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Abstract: Paradoxical associations have been observed for leisure-time physical activity (LTPA) and occupational physical activity (OPA) and several health-related outcomes. Typically, higher LTPA is associated with health benefits and high OPA with health hazards. Using data from the Tromsø Study (2015-2016), we assessed how questionnaire-based LTPA and OPA (n = 21,083) and accelerometer-measured physical activity (PA) (n = 6778) relate to pain outcomes. Leisure-time physical activity and OPA were categorized as inactive PA, low PA, and moderate-to-vigorous PA and then aggregated into 9 levels, eg, inactive LTPA/inactive OPA. Accelerometer-measured PA included counts/minute, steps/day, and WHO PA recommendations from 2010 to 2020. Three binary pain outcomes (any pain, any chronic pain, and moderate-to-severe chronic pain) were constructed based on pain location, intensity, duration, and impact on daily activities. By using Poisson regression to estimate absolute and relative associations, we found that high LTPA was associated with lower pain prevalence and vice versa for OPA. Compared to inactive LTPA, prevalence ratio (PR) with 95% confidence intervals was lowest for moderate-to-vigorous LTPA, 0.93 (0.89-0.96) for any pain, 0.88 (0.84-0.93) for any chronic pain, and 0.66 (0.59-0.75) for moderate-to-severe chronic pain. Compared to sedentary OPA, the ratio was highest for moderate-to-vigorous OPA, 1.04 (1.01-1.07) for any pain, 1.06 (1.02-1.10) for any chronic pain, and 1.33 (1.21-1.46) for moderate-to-severe chronic pain. Aggregated LTPA and OPA showed lower outcomes for moderate-to-vigorous LTPA combined with lower levels of OPA. Higher levels of accelerometer-measured PA were associated with less pain. To summarize, we found inverse associations for LTPA and OPA. Benefits from LTPA seem to depend on low levels of OPA., (Copyright © 2024 International Association for the Study of Pain.)

Abstract: Female sex is a prominent risk factor for chronic pain, although the underlying mechanisms are not fully understood. This cross-sectional study aimed to investigate the relationship between age at menopause, reproductive lifespan, and chronic pain in a sample of postmenopausal women aged 40 to 93 years. Data were collected from the Tromsø study conducted in Norway between 2015 and 2016 (Tromsø7). Chronic pain was assessed using a single question, which formed a sample size of 5741 participants. Chronic widespread pain was evaluated using the more comprehensive Graphical Index of Pain, resulting in a sample size of 5920 women. Premenopausal women and those who experienced menstrual cessation due to chemotherapy/radiation or hormonal intrauterine devices were excluded from the analysis. Adjusted relative risk ratios with 95% confidence intervals were calculated to determine associations. The results showed that early menopause was associated with a 1% increase in the prevalence of chronic pain for each year of earlier onset at menopause (0.992, CI 95% 0.985-0.998). This association was also observed in women who experienced natural menopause only. However, the association between menopause and chronic widespread pain did not reach statistical significance in the fully adjusted analysis (0.996, CI 95% 0.975-1.017). There were no significant associations found between reproductive lifespan and either outcome. In conclusion, the findings suggest that early menopause in postmenopausal women is linked to a higher prevalence of chronic pain. However, reproductive lifespan does not appear to have a significant impact on chronic pain or chronic widespread pain., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Abstract: Chronic widespread pain (CWP) is prevalent and associated with reduced life expectancy. Cardiovascular disease is one possible mechanism for this. The purpose of this study was to examine the association of CWP with arterial stiffness and carotid plaque measured using ultrasound to determine if shared environmental or genetic factors might account for any observed association. Around 3000 participants from the TwinsUK with CWP information and measures of carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and plaque were considered. The relationship between CWP and cfPWV, cIMT, and plaque was determined. UK Biobank data were used to replicate the association. Cholesky decomposition and multivariate pathway twin models were examined. Using a 2-sample Mendelian randomisation approach, the causal association between CWP and coronary artery disease was assessed. TwinsUK participants demonstrated a significant association between CWP and increased cfPWV consistent with arterial stiffening (OR = 1.35, P-value = 0.012), as well as the presence of carotid plaque (OR = 1.45, P-value = 0.8e-5). The twin modelling showed a common latent component and pathway underlying CWP, cfPWV, and carotid plaque, with genetic factors accounting for 68% and 90% of the latent factor variation, respectively. The 2-sample MR revealed a potential causal association between CWP and coronary artery disease. This study found that those with CWP have increased the risk of arterial stiffness and atherosclerosis and suggests that CWP leads to an increased risk of cardiovascular disease through genetic factors., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Contemporary evidence-based indications no longer consider age regarding eligibility for medial unicompartmental knee arthroplasty (mUKA). This has led to more surgical candidates; however, whether patients still have satisfactory outcomes lacks evidence. This study examined the association between age and change in patient-reported outcome measures after mUKA as well as the achievement of patient acceptable symptom state (PASS) and minimal important change (MIC)., Methods: We included 782 mUKAs performed between February 1, 2016, and April 26, 2023. The mean change from preoperative Oxford knee score (OKS), forgotten joint score (FJS), and activity and participation questionnaire (APQ) was assessed at 3, 12, and 24 months after surgery, respectively. The achievement of 12-month PASS (OKS ≥ 30) and MIC (changes in OKS ≥ 8; FJS ≥ 14) was also assessed. Patients were divided into the following age groups: <55, 55 to < 65, 65 to < 75 years (reference group), and ≥ 75 years. There were 432 women (55%), and patients had a mean age of 67 years (range, 29 to 93) and a mean body mass index of 30 (range, 20 to 53)., Results: Median OKS, youngest to eldest, were 34, 35, 36, and 35 (3 months); 40, 39, 41, and 43 (12 months); 42, 41, 43, and 42 (24 months), respectively. We found no differences in change in OKS between groups. Patients aged 55 to < 65 years had lower changes in FJS at 24 months and APQ at 12 and 24 months. Patients ≥ 75 years had lower 24-month changes in APQ. We found no association between age and the fraction achieving either PASS or MIC (youngest to eldest, 90, 90, 94, and 95%)., Conclusions: We found good patient-reported outcome measures improvements and satisfactory outcomes after mUKA in all age groups; however, patients aged 55 to < 65 years had worse changes in FJS and APQ. Results support contemporary indications for mUKA, and applying an age cutoff is unwarranted., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: Knowledge is needed regarding mechanisms acting between physical activity (PA) and chronic pain. We investigated whether cold pain tolerance mediates an effect of leisure-time physical activity on the risk of chronic pain 7 to 8 years later using consecutive surveys of the population-based Tromsø Study. We included participants with information on baseline leisure-time PA (LTPA) and the level of cold pressor-assessed cold pain tolerance, who reported chronic pain status at follow-up as any of the following: chronic pain for ≥3 months, widespread chronic pain, moderate-to-severe chronic pain, or widespread moderate-to-severe chronic pain. We included 6834 participants (52% women; mean age, 55 years) in counterfactual mediation analyses. Prevalence decreased with severity, for example, 60% for chronic pain vs 5% for widespread moderate-to-severe chronic pain. People with one level higher LTPA rating (light to moderate or moderate to vigorous) at baseline had lower relative risk (RR) of 4 chronic pain states 7 to 8 years later. Total RR effect of a 1-level LTPA increase was 0.95 (0.91-1.00), that is, -5% decreased risk. Total effect RR for widespread chronic pain was 0.84 (0.73-0.97). Indirect effect for moderate-to-severe chronic pain was statistically significant at RR 0.993 (0.988-0.999); total effect RR was 0.91 (0.83-0.98). Statistically significantly mediated RR for widespread moderate-to-severe chronic pain was 0.988 (0.977-0.999); total effect RR was 0.77 (0.64-0.94). This shows small mediation of the effect of LTPA through pain tolerance on 2 moderate-to-severe chronic pain types. This suggests pain tolerance to be one possible mechanism through which PA modifies the risk of moderate-to-severe chronic pain types with and without widespread pain., (Copyright © 2024 International Association for the Study of Pain.)

