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Melatonin exhibits potential for pain relief and long‐term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox‐proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community‐based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30–0.73) during the follow‐up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation. [ABSTRACT FROM AUTHOR]

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02–1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis. [ABSTRACT FROM AUTHOR]

Objective: Gout is associated with a higher risk of fracture; however, findings on the associations of hyperuricemia and urate‐lowering therapy (ULT) with the risk of fracture have been inconsistent. We examined whether lowering serum urate (SU) levels with ULT to a target level (i.e., <360 μmoles/liter) reduces the risk of fracture among individuals with gout. Methods: We emulated analyses of a hypothetical target trial using a "cloning, censoring, and weighting" approach to examine the association between lowering SU with ULT to the target levels and the risk of fracture using data from The Health Improvement Network, a UK primary care database. Individuals with gout who were age 40 years or older and for whom ULT was initiated were included in the study. Results: Among 28,554 people with gout, the 5‐year risk of hip fracture was 0.5% for the "achieving the target SU level" arm and 0.8% for the "not achieving the target SU level" arm. The risk difference and hazard ratio for the "achieving the target SU level" arm was –0.3% (95% confidence interval [95% CI] –0.5%, –0.1%) and 0.66 (95% CI 0.46, 0.93), respectively, compared with the "not achieving the target SU level" arm. Similar results were observed when the associations between lowering SU level with ULT to the target levels and the risk of composite fracture, major osteoporotic fracture, vertebral fracture, and nonvertebral fracture were assessed. Conclusion: In this population‐based study, lowering the SU level with ULT to the guideline‐based target level was associated with a lower risk of incident fracture in people with gout. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies highlighted an increased risk of venous thromboembolism (VTE) among patients with anterior cruciate ligament reconstruction (ACLR); however, the risk for those with ACL tear but without undergoing ACLR has not been reported yet. The aim of this study was to evaluate the risk of VTE among ACL tear individuals with or without ACLR derived from the general population. Methods: A cohort study was conducted using data from the IQVIA Medical Research Database of the United Kingdom. Up to five non-ACL tear individuals (n = 22,235) were matched to each case of ACL tear (n = 4474) by age, sex, body mass index and entry-time. The relation of ACL tear to VTE [pulmonary embolism (PE) and deep vein thrombosis (DVT)] was examined using a multivariable Cox proportional hazard model. A sub-cohort analysis, in which the ACL tear individuals were stratified into those with ACLR and those without ACLR, was also conducted. Results: VTE developed in 13 individuals with ACL tear and nine individuals without ACL tear (incidence rates: 3.1 vs. 0.4/1000 person-years), with multivariable-adjusted hazard ratio (HR) being 6.59 (95% CI 2.28–19.08) in 1-year follow-up. For ACL tear individuals with ACLR, the HR was 11.44 (95% CI 2.71–48.28), and for those without ACLR, the HR was 6.02 (95% CI 1.44–24.25), compared with individuals without ACL tear. Conclusion: This large-sample population-based cohort study provides the first evidence on an increased risk of VTE in ACL tear individuals regardless of subsequent ACLR, which supports the necessity for monitoring venous-thromboembolic complications in the target population, including those without ACLR. