Prevention of sickness absence through early identification and rehabilitation of at-risk patients with musculoskeletal pain (PREVSAM): a randomised controlled trial protocol.

BACKGROUND: Musculoskeletal pain is globally a leading cause of physical disability. Many musculoskeletal-related pain conditions, such as low back pain, often resolve spontaneously. In some individuals, pain may recur or persist, leading to ong-term physical disability, reduced work capacity, and sickness absence. Early identification of individuals in which this may occur, is essential for preventing or reducing the risk of developing persistent musculoskeletal pain and long-term sickness absence. The aim of the trial described in this protocol is to evaluate effects of an early intervention, the PREVSAM model, on the prevention of sickness absence and development of persistent pain in at-risk patients with musculoskeletal pain. METHODS: Eligible participants are adults who seek health care for musculoskeletal pain and who are at risk of developing persistent pain, physical disability, and sickness absence. Participants may be recruited from primary care rehabilitation centres or primary care healthcare centres in Region Västra Götaland. Participants will be randomised to treatment according to the PREVSAM model (intervention group) or treatment as usual (control group). The PREVSAM model comprises an interdisciplinary, person-centred rehabilitation programme, including coordinated measures within primary health care, and may include collaboration with participants' employers. The primary outcome sickness absence is operationalised as the number and proportion of individuals who remain in full- or part-time work, the number of gross and net days of sickness absence during the intervention and follow-up period, and time to first sickness absence spell. Secondary outcomes are patient-reported short-term sickness absence, work ability, pain, self-efficacy, health-related quality of life, risk for sickness absence, anxiety and depression symptoms and physical disability at 1 and 3 months after inclusion (short-term follow-up), and at 6 and 12 months (long-term follow-up). A cost-effectiveness analysis is planned and drug consumption will be investigated. DISCUSSION: The study is expected to provide new knowledge on the effectiveness of a comprehensive rehabilitation model that incorporates early identification of patients with musculoskeletal pain at risk for development of sickness absence and persistent pain. The study findings may contribute to more effective rehabilitation processes of this large patient population, and potentially reduce sickness absence and costs. TRIAL REGISTRATION: ClinicalTrials.gov Protocol ID: NCT03913325 , Registered April 12, 2019. Version 2, 10 July 2020. Version 2 changes: Clarifications regarding trial aim and inclusion process.

Pain intensity and pressure pain thresholds after a light dynamic physical load in patients with chronic neck-shoulder pain.

BACKGROUND: To investigate the development of pain intensity and pressure pain thresholds during and 24 h after a light dynamic physical load among patients with chronic neck-shoulder pain. METHODS: Twenty-six patients with chronic neck-shoulder pain and 12 healthy controls were included. The participants arm-cycled on an ergometer. Effort was rated with the Borg Rating of Perceived Exertion scale (RPE), and pain intensity with an numeric rating scale (NRS). Pressure pain thresholds were measured by an algometer. Participants started a pain diary 1 week before the physical exercise and continued until 1 week after. Pain intensity was assessed before, during and the following two evenings after arm-cycling. Pressure pain thresholds were assessed before, 15 min after, 105 min after and 24 h after. RESULTS: The chronic pain group showed increased pain intensity during, and the following two evenings after the arm cycling, and decreased pain thresholds immediately after the arm cycling involving painful regions. In the patient group there were no impact on pain thresholds in the neck the following day. CONCLUSIONS: Patients with chronic neck-shoulder pain reported increased pain intensity during and in the evenings after a light dynamic load involving painful regions. In addition, they showed decreased pain thresholds close to the exercise, indicating mechanical hyperalgesia.

Health-promoting factors in higher education for a sustainable working life - protocol for a multicenter longitudinal study.