In a Norwegian youth cohort followed from adolescence to young adulthood, bone mineral density (BMD) levels declined at the femoral neck and total hip from 16 to 27 years but continued to increase at the total body indicating a site-specific attainment of peak bone mass., Purpose: To examine longitudinal trends in bone mineral density (BMD) levels in Norwegian adolescents into young adulthood., Method: In a prospective cohort design, we followed 980 adolescents (473 (48%) females) aged 16-19 years into adulthood (age of 26-29) on three occasions: 2010-2011 (Fit Futures 1 (FF1)), 2012-2013 (FF2), and 2021-2022 (FF3), measuring BMD (g/cm 2 ) at the femoral neck, total hip, and total body with dual x-ray absorptiometry (DXA). We used linear mixed models to examine longitudinal BMD changes from FF1 to FF3., Results: From the median age of 16 years (FF1), femoral neck BMD (mean g/cm 2 (95% CI)) slightly increased in females from 1.070 (1.059-1.082) to 1.076 (1.065-1.088, p = 0.015) at the median age of 18 years (FF2) but declined to 1.041 (1.029-1.053, p < 0.001) at the median age of 27 years (FF3). Similar patterns were observed in males: 16 years, 1.104 (1.091-1.116); 27 years, 1.063 (1.050-1.077, p < 0.001); and for the total hip in both sexes (both p < 0.001). Total body BMD increased from age 16 to 27 years in both sexes (females: 16 years, 1.141 (1.133-1.148); 27 years, 1.204 (1.196-1.212), p < 0.001; males: 16 years, 1.179 (1.170-1.188); 27 years, 1.310 (1.296-1.315), p < 0.001)., Conclusion: BMD levels increased from 16 to 18 years at the femoral and total hip sites in young Norwegian females and males, and a small decline was observed at the femoral sites when the participants were followed up to 27 years. Total body BMD continued to increase from adolescence to young adulthood., (© 2024. The Author(s).)

Aim: To assess the relationship between periodontitis and experimental pain tolerance., Materials and Methods: Participants from the population-based seventh survey of the Tromsø Study with data on periodontitis were included (n = 3666, 40-84 years old, 51.6% women). Pain tolerance was assessed through (i) pressure pain tolerance (PPT) test with a computerized cuff pressure algometry on the leg, and (ii) cold-pressor tolerance (CPT) test where one hand was placed in circulating 3°C water. Cox proportional hazard regression was used to assess the association between periodontitis and pain tolerance adjusted for age, sex, education, smoking and obesity., Results: In the fully adjusted model using the 2012 Centers for Disease Control/American Academy of Periodntology case definitions for surveillance of periodontitis, moderate (hazard ratio [HR] = 1.09; 95% confidence interval [CI]: 1.01, 1.18) and severe (HR = 1.25, 95% CI: 1.11, 1.42) periodontitis were associated with decreased PPT. Using the 2018 classification of periodontitis, having Stage II/III/IV periodontitis was significantly associated with decreased PPT (HR = 1.09; 95% CI: 1.01, 1.18) compared with having no or stage I periodontitis. There were no significant associations between periodontitis and CPT in fully adjusted models., Conclusions: Moderate and severe periodontitis was associated with experimental PPT., (© 2024 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Background: Chronic pain is a condition with severe impact on many aspects of life, including work, functional ability and quality of life, thereby reducing physical, mental and social well-being. Despite the high prevalence and burden of chronic pain, it has received disproportionally little attention in research and public policy and the societal costs of chronic pain remain largely unknown. This study aimed to describe the long-term healthcare and work absence costs of individuals with and without self-identified chronic pain., Methods: The study population were participants in two Norwegian population health studies (HUNT3 and Tromsø6). Participants were defined as having chronic pain based on a self-reported answer to a question on chronic pain in the health studies in 2008. Individuals in the study population were linked to four national register databases on healthcare resource use and work absence., Results: In our study, 36% (n = 63,782) self-reported to have chronic pain and the average years of age was 56.6. The accumulated difference in costs between those with and without chronic pain from 2010 to 2016 was €55,003 (CI: 54,414-55,592) per individual. Extrapolating this to the entire population suggests that chronic pain imposes a yearly burden of 4% of GDP. Eighty per cent of the costs were estimated to be productivity loss., Conclusion: Insights from this study can provide a greater understanding of the extent of healthcare use and productivity loss by those with chronic pain and serve as an important basis for improvements in rehabilitation and quality of care, and the education of the public on the burden of chronic pain., Significance: This was the first study to estimate the economic burden associated with chronic pain in the general population using linked individual-level administrative data and self-reported survey answers. We provide calculations showing that annual costs of chronic pain may be as high as €12 billion or 4% of GDP. Findings from this study highlight the need for a greater understanding of the substantial healthcare use and productivity losses among individuals with chronic pain., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Arctic and alpine tundra ecosystems are large reservoirs of organic carbon 1,2 . Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere 3,4 . The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain 5-7 . This hampers the accuracy of global land carbon-climate feedback projections 7,8 . Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9-2.0 °C] in air and 0.4 °C [CI 0.2-0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22-38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration., (© 2024. The Author(s).)

