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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.

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.

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.)

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.

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: 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.)

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).)

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.)

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.

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.

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: Ropivacaine is commonly used in local infiltration anaesthesia (LIA) as pain management after total knee arthroplasty (TKA). Although considered safe, no studies evaluated the pharmacokinetics of high-dose ropivacaine infiltration in simultaneous bilateral TKA., Methods: We studied 13 patients undergoing unilateral and 15 undergoing bilateral TKA. Standard LIA technique was used with ropivacaine 0.2%, 200 ml (400 mg) injected peri-articularly in each knee. Free and total plasma concentrations of ropivacaine were measured within 24 h using liquid chromatography-mass spectrometry. A population pharmacokinetic model was built using non-linear mixed-effects models., Results: Peak free ropivacaine concentration was 0.030 (0.017-0.071) μg ml -1 (mean [99% confidence interval]) vs 0.095 (0.047-0.208) μg ml -1 , and peak total ropivacaine concentration was 0.756 (0.065-1.222) μg ml -1 vs 1.695 (0.077-3.005) μg ml -1 for unilateral and bilateral TKA, respectively. The pharmacokinetics was ascribed a one-compartment model with first-order absorption. The main identified covariates were protein binding, allometrically scaled body weight on clearance and volume, and unilateral or bilateral surgery on volume., Conclusions: This is the first study to investigate the pharmacokinetics of free and total ropivacaine after unilateral and bilateral TKA. A population model was successfully built and peak free ropivacaine concentration stayed below previously proposed toxic thresholds in patients undergoing unilateral and bilateral TKA receiving LIA with high-dose ropivacaine., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04702282., Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Tinnitus and pain have many similarities. Both are subjective sensations that may turn chronic, they are often accompanied by hypersensitivity in their respective sensory system, and overlapping brain changes have been observed. Since no population study has examined the empirical association between chronic pain and tinnitus, the present study aimed to explore the relationship in a general adult population. We used data from the seventh survey of the Tromsø Study (2015-2016). Participants (aged ≥40) responded to questions about pain and tinnitus. Using multiple logistic regression, we analysed the adjusted relationship between chronic pain and tinnitus in the full sample (n = 19,039), using several tinnitus definitions ranging from tinnitus >5 minutes within the past 12 months (broadest definition) to at least weekly and highly bothersome tinnitus (strictest definition). We also analysed relationships between number of body regions with pain, pain intensity and bothering, and tinnitus >5 minutes, among participants with chronic pain (n = 11,589). We found an association between chronic pain and tinnitus that was present irrespective of tinnitus definition, but was stronger with more bothersome tinnitus. With chronic pain, the odds of tinnitus >5 minutes was 64% higher, while odds of at least weekly, highly bothersome tinnitus was 144% higher than without chronic pain. Among participants with chronic pain, the number of pain regions was the pain variable most strongly associated with tinnitus >5 minutes (OR = 1.17 (95% CI: 1.14-1.20) for an increase of one region), whereas the other pain variables (intensity and bothering) showed weaker associations. All chronic pain variables had significant interactions with age, with the strongest associations for the youngest individuals (40-54 years). Our findings support the existence of an association between chronic pain and tinnitus and emphasises the importance of examining for comorbid pain in tinnitus patients to provide a more comprehensive treatment of tinnitus., Competing Interests: The authors have declared that no competing interests exist.

Background and purpose - Outpatient total knee and total hip arthroplasty (TKA and THA) has been shown to be feasible and safe in selected patients. However, little data is available on functional outcome and early pain in patients discharged on the day of surgery (DOS). We investigated patient-reported outcomes at 1 year and early pain in outpatient TKA and THA patients discharged on the day of surgery (DOS) (DDOS) compared with patients scheduled for outpatient surgery but not discharged on the DOS (nDDOS).Patients and methods - Prospective data on 261 consecutive patients scheduled for outpatient TKA (n = 126) and THA (n = 135) were collected. 37% of TKA patients and 33% of THA patients were discharged on the DOS. Pain scores at rest and activity and use of morphine were registered on postoperative days 1-7. Oxford Knee Score (OKS) and Oxford Hip Score (OHS) were collected preoperatively and at 3 and 12 months' follow-up.Results - DDOS and nDDOS patients were similar in respect to age, sex, procedure type (TKA vs. THA), or preoperative OKS or OHS. Neither OKS nor OHS differed between groups at 3 and 12 months' follow-up. Pain at rest and activity and use of morphine did not differ between the 2 groups on days 1-7.Interpretation - In patients scheduled for outpatient TKA and THA, we found similar patient-reported outcomes both early and at 1 year in those discharged on the DOS and those who had at least 1 overnight stay.