BACKGROUND: The World Health Organization has highlighted the importance of health promotion for health service providers in order to ensure sustainable working life for individuals involved in providing health services. Such sustainability begins when students are preparing to manage their own future health and welfare in working life. It has been suggested that universities, employees and trainee health professionals should adopt or follow a salutogenic approach that not only complements the providing of information on known health risks but also favors health promotion strategies. This paper describes the study design and data collection methods in a planned study aiming to explore health-promoting factors for a sustainable working life among students in higher education within healthcare and social work. METHODS: This protocol describes a multicenter longitudinal study involving Swedish students on higher education programs in the healthcare and social work sectors. In 2018, the study invited students on seven education programs at six universities to participate. These programs were for qualification as: biomedical laboratory scientists (n = 121); dental hygienists (n = 87); nurses (n = 1411); occupational therapists (n = 111); physiotherapists (n = 48); radiographers (n = 60); and, social workers (n = 443). In total, 2283 students were invited to participate. Participants completed a baseline, a self-reported questionnaire including six validated instruments measuring health-promoting factors and processes. There are to be five follow-up questionnaires. Three while the students are studying, one a year after graduating, and one three years after graduating. Each questionnaire captures different health-promoting dimensions, namely: health-promoting resources (i.e. sense of coherence); occupational balance; emotional intelligence; health and welfare; social interaction; and work and workplace experiences/perceptions. DISCUSSION: This study focuses on the vastly important aspect of promoting a sustainable working life for healthcare and social work employees. In contrast to previous studies in this area, the present study uses different, validated instruments in health promotion, taking a salutogenic approach. It is hoped that, by stimulating the implementation of new strategies, the study's findings will lead to education programs that prepare students better for a sustainable working life in healthcare and social work.

Microphysical explanation of the RH-dependent water affinity of biogenic organic aerosol and its importance for climate.

A large fraction of atmospheric organic aerosol (OA) originates from natural emissions that are oxidized in the atmosphere to form secondary organic aerosol (SOA). Isoprene (IP) and monoterpenes (MT) are the most important precursors of SOA originating from forests. The climate impacts from OA are currently estimated through parameterizations of water uptake that drastically simplify the complexity of OA. We combine laboratory experiments, thermodynamic modeling, field observations, and climate modeling to (1) explain the molecular mechanisms behind RH-dependent SOA water-uptake with solubility and phase separation; (2) show that laboratory data on IP- and MT-SOA hygroscopicity are representative of ambient data with corresponding OA source profiles; and (3) demonstrate the sensitivity of the modeled aerosol climate effect to assumed OA water affinity. We conclude that the commonly used single-parameter hygroscopicity framework can introduce significant error when quantifying the climate effects of organic aerosol. The results highlight the need for better constraints on the overall global OA mass loadings and its molecular composition, including currently underexplored anthropogenic and marine OA sources.

Different DHEA-S Levels and Response Patterns in Individuals with Chronic Neck Pain, Compared with a Pain Free Group-a Pilot Study.

Objective: To test, in this pilot study, whether DHEA-S (Dehydroepiandrosterone, sulfated form) plasma levels are lower among persons with chronic neck pain, compared to control persons, and to investigate the DHEA-S response after a physical exercise. Subjects: Included were 12 persons with chronic neck pain and eight controls without present pain, all 18 and 65 years of age. Exclusion criteria for both groups were articular diseases or tendinosis, fibromyalgia, systemic inflammatory and neuromuscular diseases, pain conditions due to trauma, or severe psychiatric diseases. Design and methods: The participants arm-cycled on an ergometer for 30 minutes. Blood samples were taken before, 60 minutes, and 150 minutes after this standardized physical exercise. Results: The estimated plasma DHEA-S levels at baseline were 2.0 µmol/L (95% confidence interval [CI] 1.00; 4.01) in the pain group and 4.1 µmol/L (95% CI2.0; 8.6) in the control group, adjusted for sex, age, body mass index (BMI), and Shirom-Melamed Burnout Questionnaire (SMBQ), with a ratio of 0.48 ( P = 0.094). Conclusions: In this pilot study, the plasma DHEA-S levels appeared to be lower among the persons with chronic neck pain, compared with the control group. It was indicated that DHEA-S decreased during the physical exercise in the control group, and either increased or was unaffected in the chronic pain group.