Objectives: Previous studies have suggested that experimental pain sensitivity is associated with cognitive function. The aim of this study is to assess this relationship in a large population-based sample., Methods: We included 5,753 participants (aged 40-84 years) from the seventh wave of the population-based Tromsø Study who had been examined with cognitive tests and experimental pain assessments, and for whom information on covariates were available. Cox regression models were fitted using standardized scores on cognitive tests (12-word immediate recall test, digit symbol coding test, and Mini-Mental State Examination [MMS-E]) as the independent variable and cold pressor or cuff pressure pain tolerance as the dependent variables. Statistical adjustment was made for putative confounders, namely, age, sex, education, smoking, exercise, systolic blood pressure, body mass index, symptoms indicating anxiety or depression, analgesic use, and chronic pain., Results: In multivariate analysis, cold pressor tolerance time was significantly associated with test scores on the 12-word immediate recall test (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.90-0.97, p < 0.001), the digit symbol coding test (HR 0.94, 95% CI 0.89-0.98, p = 0.004), and the MMS-E (HR 0.93, 95% CI 0.90-0.96 p < 0.001). Tolerance to cuff pressure algometry was significantly associated with 12-word immediate recall (HR 0.94-0.97, p < 0.001) and Digit Symbol Coding test scores (HR 0.93, 95% CI 0.89-0.96, p < 0.001) while there was no significant association with Mini Mental State Examination test score (HR 0.98, 95% CI 0.95-1.00, p = 0.082)., Conclusion: Lower pain tolerance was associated with poorer performance on cognitive tests., (© 2024 the author(s), published by De Gruyter.)

Background: Few previous studies have assessed overall morbidity at the individual level with respect to future risk of hip fracture. The aim of this register-based cohort study was to examine the association between morbidity measured by the medication-based Rx-Risk Comorbidity Index (Rx-Risk) and the risk of first hip fracture., Methods: Individual-level data on medications dispensed from pharmacies (2005-2016) was retrieved from the Norwegian Prescription Database and used to calculate Rx-Risk for each calendar year. Information on first hip fractures (2006-2017) was obtained from a nationwide hip fracture database. Individuals ≥ 51 years who filled at least one prescription during the study period comprised the population at risk. Using Rx-Risk as a time-varying exposure variable, relative risk estimates were obtained by a negative binomial model., Results: During 2006-2017, 94,104 individuals sustained a first hip fracture. A higher Rx-Risk was associated with increased risk of hip fracture within all categories of age and sex. Women with the highest Rx-Risk (> 25) had a relative risk of 6.1 (95% confidence interval (CI): 5.4, 6.8) compared to women with Rx-Risk ≤ 0, whereas the corresponding relative risk in women with Rx-Risk 1-5 was 1.4 (95% CI: 1.3, 1.4). Similar results were found in men. Women > 80 years with Rx-Risk 21-25 had the highest incidence rate (514 (95% CI: 462, 566) per 10, 000 person years). The relative increase in hip fracture risk with higher Rx-Risk was most pronounced in the youngest patients aged 51-65 years., Conclusions: Rx-Risk is a strong predictor of hip fracture in the general outpatient population and may be useful to identify individuals at risk in a clinical setting and in future studies., (© 2024. The Author(s).)

Background and Purpose: The overall potential pool of day-case candidates on a national level in hip and knee arthroplasty is unknown. We aimed to estimate the proportion of hip and knee arthroplasty patients eligible for day-case surgery based on contemporary widely used criteria and determine whether there has been a change in the proportion of eligible patients over time and, secondarily, to investigate the proportion of eligible patients discharged on the day of surgery., Methods: Based on data from the Danish National Patient Register, we identified all patients undergoing primary unilateral hip or knee arthroplasty from January 2010 to March 2020. Using a modification of day-case eligibility criteria proposed by a national multicenter collaboration, we sorted patients into either day-case eligible or ineligible. A day-case procedure was defined as discharge on the day of surgery., Results: We included patients comprising a total of 166,730 primary total hip (THA), total knee (TKA), and unicompartmental knee arthroplasty (UKA). 48% (95% confidence interval [CI] 48-49) were eligible for day-case surgery, with a decline from 50% (CI 49-51) in 2010 to 46% (CI 46-47) eligible in 2019. More UKA patients were day-case eligible (55%, CI 54-56) than THA (47%, CI 47-48) and TKA patients (49%, CI 48-49). A maximum of 8.0% (CI 7.4-8.5) of eligible patients were discharged on the day of surgery in 2019., Conclusion: 48% of the Danish hip and knee arthroplasty patients were potential day-case candidates, with a small decline in eligibility from 50% in 2010 to 46% in 2019. Day of surgery discharge among day-case eligible patients peaked at 8% in 2019. Thus, the potential for more day-case surgery seems large.

Context: Longitudinal data regarding vitamin D status in adolescence is scarce. This study presents population-based data from an Arctic adolescent population (n = 589) at 16 and 18 years., Objective: The aims of this study were to investigate changes in vitamin D status during 2 years in adolescence, and whether lifestyle changes were associated with serum 25-hydroxyvitamin D (s-25(OH)D) at follow-up., Methods: Fit Futures is a longitudinal study at 69°N in Norway. Participants had their s-25(OH)D levels analyzed in their first and third year of upper secondary school (median age 16 and 18 years), in Fit Futures 1 (FF1) and Fit Futures 2 (FF2), respectively. Self-reported lifestyle habits were registered through questionnaires. The association between lifestyle changes and s-25(OH)D levels at follow-up were calculated by regression analyses, controlling for baseline s-25(OH)D levels., Results: Longitudinal data were available for 309 girls and 280 boys. The proportion of adolescents with s-25(OH)D <50 nmol/L were 73.7% in FF1 and 77.1% in FF2, while the proportion <30 nmol/L constituted 35.7% in FF1 and 40.9% in FF2. Of those with s-25(OH)D <30 nmol/L (severe vitamin D deficiency) in FF1, 73.3% remained severely deficient in FF2. Among boys, an increase in UV exposure was significantly associated with higher s-25(OH)D levels in FF2 (beta; CI [nmol/L] 12.9; 9.1, 16.7). In girls, decreased vitamin/mineral supplement intake was significantly associated with lower s-25(OH)D at FF2 (-6.7; -10.2, -3.1), while increased UV (10.8; 7.0, 14.7) and combined hormonal contraceptive exposure (12.1; 6.0, 18.1) in FF2 was significantly associated with higher s-25(OH)D levels in FF2., Conclusion: Severe vitamin D deficiency was prevalent throughout adolescence. Lifestyle changes may alter s-25(OH)D levels in this age group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background and Purpose: Day-case hip and knee arthroplasty has gained in popularity, but there are conflicting results regarding readmissions. We aimed to investigate differences in 30- and 90-day readmission rates between day-case patients and patients with a single overnight stay following primary total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA)., Patients and Methods: We identified day-case (DC) and overnight (ON) THA, TKA, and UKA patients, operated on between 2010 and 2020, from the Danish National Patient Register. Day-case surgery was defined as discharge on the day of surgery. Overnight readmissions within 30 or 90 days of surgery were considered readmissions. We compared readmission rates between DC and ON patients within arthroplasty types using logistic regression adjusted for patient characteristics and year of surgery. We included 29,486 THAs (1,353 DC and 28,133 ON), 15,116 TKAs (617 DC and 14,499 ON), and 6,440 UKAs (1,528 DC and 4,914 ON)., Results: The 30-day readmission rates were: DC-THA 4.4% vs. ON-THA 4.4% (adjusted odds-ratio [aOR] 1.2, 95% confidence interval [CI] 0.91-1.6), DC-TKA 4.7% vs. ON-TKA 4.4% (aOR 1.1, CI 0.69-1.5), and DC-UKA 3.0% vs. ON-UKA 3.0% (aOR 1.1, CI 0.78-1.5). Similarly, no significant differences were present between DC and ON THA, TKA, and UKA regarding 90-day readmissions or time to readmission., Conclusion: We found no differences in readmission rates between day-case THA, TKA, and UKA patients and patients with a single overnight stay.