Background: New implants for total knee arthroplasty (TKA) are continuously introduced with the proposed benefit of increased performance and improved outcome. Little information exists on how the introduction of a novel arthroplasty implant affects the perioperative and surgical outcome immediately after implementation., Aim: To investigate how surgery-related factors and implant positioning were affected by the introduction of a novel TKA system., Methods: A novel TKA system was introduced at our institution on 30th November 2015. Seventy-five TKAs performed with the Persona TKA immediately following its introduction by 3 different surgeons (25 TKAs/surgeon) were identified as the Introduction Group. Moreover, the latest 25 TKAs performed by each surgeon prior to introduction of the Persona TKA were identified as the Control Group. A Follow-up Group of 25 TKAs/surgeon was identified starting 1-year after the end of the introduction period. Demographics, surgery-related factors and alignment data were recorded, and intergroup differences compared., Results: Following introduction of the novel implant, Persona TKA was utilized in 69% (71%), 53% (54%), and 45% (75%) of primary TKA procedures by the three surgeons, respectively (Follow-up Group). Mean surgery time was increased by 28% ( P < 0.0001) and mean intra-operative blood loss by 25% ( P = 0.002) in the Introduction Group, while only the mean surgery time was increased in the Follow-up Group by 18% ( P < 0.0001). Overall alignment was similar between the groups apart from femoral flexion (FF) and tibial slope (TS). The number of FF outliers was reduced in the Introduction Group with a more pronounced decrease in the Follow-up Group., Conclusion: Introduction of the new TKA implant increased surgical time and intraoperative blood loss immediately after its introduction. These differences diminished one year after introduction of the new implant. Fewer outliers with respect to FF and TS were seen when using the novel TKA implant. Further studies are needed to investigate if these differences persist over time and correlate with patient reported outcomes., Competing Interests: Conflict-of-interest statement: Adam Omari, Christian Skovgaard Nielsen and Kirill Gromov have nothing to disclose; Anders Troelsen reports personal fees from Zimmer Biomet as a consultant and speaker, grants from Zimmer Biomet outside the submitted work, and has been a member of the board at the European Knee Society (EKS) since 2015; Henrik Husted reports personal fees from Zimmer Biomet as a speaker, and has been a board member of rapid recovery for Zimmer Biomet., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and purpose - Previous studies have investigated risk factors related to prolonged length of stay following total knee arthroplasty (TKA), but little is known about specific factors resulting in continued hospitalization within the 1st postoperative days after unicompartmental knee arthroplasty (UKA). We investigated what specific factors prevent patients from being discharged on the day of surgery (DOS) and the first postoperative day (POD-1) following primary UKA in a fast-track setting.Patients and methods - We prospectively collected data on 100 consecutive and unselected medial UKA patients operated from December 2017 to May 2019. All patients were operated in a standardized fast-track setup with functional discharge criteria continuously evaluated from DOS and until discharge.Results - Median length of stay for the entire cohort was 1 day. 22% and 78% of all patients were discharged on DOS and POD-1, respectively. Lack of mobilization and pain separately delayed discharge in respectively 78% and 24% of patients on DOS. The main reasons for lack of mobilization were motor blockade (37%) and logistical factors (26%). For patients placed 1st or 2nd on the operating list, we estimate that the same-day discharge rate would increase to 55% and 40% respectively, assuming that pain and mobilization were successfully managed.Interpretation - One-fifth of unselected UKA patients operated in a standardized fast-track setup were discharged on DOS. Pain and lack of mobilization were the major reasons for continued hospitalization within the initial postoperative 24-48 hours. Strategies aimed at decreasing length of stay after UKA should strive to improve analgesia and postoperative mobilization.

