, we included 7 216 791 children and adolescents, of whom 3 480 730 (48·2%) were girls and 3 736 061 (51·8%) were boys, with a mean age at the start of follow-up of 7·3 years (SD 4·9; range 3-18). Median follow-up was 4·1 years (IQR 1·5-8·5). 19 496 (0·3%) individuals received 243 529 antipsychotic prescriptions over follow-up, including 225 710 (92·7%) atypical and 17 819 (7·3%) typical antipsychotic prescriptions. The annual period prevalence of antipsychotic prescriptions rose from 0·057% (95% CI 0·052-0·063%) in 2000 to 0·105% (0·100-0·111%) in 2019. From joinpoint analyses, the period prevalence of all antipsychotic prescriptions increased by an average of 3·3% per year (2·2-4·9%) and the rate of first prescriptions increased by 2·2% per year (1·7-2·7%). The most likely indications of the first identified antipsychotic prescriptions were for autism spectrum disorder (2477 [12·7%]), non-affective psychosis (1669 [8·6%]), anxiety disorders (1466 [7·5%]), ADHD (1391 [7·1%]), depression (1256 [6·4%]), and conduct disorders (1181 [6·1%]). INTERPRETATION: The observed increase in antipsychotic prescriptions over 20 years results from the accumulation of repeated prescriptions to the same individuals combined with an increase in new prescriptions. These findings highlight the need for continued monitoring of trends in antipsychotic use and, although this was not examined in this paper, the findings highlights the need for better information about long-term antipsychotic safety. FUNDING: None.

Age- and sex-specific effects of obesity, metabolic syndrome and its components on back pain: The English Longitudinal Study of Ageing.

OBJECTIVES: We aimed to investigate age- and sex-specific effects of obesity, metabolic syndrome (MetS) and its components on back pain in middle-aged and older English individuals. METHODS: We used data from the English Longitudinal Study of Ageing, wave 2 (2004-2005). Body mass index (BMI) expressed the obesity, while MetS was defined according to revised Adult Treatment Panel (ATP) III criteria. We assessed associations between obesity, MetS and its components with presence and severity of back pain and provided estimates per strata, middle-aged (50-64years) and older (65-79years), women and men. RESULTS: The study sample included 3328 participants, 1021 and 835 middle-aged women and men and 773 and 699 older women and men, respectively. We found that BMI (OR=1.07, 95% CI 1.05-1.09), MetS (OR=1.47, 95% CI 1.22-1.77), high waist circumference (WC), high triglycerides (TG), and high fasting blood glucose were associated with the presence of back pain. Effects of BMI were consistent across the strata. However, MetS was associated with back pain only in women, middle-aged (OR=1.59, 95% CI 1.14-2.21) and older (OR=1.43, 95% CI 1.01-2.05). The MetS component driving this association was high WC, supported by high TG in older women. Higher BMI, presence of MetS, high blood pressure and TG were associated with back pain severity. CONCLUSIONS: We found that obesity was associated with the presence and severity of back pain, irrespective of age and sex. However, we found women-specific effects of MetS driven by high WC, indicating that metabolic dysregulation contributes to back pain pathophysiology in women.

Effects of body weight and fat mass on back pain - direct mechanical or indirect through inflammatory and metabolic parameters?

BACKGROUND: While reports indicate the association between obesity and back pain, its mechanism is still unclear. Thus, we aimed to investigate the effects of weight and its components on back pain in middle-aged women while considering direct mechanical and indirect effects via inflammatory and metabolic parameters. METHODS: We used data from the Chingford 1000 Women Study, two follow-ups seven years apart. We assessed effects of weight, body mass index (BMI), total fat mass (TFM), total lean mass (TLM) and total bone mineral density (TBMD), measured by dual-energy X-ray absorptiometry, on back pain episode. We used inflammatory (C-reactive protein, interleukin-6, and tumour necrosis factor-alpha) and metabolic parameters (systolic and diastolic blood pressure, triglyceride, high-density lipoprotein cholesterol, and fasting blood glucose) as mediators of indirect effects. We investigated associations of interest cross-sectionally and longitudinally using binary logistic regression and parallel mediation model. RESULTS: We included 826 Chingford middle-aged women (mean age=60.7, SD=5.9) from the first used follow-up in cross-sectional and mediation analyses and 645 women that attended the follow-up seven years later, in longitudinal analyses. We found that increased weight was directly associated with increased odds of having back pain episode (OR=1.02; 95% CI 1.01-1.03), similarly as BMI (OR=1.05; 95% CI 1.02-1.08) and TFM (OR=1.03; 95% CI 1.01-1.04) consistently across the cross-sectional and longitudinal models, but not TLM or TBMD. However, we did not find consistent indirect effects of weight or its components through measured inflammatory or metabolic parameters on back pain. CONCLUSIONS: Our results show that in middle-aged women, weight, BMI and TFM are directly related to back pain, indicating prominence of mechanical loading effect.