Objectives: Accumulating evidence has revealed that dental anxiety is robustly associated with dental care-related pain and discomfort, but also with the personality trait of neuroticism (i.e. the relatively stable disposition to experience the world as distressing, threatening and unsafe). However, there is a near absence of research on these risk factors in samples for which genetic information is available. With the aim of arriving at a more refined understanding of dental anxiety, this twin cohort study assessed genetic and environmental influences on neuroticism, dental care-related pain and dental anxiety, and the relation between these phenotypes., Methods: Participants were recruited from the Norwegian Twin Registry, and data collections were carried out in 1992-98 (Time 1) and 2011 (Time 2). Well-validated questionnaires were used to assess the study variables, including Corah's Dental Anxiety Scale, the Numerical Pain Rating Scale, the NEO Personality Inventory Revised (Time 2) and Eysenck's Personality Questionnaire (Time 1). Pearson correlation analysis and generalized estimating equations (GEE) were used to investigate phenotypic associations. Analyses of genetic and environmental influences were performed using Cholesky modelling., Results: A total of 746 monozygotic (MZ) and 770 dizygotic (DZ) twins in the age group of 50-65 participated in the study. Moderate estimates of heritability for dental anxiety (0.29), treatment-related pain (0.24) and neuroticism (0.45-0.54) were found. Cholesky modelling showed furthermore that neuroticism assessed at Time 1 and Time 2 was related to dental anxiety and pain via both genetic and individual-specific environmental pathways, albeit not very strongly. The particularly high phenotypic correlation observed between dental care-related pain and anxiety (r = .68) was explained by both overlapping genetic and individual-specific environmental influences (the genetic and environmental correlations were .84 and .63 respectively)., Conclusions: The findings provide deeper insight into the aetiology of dental anxiety and confirm that while it is strongly linked to treatment-related pain experiences, this relation is to a considerable degree independent of general negative affectivity/neuroticism., (© 2022 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Background: Polyautoimmunity is defined as having 2 or more autoimmune diseases. Little is known about polyautoimmunity in patients with cutaneous lupus erythematosus (CLE)., Objectives: To estimate prevalence and 5-year incidence of non-lupus erythematosus (LE) autoimmune diseases in patients with CLE., Methods: Patients with CLE were identified In the Danish National Patient Registry and each patient was age- and sex-matched with 10 general population controls. Outcome information on non-LE autoimmune diseases was obtained by register-linkage between Danish National Patient Registry and the National Prescription Register. The risk ratio (RR) for prevalent non-LE autoimmune disease at time of CLE diagnosis was calculated in modified Poisson regression; and hazard ratios (HRs) for incident non-LE autoimmune disease were estimated in Cox regression analyses., Results: Overall, 1674 patients with CLE had a higher prevalence of a non-LE autoimmune disease than the comparators (18.5 vs 7.9%; RR 2.4; 95% CI, 2.1 to 2.6). Correspondingly, the cumulative incidence of a non-LE autoimmune disease during 5 years of follow-up was increased for the patients with CLE: HR 3.5 (95% CI, 3.0 to 4.0)., Limitations: Risk of detection and misclassification bias, mainly pertaining to the CLE group., Conclusion: Patients with CLE had higher prevalence and 5-year cumulative incidence of a non-LE autoimmune disease than the general population., Competing Interests: Dr Cordtz is employed at IQVIA outside of this work. Dr Dreyer has received speakers fee from Eli Lilly, Galderma, and Janssen and research grants from BMS (outside the present work). Drs Kofoed, Stensballe, Bliddal, Kristensen, Feldt-Rasmussen, and Nielsen and Authors Graven-Nielsen, Vittrup, Kragh, and Lund have no conflicts of interest to declare., (© 2023 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Background: Stroke lesions might alter pain processing and modulation by affecting the widely distributed network of brain regions involved. We aimed to compare pain tolerance in stroke survivors and stroke-free persons in the general population, with and without chronic pain., Methods: We included all participants of the sixth and seventh wave of the population-based Tromsø Study who had been tested with the cold pressor test (hand in cold water bath, 3°C, maximum time 106 s in the sixth wave and 120 s in the seventh) and who had information on previous stroke status and covariates. Data on stroke status were obtained from the Tromsø Study Cardiovascular Disease Register and the Norwegian Stroke Register. Cox regression models were fitted using stroke prior to study attendance as the independent variable, cold pressor endurance time as time variable and hand withdrawal from cold water as event. Statistical adjustments were made for age, sex, diabetes, hypertension, hyperlipidaemia, body mass index and smoking., Results: In total 21,837 participants were included, 311 of them with previous stroke. Stroke was associated with decreased cold pain tolerance time, with 28% increased hazard of hand withdrawal (hazard ratio [HR] 1.28, 95% CI 1.10-1.50). The effect was similar in participants with (HR 1.28, 95% CI 0.99-1.66) and without chronic pain (HR 1.29, 95% CI 1.04-1.59)., Conclusions: Stroke survivors, with and without chronic pain, had lower cold pressor pain tolerance, with possible clinical implications for pain in this group., Significance: We found lower pain tolerance in participants with previous stroke compared to stroke-free participants of a large, population-based study. The association was present both in those with and without chronic pain. The results may warrant increased awareness by health professionals towards pain experienced by stroke patients in response to injuries, diseases and procedures., (© 2023 European Pain Federation - EFIC®.)