Background: Physical inactivity and chronic pain are both major public health concerns worldwide. Although the health benefits of regular physical exercise are well-documented, few large epidemiological studies have investigated the association between specific domains of physical exercise and chronic pain in young adults. We sought to investigate the association between frequency, intensity and duration of physical exercise, and chronic pain., Methods: Data stem from the SHoT2018-study, a national health survey for higher education in Norway, in which 36,625 fulltime students aged 18-35 years completed all relevant questionnaires. Chronic pain, defined according to the International Classification of Diseases 11th Revision (ICD-11), was assessed with a newly developed hierarchical digital instrument for reporting both distribution and characteristics of pain in predefined body regions. Physical exercise was assessed using three sets of questions, measuring the number of times exercising each week, and the average intensity and the number of hours each time., Results: The majority (54%) of the students reported chronic pain in at least one location, and the prevalence was especially high among women. The overall pattern was an inverse dose-response association between exercise and chronic pain: the more frequent, harder or longer the physical exercise, the lower the risk of chronic pain. Similar findings were generally also observed for the number of pain locations: frequent exercise was associated with fewer pain locations. Adjusting for demographical, lifestyle factors and depression had little effect on the magnitude of the associations., Conclusion: Given the many health benefits of regular exercise, there is much to be gained in facilitating college and university students to be more physically active, ideally, thru a joint responsibility between political and educational institutions. Due to the cross-sectional nature of the study, one should be careful to draw a firm conclusion about the direction of causality., Competing Interests: The authors have declared that no competing interests exist.

Background: Although TKA is a common and proven reliable procedure for treating end-stage knee osteoarthritis, a minority of patients still do not achieve satisfactory levels of pain relief and functional improvement. Even though several studies have attempted to identify patients at risk of having poor clinical outcomes, few have approached this issue by considering the outcome of the patient-acceptable symptom state (PASS), defined as the value on a patient-reported outcome measure scale above which the patient deems their current symptom state acceptable., Questions/purposes: (1) What is the proportion of patients who do not attain the PASS in pain and function at 1 year after TKA? (2) Which preoperative patient factors are associated with not achieving the PASS in pain at 1 year after TKA? (3) Which preoperative patient factors are associated with not achieving the PASS in function at 1 year after TKA?, Methods: This retrospective study is a secondary analysis of the 1-year follow-up data from a prospective, international, multicenter study of a single TKA system. Inclusion criteria for that study were patients diagnosed with primary osteoarthritis or post-traumatic arthritis and who were able to return for follow-up for 10 years; exclusion criteria were infection, osteomyelitis, and failure of a previous joint replacement. Between 2011 and 2014, 449 patients underwent TKA at 10 centers in five countries. At 1 year, 13% (58 of 449) were lost to follow-up, 2% could not be analyzed (eight of 449; missing 1-year KOOS), leaving 85% (383 of 449) for analysis here. The primary outcomes were not surpassing evidence-derived PASS thresholds in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Activities in Daily Living (ADL) sub-scores. Multivariate binary logistic regressions considering preoperative demographic, radiographic, and patient-reported outcome measure data were constructed using a forward stepwise elimination algorithm to reach the simplest best-fit regression models., Results: At 1 year after TKA, 38% of the patients (145 of 383) did not reach the PASS in KOOS Pain, 36% (139 of 383) did not reach the PASS in KOOS ADL, and 29% (110 of 383) did not achieve the PASS in either KOOS Pain or ADL. After controlling for potentially confounding variables such as gender, age, BMI, and comorbidity scores, we found that men (odds ratio 2.09; p = 0.01), and patients with less-than-advanced radiographic osteoarthritis (OR 2.09; p = 0.01) were strongly associated with not achieving the PASS in pain. After controlling for the same potentially confounding variables, we found that patients with less-than-advanced radiographic osteoarthritis (OR 2.09; p = 0.01) were also strongly associated with not achieving the PASS in function., Conclusions: We found that patients with less severe osteoarthritis were much less likely to attain the PASS in pain and function at 1 year after TKA, and that men were much less likely to achieve the PASS in pain at 1 year after TKA. Based on these findings, surgeons should strongly consider delaying surgery in patients who present with less-than-severe osteoarthritis, with increased caution in men. Surgeons should counsel their patients on their expectations and their chances of achieving meaningful levels of pain and functional improvement. Future regional and national registry studies should assess the true proportion of patients attaining PASS in pain and function after TKA and confirm if the preoperative factors identified in this study remain significant in larger, more diverse patient populations., Level of Evidence: Level III, therapeutic study.