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Objective: To determine whether patients with rheumatoid arthritis (RA) are at higher risks for SARS–CoV‐2 infection and its severe outcomes before and after COVID‐19 vaccination. Methods: Using a UK primary care database, we conducted 2 cohort studies to compare the risks of SARS–CoV‐2 infection, hospitalization, and death from COVID‐19 between patients with RA and the general population according to their COVID‐19 vaccination status. We used exposure score overlap weighting to balance baseline characteristics between 2 comparison cohorts. Results: Among unvaccinated individuals, the weighted incidence rates of SARS–CoV‐2 infection (9.21 versus 8.16 of 1,000 person‐months), hospitalization (3.46 versus 2.14 of 1,000 person‐months), and death (1.19 versus 0.62 of 1,000 person‐months) were higher among patients with RA than the general population over 3 months of follow‐up; the corresponding adjusted hazard ratios (HRs) were 1.10 (95% confidence interval [95% CI] 1.00–1.24), 1.62 (95% CI 1.34–1.96), and 1.88 (95% CI 1.37–2.60), respectively. Among vaccinated individuals, the weighted rates of breakthrough infection (4.17 versus 3.96 of 1,000 person‐months; HR 1.10 [95% CI 1.00–1.20]) and hospitalization (0.42 versus 0.32 of 1,000 person‐months; HR 1.29 [95% CI 0.96–1.75]) were higher among patients with RA than the general population over 9 months of follow‐up; however, no apparent difference in the risk of these outcomes was observed over 3 and 6 months of follow‐up between 2 comparison cohorts. Conclusion: Patients with RA are still at higher risks of SARS–CoV‐2 infection and COVID‐19 hospitalization than the general population after receiving COVID‐19 vaccines. These findings support booster COVID‐19 vaccinations and adherence of other preventive strategies among patients with RA. [ABSTRACT FROM AUTHOR]

Background: Both BNT162b2 (Pfizer–BioNTech) and ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccines have shown high efficacy against COVID-19 in randomized controlled trials. However, their comparative effectiveness against COVID-19 is unclear in the real world. We evaluated the comparative effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against COVID-19 in the UK general population. Methods: We emulated a target trial using IQVIA Medical Research Database (IMRD), an electronic primary care database from the UK (2021). We included 1,311,075 participants, consisting of 637,549 men and 673,526 women age≥18 years, who received vaccination with BNT162b2 or ChAdOx1 nCoV-19 between January 1 and August 31, 2021. The outcomes consisted of confirmed diagnosis of SARS-CoV-2 infection, hospitalisation for COVID-19 and death from COVID-19 in the IMRD. We performed a cox-proportional hazard model to compare the risk of each outcome variable between the two vaccines adjusting for potential confounders with time-stratified overlap weighting of propensity score (PS). Results: During a mean of 6.7 months of follow-up, 20,070 confirmed SARS-CoV-2 infection occurred in individuals who received BNT162b2 vaccine (PS weighted incidence rate: 3.65 per 1000 person-months), and 31,611 SARS-CoV-2 infection occurred in those who received ChAdOx1 nCoV-19 vaccine (PS weighted incidence rate: 5.25 per 1000 person-months). The time-stratified PS weighted rate difference of SARS-CoV-2 infection for BNT162b2 group vs. ChAdOx1 nCoV-19 group was -1.60 per 1000 person-months (95% confidence interval [CI]: -1.76 to -1.43 per 1000 person-months), and the hazard ratio was 0.69 (95% CI: 0.68 to 0.71). The results were similar across the stratum of sex, age (<65 and ≥65 years), and study periods (i.e., alpha-variant predominance period and delta-variant predominance period). The PS weighted incidence of hospitalisation for COVID-19 was also lower in the BNT162b2 vaccine group than that in the ChAdOx1 vaccine group (RD: -0.09, 95%CI: -0.13 to -0.05 per 1000 person-months; HR: 0.65, 95%CI: 0.57 to 0.74). No significant difference in the risk of death from COVID-19 was observed between the two comparison groups. Conclusions: In this population-based study, the BNT162b2 vaccine appears to be more efficacious than the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection and hospitalisation for COVID-19 but not death from COVID-19. [ABSTRACT FROM AUTHOR]