Site-selective disulfide rebridging has emerged as a powerful strategy to modulate the structural and functional properties of proteins. Here, we introduce a novel class of electrophilic reagents, designated oxSTEF, that demonstrate excellent efficiency in disulfide rebridging via double thiol exchange. The oxSTEF reagents are prepared using an efficient synthetic sequence which may be diverted to obtain a range of derivatives allowing for tuning of reactivity or steric bulk. We demonstrate highly selective rebridging of cyclic peptides and native proteins, such as human growth hormone, and the absence of cross-reactivity with other nucleophilic amino acid residues. The oxSTEF conjugates undergo glutathione-mediated disintegration under tumor-relevant glutathione concentrations, which highlights their potential for use in targeted drug delivery. Finally, the α-dicarbonyl motif of the oxSTEF reagents enables "second phase" oxime ligation, which furthermore increases the thiol stability of the conjugates significantly.

Physical activity (PA) might influence the risk or progression of chronic pain through pain tolerance. Hence, we aimed to assess whether habitual leisure-time PA level and PA change affects pain tolerance longitudinally in the population. Our sample (n = 10,732; 51% women) was gathered from the sixth (Tromsø6, 2007-08) and seventh (Tromsø7, 2015-16) waves of the prospective population-based Tromsø Study, Norway. Level of leisure-time PA (sedentary, light, moderate, or vigorous) was derived from questionnaires; experimental pain tolerance was measured by the cold-pressor test (CPT). We used ordinary, and multiple-adjusted mixed, Tobit regression to assess 1) the effect of longitudinal PA change on CPT tolerance at follow-up, and 2) whether a change in pain tolerance over time varied with level of LTPA. We found that participants with high consistent PA levels over the two surveys (Tromsø6 and Tromsø7) had significantly higher tolerance than those staying sedentary (20.4 s. (95% CI: 13.7, 27.1)). Repeated measurements show that light (6.7 s. (CI 3.4, 10.0)), moderate (CI 14.1 s. (9.9, 18.3)), and vigorous (16.3 s. (CI 6.0, 26.5)) PA groups had higher pain tolerance than sedentary, with non-significant interaction showed slightly falling effects of PA over time. In conclusion, being physically active at either of two time points measured 7-8 years apart was associated with higher pain tolerance compared to being sedentary at both time-points. Pain tolerance increased with higher total activity levels, and more for those who increased their activity level during follow-up. This indicates that not only total PA amount matters but also the direction of change. PA did not significantly moderate pain tolerance change over time, though estimates suggested a slightly falling effect possibly due to ageing. These results support increased PA levels as a possible non-pharmacological pathway towards reducing or preventing chronic pain., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Årnes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: No previous studies have investigated the use of day-case arthroplasty in Denmark on a national scale. We investigated the frequency of day-case surgery in total hip (THA), total knee (TKA), and unicompartmental knee arthroplasty (UKA) from 2010 to 2020 in Denmark., Patients and Methods: Primary unilateral THAs, TKAs, and UKAs performed for osteoarthritis were identified in the Danish National Patient Register using procedural and diagnosis codes. Day-case surgery was defined as discharge on the day of surgery. 90-day readmissions were defined as any overnight admissions following discharge., Results: From 2010 to 2020 Danish surgical centers performed 86,070 THAs, 70,323 TKAs, and 10,440 UKAs. From 2010 to 2014, less than 0.5% of THAs and TKAs were day-case procedures. They increased to 5.4% (95% confidence interval [CI] 4.9-5.8) of THAs and 2.8% (CI 2.4-3.2) of TKAs in 2019. From 2010 to 2014, 11% of UKAs were day-case procedures, but they increased to 20% (CI 18-22) in 2019. This increase was driven by a few surgical centers (3-7 centers). In 2010, readmission rates within 90 days of surgery were 10% after THAs and 11% after TKAs, and 9.4% for both THAs and TKAs in 2019. Readmission rates after UKA fluctuated between 4% and 7%., Conclusion: From 2010 to 2020 the use of day-case surgery in THA, TKA, and UKA increased in Denmark, driven by only a few centers. During the same period readmissions did not increase.

Abstract: Epidemiological literature on the relationship between physical activity and chronic pain is scarce and inconsistent. Hence, our aim was to assess the relationship applying comprehensive methodology, including self-reported and accelerometer measures of physical activity and different severity levels of chronic pain. We used data from the Tromsø Study (2015-2016). All residents in the municipality, aged 40 years and older were invited to participate (n = 32,591, 51% women). A total of 21,083 (53%) women reported on questionnaires. Additionally, 6778 participants (54% women) were invited to wear accelerometers (6125 with complete measurements). Our exposure measures were self-reported leisure time physical activity, exercise frequency, duration, and intensity and 2 accelerometer measures (steps per day and minutes of moderate to vigorous physical activity per day). Outcome measurements were chronic pain and moderate-to-severe chronic pain. We used Poisson regression to estimate chronic pain prevalence and prevalence ratios for each physical activity measure, with adjustments for sex, age, education level, smoking history, and occupational physical activity. Our main analyses showed an inverse dose-response relationship between all physical activity measures and both severity measures of chronic pain, except that the dose-response relationship with exercise duration was only found for moderate-to-severe pain. All findings were stronger for the moderate-to-severe pain outcomes than for chronic pain. Robustness analyses gave similar results as the main analyses. We conclude that an inverse dose-response association between physical activity and chronic pain is consistent across measures. To summarize, higher levels of physical activity is associated with less chronic pain and moderate-to-severe chronic pain., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.