Background: Prolonged wound drainage after TKA is associated with increased risk of infection. To decrease wound drainage, tissue adhesive has been suggested as an adjunct to wound closure after TKA; however, no studies of which we are aware have investigated the effect of tissue adhesive in a modern fast-track TKA setting., Questions/purposes: The purpose of this study was to evaluate the effect of wound closure using a high-viscosity tissue adhesive in simultaneous bilateral TKA with respect to (1) postoperative wound drainage, measured as number of dressing changes in the first 72 hours postoperatively; and (2) wound healing assessed using the ASEPSIS score., Methods: Thirty patients undergoing simultaneous bilateral TKA were included in the study. The left knee was randomized to receive either standard three-layer closure with staples or the same closure supplemented with tissue adhesive with the opposite treatment used on the contralateral knee. One patient underwent a constrained TKA and underwent revision 2 days after the index procedure and was therefore excluded leaving 29 patients (58 knees) for analysis. Sixty-two percent (n = 18) were female. Mean age was 64 years (range, 42-78 years). Mean body mass index was 28 kg/m (range, 21-38 kg/m). Postoperative wound drainage was evaluated as drainage resulting in a dressing change. The wound dressing was changed if it was soaked to the borders of the absorbable dressing at any point. The nurses changing the dressing were blinded to treatment allocation up to the first dressing change. The number of dressing changes during the first 72 hours postoperatively was recorded. The secondary study endpoint was the ASEPSIS score, which is a clinical score assessing wound healing. ASEPSIS score, measured by a nurse not involved in the treatment, was compared between the groups at 3 weeks followup., Results: Knees with tissue adhesive underwent fewer dressing changes (median, 0; interquartile range [IQR], 0-1) compared with the contralateral knee (IQR, 1-2; difference of medians, one dressing change; p = 0.001). A total of 59% of knees in the intervention group did not undergo any dressing changes before discharge, whereas 24% of knees in the control group did not undergo any dressing changes before discharge (p = 0.02). The knees in the intervention group and the control group did not differ with respect to ASEPSIS score at 3 weeks., Conclusions: Tissue adhesive as an adjunct to standard wound closure after primary TKA reduced the number of dressing changes after surgery, but did not change the appearance or healing of the wound at 3 weeks based on the ASEPSIS scores. Whether the small differences observed here in terms of the number of dressing changes performed will justify the additional costs associated with using this product or whether there are other differences associated with the use of tissue adhesive that may prove important such as patient preferences or longer term differences in wound healing or infection should be studied in the future., Level of Evidence: Level I, therapeutic study.

Background: Previous research shows that physical activity has a protective effect on mental distress in adults, but the relationship is less researched and seems more ambiguous for adolescents. Studies in this field have typically been cross-sectional by design and based on self-reported physical activity measures, which are known to be vulnerable to response bias. The aim of this study was to investigate the relationship between change in objectively assessed physical activity as measured by accelerometer and change in mental distress among adolescents using longitudinal data from The Tromsø Study: Fit Futures., Method: This study was based on data from 676 upper-secondary school students (mean age 16.23 years at baseline, 45.26% boys) from The Tromsø Study: Fit Futures. Physical activity, mental distress and covariates were measured at baseline (T1) and follow-up (T2) 2 years later. Physical activity was objectively measured with an ActiGraph GT3X accelerometer over 7 days. Mental distress was measured with the Hopkins Symptom Checklist-10 (HSCL-10). Change score variables were computed as the difference between T1 and T2 in number of steps, number of minutes of moderate to vigorous physical activity (MVPA) and mental distress between T1 and T2, and analyzed using linear regression analysis., Results: Changes in steps per day were not associated with changes in mental distress in neither the crude, partially, nor fully adjusted model. Neither was changes in minutes of MVPA per day. Interaction effects between change in both steps per day and minutes of MVPA and gender were also not statistically significant, nor was the interaction effects between baseline levels of mental distress and physical activity., Conclusion: The results of our study indicate that for adolescents in the sample, change in physical activity is unrelated to change in mental distress over a two-year period.