Specific body mass index trajectories were related to musculoskeletal pain and mortality: 19-year follow-up cohort.

OBJECTIVE: We aimed to study 19-year body mass index (BMI) patterns and their (1) bidirectional relationship with musculoskeletal pain and (2) mortality risk. STUDY DESIGN AND SETTING: We used data from the Chingford study and group-based trajectory modelling to define 19-year BMI patterns. We investigated whether baseline back, hand, hip, and knee pain (as single- and multi-site) predicted 19-year BMI trajectory, and whether 19-year BMI patterns predicted pain in year 20. We explored BMI trajectories and mortality risk over 25 years (life expectancy). RESULTS: We included 938 women (mean age: year-1=54, year-20=72) and found seven distinct 19-year BMI trajectories: two normal-weighted (reference), slightly overweight, lower and upper overweight-to-obese, lower and upper obese. BMI patterns capturing the increase overweight-to-obese (BMI 27-34 overtime) were bidirectionally related to knee and multi-site pain. The lower obese pattern (BMI 33-38) was unidirectionally associated with lower limb pain. Women with BMI above 40 had an increased all-cause and cardiovascular mortality risk. CONCLUSION: For most postmenopausal women, the overweight WHO category was a transition. Two patterns capturing increase overweight-to-obese were mutually related to musculoskeletal pain, i.e., knee and multi-site pain contributed to becoming obese, and trajectories of becoming obese increased the odds of experiencing pain later.

Association of Lumbar Spine Radiographic Changes With Severity of Back Pain-Related Disability Among Middle-aged, Community-Dwelling Women.

Importance: Previous studies, using mostly cross-sectional data, provide conflicting evidence of an association between lumbar spine radiographic changes and the severity of back pain-related disability. Such conflicting evidence may be associated with widely unnecessary diagnostic imaging of the lumbar spine. Objective: To examine both cross-sectional and longitudinal associations between lumbar spine radiographic changes and the severity of back pain-related disability among middle-aged, community-dwelling women. Design, Setting, and Participants: This population-based prospective cohort study used data from the Chingford 1000 Women Study. Analyses included data collected from year 6 (1994-1996; physical activity was measured), year 9 (1997-1999; treated as baseline), and year 15 (2003-2005), with a total length of follow-up for longitudinal analyses of 6 years. Data were analyzed from April 17 to November 3, 2020. Exposures: Primary exposure was lumbar spine radiographic changes, defined using the Kellgren-Lawrence (K-L) grade. Secondary exposures were defined using presence of osteophytes and disc space narrowing. The composite score combined the number of lumbar spine segments with definite changes detected on radiographic images (ie, radiographic changes) (K-L grade ≥2, which means at least definite osteophyte and possible narrowing of disc space are present; osteophyte and disc space narrowing grade ≥1, which means at least mild or definite changes are present). Main Outcomes and Measures: Self-reported back pain-related disability measured in years 9 and 15 assessed by the St Thomas disability questionnaire. Results: Among 650 women (mean [SD] age, 61.3 [5.9] years) in cross-sectional analyses and 443 women (mean [SD] age, 60.6 [6.0] years) in longitudinal analyses, there was no evidence to support an association between higher number of lumbar segments with radiographic changes (K-L grade, osteophytes, and disc space narrowing) and more severe back pain-related disability (eg, cross-sectional analyses using the K-L grade; 1 segment vs 0 segment: adjusted odds ratio, 1.22 [95% CI, 0.76-1.96]). No interactions were found of an association between lumbar spine radiographic changes and the severity of back pain-specific disability with age, body mass index, or smoking status. Conclusions and Relevance: In this cohort of middle-aged, community-dwelling women, there was no evidence to support an association between a higher number of lumbar segments with radiographic changes (K-L grade, osteophytes, and disc space narrowing) and more severe back pain-related disability cross-sectionally or over time. These findings provide further evidence against routinely using diagnostic imaging of the lumbar spine.