Background: In this study, we examined the association between obesity and patient-reported outcome measures after medial unicompartmental knee arthroplasty (MUKA), assessed through score changes, Patient Acceptable Symptom State (PASS), and minimal important change (MIC). Second, the association between obesity and early readmissions was examined., Methods: A total of 450 MUKAs (mean body mass index [BMI] 30.3, range, 19.6-53.1), performed from February 2016 to December 2020, were grouped using BMI: <30, 30-34.9, and >34.9. Oxford Knee Score (OKS), Forgotten Joint Score (FJS), and Activity and Participation Questionnaire (APQ) were assessed preoperatively and at 3, 12, and 24 months, postoperatively. The 12-month PASS and MIC were also assessed, defining PASS as OKS = 30, MIC-OKS as change in OKS = 8, and MIC-FJS as change in FJS = 14., Results: No significant differences in OKS change were found between BMI groups. After 12 months, patients who had a BMI of 30-34.9 had lower change in FJS (estimate -8.1, 95% CI -14.9 to -1.4) and were less likely to reach PASS (odds ratio 0.4, 95% CI 0.2-0.7) as well as MIC-FJS (odds ratio 0.5, 95% CI 0.2-0.9). Both obese groups had lower change in APQ after 12 months. Differences in 90-day readmission rates were nonsignificant between groups., Conclusion: Our findings of no differences in OKS improvement between BMI groups and achieving MIC for BMI > 34.9 suggest good improvements in obese patients despite lower preoperative scores, supporting contemporary indications for MUKA. Lower APQ development and achievement of 12-month PASS may be used when addressing expectations of recovery., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The PRECISE Study, a multi-phase cross-sectional seroprevalence study of anti-SARS-CoV-2 antibodies in Irish healthcare workers (HCW) investigated: (1) risk factors for SARS-CoV-2 seropositivity, (2) the durability of antibody responses in a highly vaccinated HCW cohort, and (3) the neutralisation capacity of detected antibodies, prior to booster COVID-19 vaccination., Materials and Methods: Serology samples were collected across two hospital sites in November 2021 and analysed using the Roche Elecsys Anti-SARS-CoV-2/Elecsys-S Anti-SARS-CoV-2 assays to detect anti-nucleocapsid (N) and anti-spike (S) antibodies respectively. Paired serology results from prior study phases were used to analyse changes in individual HCW serostatus over time. Risk-factors for SARS-CoV-2 infection were assessed for demographic and work-related factors. Antibody neutralisation capacity was assessed in a subset of samples via an in vitro ACE2 binding enzyme-linked immunosorbent assay., Results: 2,344 HCW samples were analysed. Median age was 43 years (IQR 33-50) with 80.5% ( n = 1,886) female participants. Irish (78.9%, n = 1,850) and Asian (12.3%, n = 288) were the most commonly reported ethnicities. Nursing/midwifery (39.3%, n = 922) was the most common job role. 97.7% of participants were fully vaccinated, with Pfizer (81.1%, n = 1,902) and AstraZeneca (16.1%, n = 377) the most common vaccines received. Seroprevalence for anti-SARS-CoV-2 antibodies indicating prior infection was 23.4%, of these 33.6% represented previously undiagnosed infections. All vaccinated participants demonstrated positive anti-S antibodies and in those with paired serology, no individual demonstrated loss of previously positive anti-S status below assay threshold for positivity. Interval loss of anti-N antibody positivity was demonstrated in 8.8% of previously positive participants with paired results. Risk factors for SARS-CoV-2 seropositivity suggestive of previous infection included age 18-29 years (aRR 1.50, 95% CI 1.19-1.90, p < 0.001), India as country of birth (aRR 1.35, 95% CI 1.01-1.73, p = 0.036), lower education level (aRR 1.35, 95% CI 1.11-1.66, p = 0.004) and HCA job role (aRR 2.12, 95% CI 1.51-2.95, p < 0.001). Antibody neutralisation varied significantly by anti-SARS-CoV-2 antibody status, with highest levels noted in those anti-N positive, in particular those with vaccination plus previous SARS-CoV-2 infection., Conclusion: All vaccinated HCWs maintained anti-S positivity prior to COVID-19 booster vaccination, however anti-N positivity was more dynamic over time. Antibody neutralisation capacity was highest in participants with COVID-19 vaccination plus prior SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McGrath, Kenny, Nielsen, Domegan, Walsh, Rooney, Walsh, Conlon, Brady, Ibrahim, Dunne, McCormack, Corcoran, Allen, Fleming and Bergin.)

There is limited knowledge on the association between different health complaints and the development of persistent musculoskeletal pain in adolescents. The aims of this study were to assess whether specific health complaints, and an accumulation of health complaints, in the first year of upper-secondary school, were associated with persistent musculoskeletal pain 2 years later. We used data from a population-based cohort study (the Fit Futures Study in Norway), including 551 adolescents without persistent musculoskeletal pain at baseline. The outcome was persistent musculoskeletal pain (≥3 months) 2 years after inclusion. The following self-reported health complaints were investigated as individual exposures at baseline: asthma, allergic rhinitis, atopic eczema, headache, abdominal pain and psychological distress. We also investigated the association between the accumulated number of self-reported health complaints and persistent musculoskeletal pain 2 years later. Logistic regression analyses estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs). At the 2-year follow-up, 13.8% (95% CI [11.2-16.9]) reported persistent musculoskeletal pain. Baseline abdominal pain was associated with persistent musculoskeletal pain 2 years later (OR 2.33, 95% CI [1.29-4.19], p = 0.01). Our analyses showed no statistically significant associations between asthma, allergic rhinitis, atopic eczema, headache or psychological distress and persistent musculoskeletal pain at the 2-year follow-up. For the accumulated number of health complaints, a higher odds of persistent musculoskeletal pain at the 2-year follow-up was observed for each additional health complaint at baseline (OR 1.33, 95% CI [1.07-1.66], p = 0.01). Health care providers might need to take preventive actions in adolescents with abdominal pain and in adolescents with an accumulation of health complaints to prevent development of persistent musculoskeletal pain. The potential multimorbidity perspective of adolescent musculoskeletal pain is an important topic for future research to understand the underlying patterns of persistent pain conditions in adolescents., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Smedbråten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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 sizes 1 . 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 panel 2 ) 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., (© 2022. The Author(s).)

Objectives: Staphylococcus aureus carriage increases the risk of infection. We used social network analysis to evaluate whether contacts have the same S. aureus genotype indicating direct transmission or whether contagiousness is an indirect effect of contacts sharing the same lifestyle or characteristics., Methods: The Fit Futures 1 study collected data on social contact among 1038 high school students. S. aureus carriage was determined from two nasal swab cultures and the genotype was determined by spa-typing of positive throat swabs., Results: S. aureus carriage and spa-type were transmitted in the social network (P < 0.001). The probability of carriage increased by 5% for each S. aureus positive contact. Male sex was associated with a 15% lower risk of transmission compared to the female sex, although the carriage prevalence was higher for men (36% vs 24%). Students with medium physical activity levels, medium/high alcohol use, or normal weight had a higher number of contacts and an increased risk of transmission (P < 0.002)., Conclusion: We demonstrated the direct social transmission of S. aureus. Lifestyle factors are associated with the risk of transmission, suggesting the effects of indirect social groups on S. aureus carriage, such as friends having more similar environmental exposures. The male predominance in the carriage is determined by sex-specific predisposing host characteristics as the social transmission is less frequent in males than females. Information on social networks may add to a better understanding of S. aureus epidemiology., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare, (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract: Sex differences in chronic pain are well established with documented predominance in women. This study assessed relationships between age at menarche and chronic pain, site-specific chronic pain, pain characteristics, and chronic widespread pain (CWP). We used data from the Tromsø Study conducted in 2007 to 2008 and 2015 to 2016 (Tromsø 6 and Tromsø 7 waves) including participants aged 30 to 99 years. The associations between age at menarche and chronic pain were examined in Tromsø 6 (n = 6449), Tromsø 7 (n = 5681), and the combination of Tromsø 6 and Tromsø 7 (n = 12,130). Tromsø 7 data were used further to examine the associations between age at menarche and site-specific chronic pain, 4 pain characteristics (pain duration, pain intensity, episode duration, and episode frequency), and CWP. All analyses were adjusted for body mass index, age, and economic status of the household in childhood. Lower age at menarche was associated with an increased risk of chronic pain in all 3 samples (risk ratio for each year delay in menarche 0.98, 95% CI [0.97 to 0.99] across samples). Risk differences were -0.014, CI 95% (-0.02 to -0.005) in Tromsø 6, -0.011, CI 95% (-0.02 to -0.02) in Tromsø 7, and -0.012, CI 95% (-0.02 to -0.01) in the combined sample. Age at menarche was significantly associated with chronic pain in the neck, abdomen, and both arms, and CWP. Of the 4 pain characteristics, pain duration was statistically significant. We conclude that early menarche is an independent risk factor for pain across a broad spectrum of pain outcomes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Both diabetes mellitus (DM) and the metabolic syndrome (MetS) are associated with autonomic neuropathy, which predisposes to cardiac events and death. Measures of heart rate variability (HRV) can be used to monitor the activity of the autonomic nervous system (ANS), and there are strong indications that HRV can be used to study the progression of ANS-related diabetes complications. This study aims to investigate differences in HRV in healthy, MetS and diabetic populations. Based on 7880 participants from the sixth health survey in Tromsø (Tromsø 6, 2007-2008), we found a significant negative association between the number of MetS components and HRV as estimated from short-term pulse wave signals (PRV). This decrease in PRV did not appear to be linear, instead it leveled off after the third component, with no significant difference in PRV between the MetS and DM populations. There was a significant negative association between HbA1c and PRV, showing a decrease in PRV occurring already within the normal HbA1c range. The MetS and DM populations are different from healthy controls with respect to PRV, indicating impaired ANS in both conditions. In the future, a study with assessment of PRV measurements in relation to prospective cardiovascular events seems justified., (© 2022. The Author(s).)