Psoriasin (S100A7) promotes stress-induced angiogenesis.

BACKGROUND: Vascular modifications occur early in the development of psoriasis, and angiogenesis is one of the key features in the pathogenesis of the disease. OBJECTIVES: To identify the role of the S100 protein psoriasin in psoriasis-associated angiogenesis. METHODS: The role of psoriasin in mediating angiogenesis was investigated by silencing psoriasin with small interfering RNA (siRNA) and measuring psoriasis-associated angiogenic factors in human epidermal keratinocytes. The secretion of psoriasin and the effect of psoriasin on general regulators of angiogenesis in keratinocytes, and on endothelial cell migration, proliferation, tube formation and production of angiogenic mediators, was evaluated. RESULTS: Reactive oxygen species (ROS) and hypoxia induced the expression of psoriasin. Downregulation of psoriasin in keratinocytes using siRNA altered the ROS-induced expression of the psoriasis-associated angiogenic factors vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor-like growth factor, matrix metalloproteinase 1 and thrombospondin 1. Overexpression of psoriasin altered several regulators of angiogenesis and led to the secretion of psoriasin. Treatment with extracellular psoriasin induced proliferation, migration and tube formation in dermal-derived endothelial cells to a similar extent as VEGF and interleukin-17, and induced the expression and release of proangiogenic mediators. These effects were suggested to be mediated by the PI3K and nuclear factor kappa B pathways. CONCLUSIONS: These findings suggest that psoriasin expression is promoted by oxidative stress in keratinocytes and amplifies the ROS-induced expression of angiogenic factors relevant to psoriasis. Moreover, extracellularly secreted psoriasin may act on dermal endothelial cells to contribute to key features angiogenesis.

Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels.

OBJECTIVE: Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. METHOD: We measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). RESULTS: Plasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. CONCLUSION: We suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

Genetic variations of NLRP1: susceptibility in psoriasis.

BACKGROUND: NACHT, LRR and PYD domain-containing protein (NLRP)1 is part of the inflammasome multiprotein complex involved in the production of interleukin (IL)-1ß and IL-18, two cytokines strongly implicated in psoriasis pathogenesis. Genetic variations in NLRP1 are associated with a predisposition for chronic inflammatory conditions. OBJECTIVES: The aim of the study was to investigate the role of genetic variation in the NLRP1 inflammasome in psoriasis susceptibility. MATERIAL AND METHODS: Four haplotype-tagging single-nucleotide polymorphisms (SNPs) (rs6502867, rs8079034, rs878329 and rs12150220) were investigated by TaqMan allelic discrimination in a patient sample comprising 1847 individuals from 478 families and 802 healthy controls. RESULTS: Using the transmission disequilibrium test, a significant increase in the transmission of the NLRP1 rs8079034C and rs878329C alleles to patients with psoriasis was demonstrated (P = 0·006 and P = 0·033, respectively). Furthermore, homozygosity for the rs878329C allele correlated with a younger age of onset. We also observed an increase in the expression of NLRP1 mRNA in the peripheral blood cells of patients with psoriasis. This was accompanied by a higher level of circulating IL-18 and appeared to be associated with the rs878329C allele. CONCLUSIONS: Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.

Global emissions of terpenoid VOCs from terrestrial vegetation in the last millennium.