Rugby Health and Well-Being Study: protocol for a UK-wide survey with health data cross-validation.

INTRODUCTION: Rugby football (Union and League) provides physical activity (PA) with related physical and mental health benefits. However, as a collision sport, rugby research and media coverage predominantly focus on injuries in elite players while the overall impact on health and well-being remains unclear. This study aims to provide a greater understanding of the risks and benefits of rugby participation in a diverse sample of men and women, current and former rugby Union and League players from recreational to the elite level of play. We will explore: (1) joint-specific injuries and concussion; (2) joint pain and osteoarthritis (OA); (3) medical and mental health conditions; (4) PA and sedentary behaviour and (5) well-being (quality of life, flourishing and resilience). METHODS AND ANALYSIS: The Rugby Health and Well-being Study is designed in two phases: (1) a UK-wide cross-sectional survey and (2) cross-validation using health register data from Scotland. Participants will be at least 16 years old, current or former rugby players who have played rugby for at least one season. We will report standardised, level of play-, sex- and age-stratified prevalence of joint injury, concussion, medical conditions and PA. We will describe injury/concussion prevention expectations and protective equipment use. Rugby-related factors associated with injury, pain, OA, PA, health and well-being will be explored in regression models. We will compare joint pain intensity and duration, elements of pain perception and well-being between recreational and elite players and further investigate these associations in regression models while controlling for confounding variables. In the second phase, we will validate self-reported with health register data, and provide further information on healthcare use. ETHICS AND DISSEMINATION: The Yorkshire and the Humber-Leeds East Research Ethics Committee (REC reference: 19/HY/0377) has approved this study (IRAS project ID 269424). The results will be disseminated through scientific publications, conferences and social media.

Expression of mitochondrial TSPO and FAM173B is associated with inflammation and symptoms in patients with painful knee osteoarthritis.

OBJECTIVES: To characterize the expression profiles of two nuclear-encoded mitochondrial genes previously associated with chronic pain, the translocator protein (TSPO) and family with sequence similarity 173B (FAM173B), in different knee compartments from patients with painful knee OA. Also, to examine their association with the joint expression of inflammatory cytokines/chemokines and clinical symptoms. METHODS: The study was performed on 40 knee OA patients and 19 postmortem (PM) controls from which we collected the knee tissues: articular cartilage (AC), synovial membrane (SM) and subchondral bone (SB). Quantitative real-time polymerase chain reaction was used to determine the relative mRNA levels of TSPO, FAM173B, and inflammatory mediators IL6, IL8, IL10, IL12, MCP1, CCL11 and CCL17. OA patients rated their pain intensity (visual analogue scale), severity of knee-related outcomes (KOOS) and pain sensitivity assessed by pressure algometry. RESULTS: The gene expression of TSPO in SM was elevated in OA patients compared with control subjects while there were no group differences in AC and SB. Expression of FAM173B was reduced in SM but elevated in SB in OA patients compared with controls. The expression of TSPO and FAM173B in SM and SB was associated with the expression of inflammatory substances, but not in AC. Synovial expression of TSPO correlated with lower pain intensity and FAM173B with increased pressure pain sensitivity in OA. CONCLUSION: Our results suggest that altered expression of TSPO and FAM173B is associated with joint expression of inflammatory mediators and with clinical symptoms indicating the relevance for the pathophysiology of knee OA.

Pain trajectory defines knee osteoarthritis subgroups: a prospective observational study.