Context: Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age., Objective: We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI)., Methods: Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established "LMS" growth chart algorithm in R., Results: Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (β = 0.5, P < 0.001) and leptin (β = 0.6, P < 0.001), and inversely correlated with serum levels of sex hormone-binding globulin (SHBG) (β = -0.4, P < 0.001). Biomarker z-score profiles differed significantly between cohort subgroups stratified by puberty phenotype and BMI weight class., Conclusion: Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: The coronavirus outbreak causes postponement of elective surgery. We evaluated how pain, function and general health were impacted by postponing elective knee and hip arthroplasty in patients with knee and hip osteoarthritis with no known surgery rescheduling date due to the coronavirus outbreak., Methods: This study included 194 patients from a Danish public hospital with postponed elective primary knee or hip arthroplasty due to the lockdown. Patients responded to questionnaires when their surgery was cancelled and before surgery. Changes in pain and function were evaluated with the Oxford Knee and Hip Scores (OKS, OHS) and their general health with the EuroQol 5-dimension scale (EQ5D). Additionally, we asked about the patients' concerns and whether they felt improved, unchanged or deteriorated during the waiting period., Results: Complete data were obtained for 110 (57%) patients, 59 and 51 awaiting knee or hip arthroplasty (median age 71 years, 62% were female), respectively. Arthroplasty was postponed for a median (range) 98 (63-161) days. A total of 34% were concerned that the postponement would lead to a poorer outcome. Mean OKS and OHS differences were 0 (95% confidence interval (CI): -1-1) and -1 (95% CI: -2-0) from surgery cancellation to re-scheduled surgery. The mean EQ5D index difference was 0.0 (95% CI: 0.0-0.1) for both groups. A total of 75 (68%) patients felt an important deterioration of their condition., Conclusions: Pre-operatively, patients worried about experiencing an altered treatment outcome due to postponed surgery and felt that their condition had deteriorated during the waiting period although this was not reflected in patient-reported outcome measures., Funding: Department of Orthopaedic Surgery., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Abstract: It is a common belief that weather affects pain. Therefore, we hypothesized that weather can affect pain tolerance. This study used data from over 18,000 subjects aged 40 years or older from the general population, who participated in the Tromsø Study 7. They underwent a one-time assessment of cuff algometry pressure pain tolerance (PPT) and cold pain tolerance (CPT), tested with a cold pressor test. The results showed a clear seasonal variation in CPT. The rate of withdrawal in the cold pressor test was up to 75% higher in months in the warmer parts of the year compared with January 2016. There was no seasonal variation in PPT. The study not only found a nonrandom short-term variation in PPT but also indications of such a variation in CPT. The intrinsic timescale of this short-term variation in PPT was 5.1 days (95% % confidence interval 4.0-7.2), which is similar to the observed timescales of meteorological variables. Pressure pain tolerance and CPT correlated with meteorological variables, and these correlations changed over time. Finally, temperature and barometric pressure predicted future values of PPT. These findings suggest that weather has a causal and dynamic effect on pain tolerance, which supports the common belief that weather affects pain., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Male sex is associated with higher risk of both colonisation and infection with Staphylococcus aureus (S. aureus). However, the role of sex-steroids in colonisation among men is largely unknown. Thus, the aim of this study was to investigate possible associations between circulating sex-steroids and nasal carriage of S. aureus in a general male population. The population-based Tromsø6 study (2007-2008) included 752 males aged 31-87 years with serum sex-steroids measured by liquid chromatography tandem mass spectrometry and two nasal swab samples for the assessment of S. aureus carriage. Multivariable logistic regression models were used to study the association between sex-steroid concentrations and S. aureus persistent nasal carriage (two positive swabs vs. others), while adjusting for potential confounding factors.S. aureus persistent nasal carriage prevalence was 32%. Among men aged 55 years and above (median age 65 years), there was an inverse dose-response relationship between serum concentration of testosterone and persistent nasal carriage, and carriers had significantly lower mean levels of testosterone (P = 0.028, OR = 0.94 per nmol/l change in testosterone; 95% CI = 0.90-0.98). This association was attenuated when adjusting for body mass index and age (OR = 0.96 per nmol/l change in testosterone; 95% CI = 0.91-1.01). There was no association in the total population. This large population-based study suggests that testosterone levels may be inversely related to S. aureus persistent nasal carriage in older men. Future studies addressing biological mechanisms underlying the male predisposition to S. aureus colonisation and infection may foster preventive interventions that take sex-differences into account.

Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.