Objective: Gout patients often have multiple comorbidities, making them susceptible to SARS–CoV‐2 infection and poor outcomes. This study was undertaken to examine the association between gout and the risk of SARS–CoV‐2 infection and severe outcomes, especially in patients who have received a SARS–CoV‐2 vaccine. Methods: We conducted 2 cohort studies using The Health Improvement Network in the UK. Individuals with gout and those without gout from the general population were followed up from December 8, 2020 to October 31, 2021. We estimated the rate difference (RD) and hazard ratio (HR) of SARS–CoV‐2 infection and severe outcomes (i.e., hospitalization and death within 30 days after SARS–CoV‐2 infection) for individuals with gout versus those without gout using a Cox proportional hazards model according to SARS–CoV‐2 vaccination status. We adjusted for potential confounders by using overlap weighting of exposure scores. Results: Among the vaccinated cohort, 1,955 cases of breakthrough COVID‐19 infection occurred in 54,576 individuals with gout (4.68 cases per 1,000 person‐months), and 52,468 cases occurred in 1,336,377 individuals without gout (3.76 cases per 1,000 person‐months). The partially adjusted RD of breakthrough infection was 0.91 cases per 1,000 person‐months (95% confidence interval [95% CI] 0.62–1.20 cases per 1,000 person‐months), and the partially adjusted HR was 1.24 (95% CI 1.19–1.30). Gout was also associated with an increased risk of hospitalization (adjusted HR 1.30 [95% CI 1.10–1.53]) and death (adjusted HR 1.36 [95% CI 0.87–2.13]). Women with gout had an increased risk of hospitalization (adjusted HR 1.55 [95% CI 1.15–2.10]) and death (adjusted HR 2.46 [95% CI 1.12–5.41]). Similar associations with gout were observed in the unvaccinated cohort. Conclusion: These general population data suggest that individuals with gout, especially women, have higher risks of SARS–CoV‐2 infection and severe outcomes, even when vaccinated. [ABSTRACT FROM AUTHOR]

Background: Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown.Objective: To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD.Design: Cohort study.Setting: The Health Improvement Network U.K. primary care database (2000 to 2019).Participants: Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD.Measurements: The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators.Results: Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07).Limitation: Residual confounding cannot be ruled out.Conclusion: In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD.Primary Funding Source: Project Program of National Clinical Research Center for Geriatric Disorders. [ABSTRACT FROM AUTHOR]

Objectives To examine trends in the initial prescription of commonly-prescribed analgesics and patient- as well as practice-level factors related to their selection in incident OA. Methods Patients consulting with incident clinical OA between 2000–2016 were identified within The Health Improvement Network in the United Kingdom (UK) general practice. Excluded were patients who had history of cancer or were prescribed the analgesics of interest within 6 months before diagnosis of OA. Initial analgesic prescription included oral non-selective NSAID, oral selective cyclooxygenase-2 inhibitor, topical NSAID, paracetamol, topical salicylate or oral/transdermal opioid within 1 month after OA diagnosis. Results ∼44% of patients with incident OA (n  = 125 696) were prescribed one of these analgesics. Incidence of oral NSAID prescriptions decreased whereas other analgesic prescriptions, including oral opioid prescriptions, increased (all P -for-trend < 0.001). Patients with a history of gastrointestinal disease were more likely to receive topical NSAIDs, paracetamol or oral/transdermal opioids. Only 38% of patients with history of gastrointestinal disease and 21% of patients without it had co-prescription of gastroprotective agent with oral NSAIDs. Oral/transdermal opioid prescription was higher among the elderly (≥65 years), women, obesity, current smoker, and patients with gastrointestinal, cardiovascular or chronic kidney disease. Prescription of oral opioids increased with social deprivation (P -for-trend < 0.05) and was highest in Scotland, whereas transdermal opioid prescription was highest in Northern Ireland (all P -for-homogeneity-test < 0.05). Conclusion The initial prescription pattern of analgesics for OA has changed over time in the UK. Co-prescription of gastroprotective agents with oral NSAIDs remains suboptimal, even among those with prior gastrointestinal disease. [ABSTRACT FROM AUTHOR]