Background: Use of hormonal contraceptives has been associated with Staphylococcus aureus nasal carriage in adult women. However, the role of hormonal contraceptives in S. aureus colonization among adolescents and associations with progestin only contraceptives are unknown., Methods: We obtained nasal and throat swab samples from 439 girls aged 17-21 years in the population-based Tromsø study Fit Futures, 2012-2013, Norway, with information on lifestyle, health and biomarkers. We used multivariable logistic regression to study the association between use of hormonal contraceptives and Staphylococcus aureus carriage while adjusting for potential confounding factors., Results: Staphylococcus aureus nasal carriage prevalence were 34%, 42%, and 61% among progestin-only users, non-users, and progestin-estrogen combination contraceptive users, respectively (P<0.001). Use of combination contraceptives doubled the odds of nasal carriage (non-users reference; OR = 2.31, 95%CI = 1.43-3.74). The OR of nasal carriage was 0.29 among progestin-only users compared to combination contraceptives users (95% CI = 0.12-0.67)., Discussion: In this study, use of combination hormonal contraceptives was associated with higher risk of Staphylococcus aureus nasal carriage in adolescent girls. Experimental design studies are needed to establish the role of exogenous sex steroids in Staphylococcus aureus colonization in women., Competing Interests: The authors have declared that no competing interests exist.

In wet tundra ecosystems, covering vast areas of the Arctic, the belowground plant biomass exceeds the aboveground, making root dynamics a crucial component of the nutrient cycling and the carbon (C) budget of the Arctic. In response to the projected climatic scenarios for the Arctic, namely increased temperature and changes in precipitation patterns, root dynamics may be altered leading to significant changes in the net ecosystem C budget. Here, we quantify the single and combined effects of 1 year of increased winter snow deposition by snow fences and summer warming by open-top chambers (OTCs) on root dynamics in a wetland at Disko Island (West Greenland). Based on ingrowth bags, snow accumulation decreased root productivity by 42% in the 0-15 cm soil depth compared to ambient conditions. Over the growing season 2014, minirhizotron observations showed that root growth continued until mid-September in all treatments, and it peaked between the end of July and mid-August. During the season, plots exposed to experimental warming showed a significant increase in root number during September (between 39 and 53%) and a 39% increase in root length by the beginning of September. In addition, a significant reduction of root diameter (14%) was observed in plots with increased snow accumulation. Along the soil profile (0-40 cm) summer warming by OTCs significantly increased the total root length (54%), root number (41%) and the root growth in the 20-30 cm soil depth (71%). These results indicate a fast response of this ecosystem to changes in air temperature and precipitation. Hence, on a short-term, summer warming may lead to increased root depth and belowground C allocation, whereas increased winter snow precipitation may reduce root production or favor specific plant species by means of reduced growing season length or increased nutrient cycling. Knowledge on belowground root dynamics is therefore critical to improve the estimation of the C balance of the Arctic.

Background: The nature of the relationship between fatigue and its risk factors is poorly understood. In the present study the genetic and environmental association between anxiety-depression, musculoskeletal (MS) pain and fatigue was examined, and the role of neuroticism as a shared risk factor that may possibly explain the co-occurrence between these phenotypes was investigated in a combined cross-sectional and longitudinal twin design., Methods: The sample consisted of 746 monozygotic (MZ) and 770 dizygotic (DZ) twins in the age group of 50-65 (mean = 57.11 years, SD = 4.5). Continuous measures of fatigue symptoms and the other phenotypes were employed. Using Cholesky modeling, genetic and environmental influences on the phenotypes, and the associations among them, were determined. Analyses were performed using measures of neuroticism obtained concurrently and 13-19 years earlier., Results: Results from multiple regression analyses showed that neuroticism, anxiety-depression symptoms, and MS pain were all significantly associated with fatigue, controlling for sex, education, and general health indices. The best-fitting biometric models included additive genetic and individual-specific environmental effects. Heritabilities in the 0.40-0.53 range were demonstrated. Furthermore, while there was a considerable overlap in genetic risk factors between the four phenotypes, a substantial proportion of the genetic risk shared between anxiety-depression and fatigue, and between MS pain and fatigue, was independent of neuroticism., Conclusion: Evidence for a common underlying susceptibility to report fatigue symptoms, genetically linked to neuroticism, anxiety-depression, and MS pain, was found. Both unique and pleiotropic effects appear to be involved in the genetic architecture of the phenotypes., Competing Interests: The authors have declared that no competing interests exist.