Objectives: To examine the possible bidirectional association between insomnia and comorbid chronic low back pain (LBP) and lower limb pain and to explore whether high-sensitivity C-reactive protein (hsCRP) amplifies these associations., Methods: We calculated adjusted risk ratios (RR) with 95% confidence intervals (CI) for the development of insomnia and mild-to-severe chronic LBP and lower limb pain at 11 years follow-up in participants aged ≥32 years and with hsCRP ≤10 mg/L at baseline in 2007-2008: 3,714 without chronic LBP or lower limb pain (sample 1) and 7,892 without insomnia (sample 2)., Results: Compared to participants without chronic pain, participants with comorbid chronic LBP and lower limb pain had a RR of insomnia of 1.37 (95% CI 1.12-1.66). Compared with participants without insomnia, participants with insomnia did not have an increased risk of comorbid chronic LBP and lower limb pain (RR: 1.06, 95% CI 0.76-1.46); however, participants with insomnia had a RR of chronic LBP of 1.20 (95% CI 1.02-1.42). There was no strong amplifying effect of elevated hsCRP (3.00-10.0 mg/L) on these associations., Conclusions: These findings suggest that elevated hsCRP does not amplify the associations between insomnia and mild-to-severe chronic LBP and lower limb pain. Further research using data on the temporal relation between insomnia, chronic pain, and inflammatory responses are required to fully understand the causal pathways., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

An extensive multi-country outbreak of multidrug-resistant monophasic Salmonella Typhimurium infection in 10 countries with 150 reported cases, predominantly affecting young children, has been linked to chocolate products produced by a large multinational company. Extensive withdrawals and recalls of multiple product lines have been undertaken. With Easter approaching, widespread product distribution and the vulnerability of the affected population, early and effective real-time sharing of microbiological and epidemiological information has been of critical importance in effectively managing this serious food-borne incident.

Objectives: Anodal transcranial direct current stimulation (tDCS) of primary motor cortex (M1) and cathodal of the primary sensory cortex (S1) have previously shown to modulate the sensory thresholds when administered with the reference electrode located over the contralateral supraorbital area (SO). Combining the two stimulation paradigms into one with simultaneous stimulation of the two brain areas (M1 + S1 - tDCS) may result in a synergistic effect inducing a prominent neuromodulation, noticeable in the pain thresholds. The aim of this study is to assess the efficacy of the novel M1 + S1 - tDCS montage compared to sham-stimulation in modulating the pain thresholds in healthy adults., Methods: Thirty-nine (20 males) subjects were randomly assigned to either receiving 20 min. active M1 + S1 - tDCS or sham tDCS in a double-blinded single session study. Thermal and mechanical pain thresholds were assessed before and after the intervention., Results: There were no significant differences in the pain thresholds within either group, or between the M1 + S1 - tDCS group and the Sham-tDCS group (p>0.05), indicating that the intervention was ineffective in inducing a neuromodulation of the somatosensory system., Conclusions: Experimental investigations of novel tDCS electrode montages, that are scientifically based on existing studies or computational modelling, are essential to establish better tDCS protocols. Here simultaneous transcranial direct current stimulation of the primary motor cortex and primary sensory cortex showed no effect on the pain thresholds of the neck musculature in healthy subjects. This tDCS montage may have been ineffective due to how the electrical field reaches the targeted neurons, or may have been limited by the design of a single tDCS administration. The study adds to the existing literature of the studies investigating effects of new tDCS montages with the aim of establishing novel non-invasive brain stimulation interventions for chronic neck pain rehabilitation. North Denmark Region Committee on Health Research Ethics (VN-20180085) ClinicalTrials.gov (NCT04658485)., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The identification of growth inhibitory compounds with the ability to selectively target the cellular oxygenation state may be of therapeutic interest. Here, a phenotypic screen of a covalent fragment library revealed diverse compounds containing propiolamide warheads with selective toxicity for liver cancer cells in normoxic conditions. Target identification and validation through CETSA and direct pulldown experiments demonstrated that several compounds target glutathione peroxidase 4 (GPX4) and induce ferroptotic cell death. Although being an oxidative cell death mechanism, ferroptosis can be induced also under hypoxic conditions. Prompted by the selective toxicity discovered in the screen, we mapped the oxygen-dependence of several ferroptosis-inducing compounds across three different cell lines. These studies revealed combinations with notable reductions in sensitivity under hypoxic conditions. These observations are mechanistically interesting and may be relevant for the use of ferroptosis-inducers as anti-cancer agents., (© 2021 Wiley-VCH GmbH.)

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISIs) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e., morning and afternoon sessions on 2 d, 5-7 d apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intraobserver nor interobserver measures of SICI differed significantly between examinations, except for T-SICI at ISI 3 ms ( p  = 0.00035) and A-SICI at ISI 2.5 ms ( p  = 0.0103). Intraday reliability was poor-to-good for A-SICI and moderate-to-good for T-SICI. Interday and interobserver reliabilities of T-SICI and A-SICI were moderate-to-good. Although between-subject variation constituted most of the total variation, SICI repeatability in an individual subject was poor. The two SICI protocols showed no considerable systematic bias across sessions and had a comparable test-retest reliability profile. Findings from the present study suggest that both SICI protocols may be reliably and reproducibly employed in research studies, but should be used with caution for individual decision-making in clinical settings. Studies exploring reliability in patient cohorts are warranted to investigate the clinical utility of these two SICI protocols., (Copyright © 2021 Nielsen et al.)

Background and purpose - Discharge on the day of surgery (DDOS) after total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been shown to be safe in selected patients. Concerns have been raised that discharging patients on the day of surgery (DOS) could lead to an increased burden on other parts of the healthcare system when compared with patients not discharged on the DOS (nDDOS). Therefore, we investigated whether discharging patients on the day of surgery (DOS) after THA and TKA leads to increased contacts with the primary care sector or other departments within the secondary care sector.Patients and methods - Prospective data on 261 consecutive patients scheduled for outpatient THA (n = 135) and TKA (n = 126) were collected as part of a previous cohort study. 33% of THA patients and 37% of TKA patients were discharged on the DOS. Readmissions within 3 months after surgery were recorded. Contacts with the discharging department, other departments, and primary care physicians within 3 weeks were registered.Results - No statistically significant differences were found when comparing DDOS patients and patients not discharged on the DOS (nDDOS) with regard to readmissions, physical contacts with the discharging department, and contacts with other departments as well as general practitioners. THA DDOS patients had significantly fewer contacts with the discharging department by telephone than THA nDDOS patients. TKA DDOS patients had significantly more contacts with the discharging department by telephone than TKA nDDOS patients.Interpretation - Patients discharged on the DOS following THA or TKA generally have similar postoperative contacts with the healthcare system when compared with patients not discharged on the DOS.

Background and Purpose: Short-interval intracortical inhibition by threshold tracking (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A-SICI). This study compared A-SICI and T-SICI for sensitivity and clinical usefulness as biomarkers for ALS., Methods: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow-up. T-SICI and A-SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age-matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients., Results: Motor neuron disease patients had significantly reduced T-SICI and A-SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T-SICI and A-SICI respectively at 1-3.5 ms). Paradoxically, T-SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10 -6 )., Conclusions: Amplitude-based measure of cortical inhibition and T-SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T-SICI most abnormal before UMN signs have developed. The gradation in T-SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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