Previous studies comparing risk of fracture among Proton Pump Inhibitors (PPIs) users with that among non-users were susceptible to confounding by indication. Epidemiologic studies of this association using an active medication as a comparator would appropriately address this bias. We conducted a propensity-score matched cohort study to compare the risk of incident fracture over five years among initiators of PPIs with initiators of histamine 2 receptor antagonist (H2RA) using data collected from The Health Improvement Network (THIN) database in the United Kingdom (2000–2016). The prevalence of PPIs prescription increased 3.8-fold from 2000 (7.9%) to 2012 (30.3%) and remained stable since then. Of the 50,265 propensity-score matched participants in each cohort (mean age was 65 years, and 57% were women), 370 (1.9/1000 person-years) incident hip fracture occurred in the PPIs initiators and 294 (1.5/1000 person-years) in the H2RA initiators during the follow-up period. The rate difference of incident hip fracture for PPIs initiation was 0.4 (95% confidence interval [CI]: 0.2–0.7)/1000 person-years compared with H2RA initiation and the corresponding hazard ratio (HR) was 1.27 (95%CI: 1.09–1.48). Compared with non-PPI use, multivariable-adjusted odds ratios (ORs) of hip fracture were 1.17 (95%CI: 0.94–1.46), 1.55 (95%CI: 1.23–1.96), and 1.67 (95%CI: 1.33–2.10) for 1–2, 3–9 and ≥ 10 prescriptions of PPIs, respectively (P for trend = 0.001). We found that PPIs prescription has been increasing rapidly over the past decade in the United Kingdom, and the initiation of PPIs was associated with a higher risk of hip fracture than initiation of H2RA. • No study has been conducted to compare the risk of fracture among PPI initiators with that among an active comparator. • Number of PPIs prescriptions for subjects aged 50 years and older had been increasing significantly over the past decade. • Initiation of PPIs was associated with a higher risk of hip fracture than initiation of a similarly medication, H2RA. • Our findings were independent of major confounding factors and were consistent in several sensitivity analyses. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the association of regular opioid use, compared with non-opioid analgesics, with incident dementia and neuroimaging outcomes among chronic pain patients., Design: The primary design is a prospective cohort study. To triangulate evidence, we also conducted a nested case-control study analyzing opioid prescriptions and a cross-sectional study analyzing neuroimaging outcomes., Setting and Participants: Dementia-free UK Biobank participants with chronic pain and regular analgesic use., Measurements: Chronic pain status and regular analgesic use were captured using self-reported questionnaires and verbal interviews. Opioid prescription data were obtained from primary care records. Dementia cases were ascertained using primary care, hospital, and death registry records. Propensity score-matched Cox proportional hazards analysis, conditional logistic regression, and linear regression were applied to the data in the prospective cohort, nested case-control, and cross-sectional studies, respectively., Results: Prospective analyses revealed that regular opioid use, compared with non-opioid analgesics, was associated with an increased dementia risk over the 15-year follow-up (Hazard ratio [HR], 1.18 [95% confidence interval (CI): 1.08-1.30]; Absolute rate difference [ARD], 0.44 [95% CI: 0.19-0.71] per 1000 person-years; Wald χ 2 = 3.65; df = 1; p <0.001). The nested case-control study suggested that a higher number of opioid prescriptions was associated with an increased risk of dementia (1 to 5 prescriptions: OR = 1.21, 95% CI: 1.07-1.37, Wald χ 2 = 3.02, df = 1, p = 0.003; 6 to 20: OR = 1.27, 95% CI: 1.08-1.50, Wald χ 2 = 2.93, df = 1, p = 0.003; more than 20: OR = 1.43, 95% CI: 1.23-1.67, Wald χ 2 = 4.57, df = 1, p < 0.001). Finally, neuroimaging analyses revealed that regular opioid use was associated with lower total grey matter and hippocampal volumes, and higher white matter hyperintensities volumes., Conclusion: Regular opioid use in chronic pain patients was associated with an increased risk of dementia and poorer brain health when compared to non-opioid analgesic use. These findings imply a need for re-evaluation of opioid prescription practices for chronic pain patients and, if further evidence supports causality, provide insights into strategies to mitigate the burden of