Background: Increased pain sensitivity is a putative risk factor for chronic pain and consequently for analgesic use. Conversely, analgesic use may be a cause of increased pain sensitivity, e.g., through opioid-induced hyperalgesia. We aimed to study the association between pain sensitivity and analgesic use in a general population, and to test the hypothesis that increased baseline pain sensitivity is a risk factor for future persistent analgesic use., Methods: The Tromsø Study (2007-08), a population-based health study, was linked with eight years of prescription data from the Norwegian Prescription Database. The cold pressor test was completed in 10,486 participants aged 30+ years, and we used cold pressor endurance time as a proxy measure of pain sensitivity. Cross-sectional associations with different measures of analgesic use were assessed. Furthermore, a cohort of 9,657 persons was followed for 4.5 years., Results: In the cross-sectional analysis, increased pain sensitivity was associated with analgesic use; regular users of opioids alone were more pain sensitive than regular users of non-opioid analgesics. Increased baseline pain sensitivity was a risk factor for persistent analgesic use, i.e., using non-steroidal anti-inflammatory drugs, paracetamol, or opioids for ≥ 90 days and proportion-of-days-covered ≥ 40% (HR = 1.22, 95% CI 1.06-1.40), although not statistical significant after confounder adjustment., Conclusions: Increased pain sensitivity was associated with analgesic use in general, and reduced pain tolerance was found for both opioid and non-opioid analgesic users. The data suggest that hyperalgesia is an effect of analgesics, whereas pain tolerance has little impact on future analgesic use.

Background: Unrecognized myocardial infarction (MI) is a prevalent condition associated with a similar risk of death as recognized MI. It is unknown why some persons experience MI with few or no symptoms; however, one possible explanation is attenuated pain sensitivity. To our knowledge, no previous study has examined the association between pain sensitivity and recognition of MI., Methods and Results: We conducted a population-based cross-sectional study with 4849 included participants who underwent the cold pressor test (a common experimental pain assay) and ECG. Unrecognized MI was present in 387 (8%) and recognized MI in 227 (4.7%) participants. Participants with unrecognized MI endured the cold pressor test significantly longer than participants with recognized MI (hazard ratio for aborting the cold pressor test, 0.64; CI, 0.47-0.88), adjusted for age and sex. The association was attenuated and borderline significant after multivariable adjustment. The association between unrecognized MI and lower pain sensitivity was stronger in women than in men, and statistically significant in women only, but interaction testing was not statistically significant (P for interaction=0.14)., Conclusions: Our findings suggest that persons who experience unrecognized MI have reduced pain sensitivity compared with persons who experience recognized MI. This may partially explain the lack of symptoms associated with unrecognized MI., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The aim of this study was to examine if gradual withdrawal of remifentanil infusion prevented opioid-induced hyperalgesia (OIH) as opposed to abrupt withdrawal. OIH duration was also evaluated., Methods: Nineteen volunteers were enrolled in this randomized, double-blinded, placebo-controlled, crossover study. All went through three sessions: abrupt or gradual withdrawal of remifentanil infusion and placebo. Remifentanil was administered at 2.5 ng ml(-1) for 30 min before abrupt withdrawal or gradual withdrawal by 0.6 ng ml(-1) every five min. Pain was assessed at baseline, during infusion, 45-50 min and 105-110 min after end of infusions using the heat pain test (HPT) and the cold pressor test (CPT)., Results: The HPT 45 min after infusion indicated OIH development in the abrupt withdrawal session with higher pain scores compared with the gradual withdrawal and placebo sessions (both P<0.01. Marginal mean scores: placebo 2.90; abrupt 3.39; gradual 2.88), but no OIH after gradual withdrawal compared with placebo (P=0.93). In the CPT 50 min after end of infusion there was OIH in both remifentanil sessions compared with placebo (gradual P=0.01, abrupt P<0.01. Marginal mean scores: placebo 4.56; abrupt 5.25; gradual 5.04). There were no differences between the three sessions 105-110 min after infusion., Conclusions: We found no development of OIH after gradual withdrawal of remifentanil infusion in the HPT. After abrupt withdrawal OIH was present in the HPT. In the CPT there was OIH after both gradual and abrupt withdrawal of infusion. The duration of OIH was less than 105 min for both pain modalities., Clinical Trial Registration: NCT 01702389. EudraCT number 2011-002734-39., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background. Chronic pain is associated with increased morbidity and mortality, predominated by cardiovascular disease and cancer. Investigating related risk factor measures may elucidate the biological burden of chronic pain. Objectives. We hypothesized that chronic pain severity would be positively associated with the risk factor composite. Methods. Data from 12,982 participants in the 6th Tromsø study were analyzed. Questionnaires included demographics, health behaviors, medical comorbidities, and chronic pain symptoms. The risk factor composite was comprised of body mass index, fibrinogen, C-reactive protein, and triglycerides. Chronic pain severity was characterized by frequency, intensity, time/duration, and total number of pain sites. Results. Individuals with chronic pain had a greater risk factor composite than individuals without chronic pain controlling for covariates and after excluding inflammation-related health conditions (p < 0.001). A significant "dose-response" relationship was demonstrated with pain severity (p < 0.001). In individuals with chronic pain, the risk factor composite varied by health behavior, exercise, lower levels and smoking, and higher levels. Discussion. The risk factor composite was higher in individuals with chronic pain, greater with increasing pain severity, and influenced by health behaviors. Conclusions. Identification of a biological composite sensitive to pain severity and adaptive/maladaptive behaviors would have significant clinical and research utility.