Knee osteoarthritis (OA) is a heterogeneous disease, and identification of its subgroups/phenotypes can improve patient treatment and drug development. We aimed to identify homogeneous OA subgroups/phenotypes using pain development over time; to understand the interplay between pain and functional limitation in time course; and to investigate subgroups' responses to available pharmacological and surgical treatments. We used group-based trajectory modelling to identify pain trajectories in the phase-3 VIDEO trial (n = 474, 3-year follow-up) and also in the Osteoarthritis Initiative cohort study (n = 4796, 9-year follow-up). We extended trajectory models by (1) fitting dual trajectories to investigate the interplay between pain and functional limitation over time, and (2) including analgesic use as a time-varying covariate. Also, we investigated the relationship between trajectory groups and knee replacement in regression models. We identified 4 pain trajectory groups in the trial and 6 in the cohort. These overlapped and led us to define 4 OA phenotypes: low-fluctuating, mild-increasing, moderate-treatment-sensitive, and severe-treatment-insensitive pain. Over time, functional knee limitation followed the same trajectory as pain with almost complete concordance (94.3%) between pain and functional limitation trajectory groups. Notably, we identified a phenotype with severe pain that did not benefit from available treatments, and another one most likely to benefit from knee replacement. Thus, knee OA subgroups/phenotypes can be identified based on patients' pain experiences in studies with long and regular follow-up. We provided a robust approach, reproducible between different study designs, which informs clinicians about symptom development and delivery of treatment options and opens a new avenue toward personalized medicine in OA.

Biomarker of extracellular matrix remodelling C1M and proinflammatory cytokine interleukin 6 are related to synovitis and pain in end-stage knee osteoarthritis patients.

Little is known about local and systemic biomarkers in relation to synovitis and pain in end-stage osteoarthritis (OA) patients. We investigated the associations between the novel extracellular matrix biomarker, C1M, and local and systemic interleukin 6 (IL-6) with synovitis and pain. Serum C1M, plasma, and synovial fluid IL-6 (p-IL-6, sf-IL-6) were measured in 104 end-stage knee OA patients. Contrast-enhanced magnetic resonance imaging was used to semiquantitatively assess an 11-point synovitis score; pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Neuropathic Pain Questionnaire (NPQ). Linear regression was used to investigate associations between biomarkers and synovitis, and biomarkers and pain while controlling for age, sex, and body mass index. We also tested whether associations between biomarkers and pain were confounded by synovitis. We found sf-IL-6 was associated with synovitis in the parapatellar subregion (B = 0.006; 95% confidence interval [CI] 0.003-0.010), and no association between p-IL-6 and synovitis. We also observed an association between C1M and synovitis in the periligamentous subregion (B = 0.013; 95% CI 0.003-0.023). Furthermore, sf-IL-6, but not p-IL-6, was significantly associated with pain, WOMAC (B = 0.022; 95% CI 0.004-0.040), and NPQ (B = 0.043; 95% CI 0.005-0.082). There was no association between C1M and WOMAC pain, but we did find an association between C1M and NPQ (B = 0.229; 95% CI 0.036-0.422). Lastly, synovitis explained both biomarker-NPQ associations, but not the biomarker-WOMAC association. These results suggest that C1M and IL-6 are associated with synovitis and pain, and synovitis is an important confounding variable when studying biomarkers and neuropathic features in OA patients.

Prenatal exposure to anxiolytic and hypnotic medication in relation to behavioral problems in childhood: A population-based cohort study.

Benzodiazepines and benzodiazepine-related medications (BBRMs) are anxiolytics and hypnotics acting on γ-amino butyric acid (GABA)A receptors. BBRMs are assumed to have a low potential for major congenital malformations, but research on more subtle and protracted developing symptoms of these medications is lacking. Therefore, we prospectively investigated the association between BBRM use in pregnancy and long-term effects on child behavior in a large population-based cohort study. The study population consisted of 104 children prenatally exposed to BBRM, 527 children exposed to maternal prenatal anxiety or phobic anxiety symptoms (without exposure to BBRM), and 5609 control children. At child age, 6years, Oppositional Defiant Disorder (ODD), Aggressive Behavior and Anxiety Problems were assessed by the Child Behavior Checklist (CBCL) reported by the mother and the Teacher Report Form (TRF). Children prenatally exposed to BBRM had higher scores of ODD and aggressive behavior, but not of anxiety. However, these associations were explained by maternal anxiety symptoms during pregnancy. Moreover, prenatal exposure to anxiety (without exposure to BBRM) was associated with increased scores of child ODD, aggressive behavior, and anxiety. In conclusion, the current study demonstrates that prenatal BBRM exposure was not independently associated with ODD and aggressive behavior in childhood when prenatal anxiety symptoms were taken into account.