dementia., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The incidence of gout in the UK appears to have declined since 2013; however, whether such a trend occurred across participants born in different years (ie, birth cohort) is unknown. We aimed to examine the effects of the birth cohort on gout incidence using an age-period-cohort (APC) model., Design: Cross-sectional study., Setting: Nationwide data from the UK primary care database., Participants: Individuals between 30 and 89 years of age were included. We excluded individuals who had gout history when entering the database and individuals with less than 1 year of continuous follow-up between 1 January 1999 and 31 December 2019., Primary and Secondary Outcome Measures: Gout was identified using READ codes assigned by general practitioners. The incidence of gout between 1999-2013 and 2011-2019 was analysed with APC model., Results: The incidence of gout between 1999 and 2013 increased with birth cohorts. Compared with those born in 1949-1953 (reference), the age-adjusted and period-adjusted rate ratios (RRs) of incident gout increased from 0.39 (95% CI 0.34 to 0.46) in participants born in 1910-1914 to 2.36 (95% CI 2.09 to 2.66) in participants born in 1979-1983 (p for trend <0.001). In contrast, the incidence of gout between 2011 and 2019 decreased with birth cohorts. Compared with those born in 1949-1953 (reference), the age-adjusted and period-adjusted RRs of incident gout declined from 2.75 (95% CI 2.30 to 3.28) in participants born in 1922-1926 to 0.75 (95% CI 0.65 to 0.87) in participants born in 1976-1980 but then increased slightly to 0.95 (95% CI 0.77 to 1.17) in participants born in 1985-1989., Conclusions: The gout incidence between 1999 and 2013 in the UK increased with the birth cohorts and then decreased between 2011 and 2019 except for those born after 1980. Future monitoring is needed to help identify aetiological factors and guide preventive and treatment strategies for gout., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Several professional organizations have recommended tramadol as one of the first-line or second-line therapies for patients with chronic noncancer pain and its prescription has been increasing rapidly worldwide; however, the safety profile of tramadol, such as risk of fracture, remains unclear. This study aimed to examine the association of tramadol with risk of hip fracture. Among individuals age 50 years or older without a history of hip fracture, cancer, or opioid use disorder in The Health Improvement Network (THIN) database in the United Kingdom general practice (2000-2017), five sequential propensity score-matched cohort studies were assembled, ie, participants who initiated tramadol or those who initiated one of the following medications: codeine (n = 146,956) (another commonly used weak opioid), naproxen (n = 115,109) or ibuprofen (n = 107,438) (commonly used nonselective nonsteroidal anti-inflammatory drugs [NSAIDs]), celecoxib (n = 43,130), or etoricoxib (n = 27,689) (cyclooxygenase-2 inhibitors). The outcome was incident hip fracture over 1 year. After propensity-score matching, the included participants had a mean age of 65.7 years and 56.9% were women. During the 1-year follow-up, 518 hip fracture (3.7/1000 person-years) occurred in the tramadol cohort and 401 (2.9/1000 person-years) occurred in the codeine cohort. Compared with codeine, hazard ratio (HR) of hip fracture for tramadol was 1.28 (95% confidence interval [CI] 1.13 to 1.46). Risk of hip fracture was also higher in the tramadol cohort than in the naproxen (2.9/1000 person-years for tramadol, 1.7/1000 person-years for naproxen; HR = 1.69, 95% CI 1.41 to 2.03), ibuprofen (3.4/1000 person-years for tramadol, 2.0/1000 person-years for ibuprofen; HR = 1.65, 95% CI 1.39 to 1.96), celecoxib (3.4/1000 person-years for tramadol, 1.8/1000 person-years for celecoxib; HR = 1.85, 95% CI 1.40 to 2.44), or etoricoxib (2.9/1000 person-years for tramadol, 1.5/1000 person-years for etoricoxib; HR = 1.96, 95% CI 1.34 to 2.87) cohort. In this population-based cohort study, the initiation of tramadol was associated with a higher risk of hip fracture than initiation of codeine and commonly used NSAIDs, suggesting a need to revisit several guidelines on tramadol use in clinical practice. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)