Unlabelled: Parametric statistical methods are common in human pain research. They require normally distributed data, but this assumption is rarely tested. The current study analyzes the appropriateness of parametric testing for outcomes from the cold pressor test (CPT), a common human experimental pain test. We systematically reviewed published CPT studies to quantify how often researchers test for normality and how often they use parametric versus nonparametric tests. We then measured the normality of CPT data from 7 independent small to medium cohorts and 1 study of >10,000 subjects. We then examined the ability of 2 common mathematical transformations to normalize our skewed data sets. Lastly, we performed Monte Carlo simulations on a representative data set to compare the statistical power of the parametric t-test versus the nonparametric Wilcoxon Mann-Whitney test. We found that only 39% of published CPT studies (47/122) mentioned checking data distribution, yet 72% (88/122) used parametric statistics. Furthermore, among our 8 data sets, CPT outcomes were virtually always nonnormally distributed, and mathematical transformations were largely ineffective in normalizing them. The simulations demonstrated that the nonparametric Wilcoxon Mann-Whitney test had greater statistical power than the parametric t-test for all scenarios tested: For small effect sizes, the Wilcoxon Mann-Whitney test had up to 300% more power., Perspective: These results demonstrate that parametric analyses of CPT data are routine but incorrect and that they likely increase the chances of failing to detect significant between-group differences. They suggest that nonparametric analyses become standard for CPT studies and that assumptions of normality be routinely tested for other types of pain outcomes as well., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

We tested whether cardiovascular stress responsiveness is elevated in individuals experiencing chronic pain in a large general population sample. Blood pressure (BP) and heart rate (HR) were assessed at rest, during the cold pressor test, and during subsequent recovery in 554 individuals reporting daily chronic pain and 3,082 individuals free of chronic pain. After correcting for potential confounds, differences as a function of chronic pain status were noted for only 5 of 23 cardiovascular outcomes despite very high statistical power. Compared to the pain-free group, the chronic pain group displayed higher baseline HR/mean arterial pressure (MAP) ratio (p = .03), greater systolic BP (SBP) reactivity during the cold pressor test (p = .04), and higher HR/MAP ratio (p = .047) and significantly less SBP (p = .017) and MAP (p = .041) return to baseline during recovery. Findings suggest that changes in cardiovascular stress responsiveness associated with chronic pain are of limited clinical significance and unlikely to contribute to increased cardiovascular risk in the chronic pain population.

Unlabelled: Widespread hyperalgesia is well documented among adult patients with irritable bowel syndrome (IBS), but little is known about pain sensitivity among adolescents with IBS. We examined pain sensitivity in 961 adolescents from the general population (mean age 16.1 years), including pain threshold and tolerance measurements of heat (forearm) and pressure pain (fingernail and shoulder) and cold pressor tolerance (hand). Adolescents with IBS symptoms (Rome III criteria) had lower heat pain thresholds compared to controls after adjustments for sex, comorbid pain, and psychological distress (mean difference = -.8 °C; 95% confidence interval [CI] = -1.6 to -.04). Similar results were found for pressure pain threshold at the shoulder (mean difference = -46 kPa; 95% CI = -78 to -13) and fingernail (mean difference = -62 kPa; 95% CI = -109 to -15), and for an aggregate of all 3 threshold measures (z-score difference = -.4; 95% CI = -.6 to -.2), though pressure pain threshold differences were nonsignificant after the final adjustments for psychological distress. No difference of pain tolerance was found between the IBS cases and controls. Our results indicate that adolescents in the general population with IBS symptoms, like adults, have widespread hyperalgesia., Perspective: This is the first report of widespread hyperalgesia among adolescents with IBS symptoms in the general population, with lower pain thresholds found to be independent of sex and comorbid pain. Our results suggest that central pain sensitization mechanisms in IBS may contribute to triggering and maintaining chronic pain symptoms., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: An inverse association between resting blood pressure (BP) and acute pain sensitivity is well documented. Whether BP-related hypoalgesia differs by gender is unclear from prior work. Whether it increases proportionally with BP throughout the full BP range is also unknown. We examined BP-related hypoalgesia in a general population sample (n = 10,371, aged 30-87) of equal gender distribution reflecting the extremely low through hypertensive BP range. Resting BP was assessed and individuals participated in a standardized cold pressor test, providing pain ratings every 9 seconds. For systolic BP (SBP), a significant SBP × Gender interaction was observed on mean pain ratings (P < .001). Females displayed significant BP-related hypoalgesia (P < .001), with males showing a 38% smaller effect (P < .001). A similar DBP × Gender interaction was also observed (P < .05). Spline regression indicated a significant (P < .001) change in slope of the SBP-pain association at 140 mmHg. Among individuals with lower resting SBP (<140/90), increasing hypoalgesia with increasing SBP levels was observed (P < .001), with no further increases in those with higher BP (≥140/90; P > .10). This is the first large-scale study to confirm past results suggesting that BP-related hypoalgesia differs by gender; that is, females exhibited greater hypoalgesia. BP-related hypoalgesia appears subject to ceiling effects in the hypertensive BP range., Perspective: Females show greater BP-related hypoalgesia than males, highlighting gender differences in endogenous antinociceptive systems. Extent of BP-related hypoalgesia does not increase further once resting pressures reach the hypertensive range, suggesting persistent maximal demands on these antinociceptive systems among hypertensive individuals., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Not only are some clinical conditions experienced as more painful than others, but the variability in pain ratings of patients with the same disease or trauma is enormous. Available evidence indicates that to a large extent these differences reflect individual differences in pain sensitivity. Pain sensitivity can be estimated only through the use of well-controlled experimental pain stimuli. Such estimates show substantial heritability but equally important environmental effects. The genetic and environmental factors that influence pain sensitivity differ across pain modalities. For example, genetic factors that influence cold pressor pain have little impact on phasic heat pain and visa versa. Individual differences in pain sensitivity can complicate diagnosis, among other reasons because low sensitivity to pain may delay self-referral. Inclusion of patients with reduced pain sensitivity can attenuate treatment effects in clinical trials, unless controlled for. Measures of pain sensitivity are predictive of acute postoperative pain, and there is preliminary evidence that heightened pain sensitivity increases risk for future chronic pain conditions. At this time, however, it is unclear which experimental pain modalities should be used as predictors for future pain conditions. Careful assessment of each individual's pain sensitivity may become invaluable for the prevention, evaluation, and treatment of pain., Perspective: Large individual differences in pain sensitivity can complicate diagnosis and pain treatment and can confound clinical trials. Pain sensitivity may also be of great importance for the development of clinical pain. Thus, assessment of pain sensitivity may be relevant for the prevention, evaluation, and treatment of acute and chronic pain.

Background: Medically induced abortion through week 9 is a well established procedure. The article concerns satisfaction among women who choose to do this at home, and possible associations between satisfaction, socio-demographic--and clinical factors., Material and Methods: 110 women with pregnancy duration < 7 weeks, who wished to medically terminate the pregnancy at home and presented themselves at Ullevaal University Hospital, were included in the study. The woman's satisfaction with the procedure was the main variable, but anxiety and pain were also recorded. Data were retrieved from hospital journals and questionnaires filled in before and 1 and 3 weeks after the abortion. The degree of satisfaction was recorded on a scale from 1 to 10, where 1 was not content and 10 was very content. Follow-up data were available for 105 women., Results: 90 of 105 women were very content (> 7 on the satisfaction scale) with the treatment. Discomfort and pain during the abortion and marital status seemed to influence the results. The degree of pain varied much. No serious complications were observed., Interpretation: The study showed a high degree of satisfaction with medically induced abortion at home early in the pregnancy. The study has a relatively small sample size and no control group, so the results on factors affecting satisfaction are uncertain. Medical abortion at home should be an opportunity for women applying for early pregnancy termination; as long as the women are well informed, are offered sufficient pain relief and a well functioning follow-up programme.