We investigated the millennial variability (1000 A.D.-2000 A.D.) of global biogenic volatile organic compound (BVOC) emissions by using two independent numerical models: The Model of Emissions of Gases and Aerosols from Nature (MEGAN), for isoprene, monoterpene, and sesquiterpene, and Lund-Potsdam-Jena-General Ecosystem Simulator (LPJ-GUESS), for isoprene and monoterpenes. We found the millennial trends of global isoprene emissions to be mostly affected by land cover and atmospheric carbon dioxide changes, whereas monoterpene and sesquiterpene emission trends were dominated by temperature change. Isoprene emissions declined substantially in regions with large and rapid land cover change. In addition, isoprene emission sensitivity to drought proved to have significant short-term global effects. By the end of the past millennium MEGAN isoprene emissions were 634 TgC yr-1 (13% and 19% less than during 1750-1850 and 1000-1200, respectively), and LPJ-GUESS emissions were 323 TgC yr-1(15% and 20% less than during 1750-1850 and 1000-1200, respectively). Monoterpene emissions were 89 TgC yr-1(10% and 6% higher than during 1750-1850 and 1000-1200, respectively) in MEGAN, and 24 TgC yr-1 (2% higher and 5% less than during 1750-1850 and 1000-1200, respectively) in LPJ-GUESS. MEGAN sesquiterpene emissions were 36 TgC yr-1(10% and 4% higher than during 1750-1850 and 1000-1200, respectively). Although both models capture similar emission trends, the magnitude of the emissions are different. This highlights the importance of building better constraints on VOC emissions from terrestrial vegetation.

Contact formation in random networks of elongated objects.

The effect of steric hindrance is an important aspect of granular packings as it gives rise to, e.g., limitations on the densities of ordered and disordered packings, both of which are essentially defined by the geometry of the constituents. Here we focus on the random packing of rods via deposition and their distributions of contact number and segment length. Such statistical properties are relevant for mechanical properties of the structures, but the (quite large) steric effects on them have not been addressed in previous studies. We therefore develop a theory that describes the statistical properties of rod packings, while taking into account that the deposited rods cannot overlap and thus induce steric hindrances. The distributions derived from the theory are compared with experimental results and numerical simulations of networks constructed via deposition. The results explain the non-Poisson statistics observed in the experiments and show that the induced steric range of the rods can be large compared to their diameter and decreases with compactification of the pile, implying local orientational ordering of the structure.

Activation-induced cytidine deaminase (AID) is strongly expressed in the fetal bovine ileal Peyer's patch and spleen and is associated with expansion of the primary antibody repertoire in the absence of exogenous antigens.

Due to a limited range of immunoglobulin (Ig) genes, cattle and several other domestic animals rely on postrecombinatorial amplification of the primary repertoire. We report that activation-induced cytidine deaminase (AID) is strongly expressed in the fetal bovine ileal Peyer's patch and spleen but not in fetal bone marrow. The numbers of IGHV (immunoglobulin heavy chain variable) mutations correlate with AID expression. The mutational profile in the fetuses is similar to postnatal and immunized calves, with targeting of complementarity-determining region (CDR) over framework region (FR), preference of replacement over silent mutations in CDRs but not in FRs, and targeting of the AID hotspot motif RGYW/WRCY. Statistical analysis indicates negative selection on FRs and positive selection on CDRs. Our results suggest that AID-mediated somatic hypermutation and selection take place in bovine fetuses, implying a role for AID in the diversification of the primary antibody repertoire in the absence of exogenous antigens.

Systemic up-regulation of TLR4 causes lipopolysaccharide-induced augmentation of nasal cytokine release in allergic rhinitis.

BACKGROUND: Allergic rhinitis is a systemic disorder, and it is clinically well recognized that it can be aggravated by infection. Activation of the innate immune system constitutes a critical element in the process. Toll-like receptors (TLRs) comprise a part of the innate immune system, and lipopolysaccharide (LPS)-induced activation of TLR4 represents bacterial-induced interactions in various model systems. The present study examines how TLR2 and TLR4 expression is affected by symptomatic allergic rhinitis, and if LPS added upon allergen affects nasal cytokine release. METHODS: In patients with pollen-induced allergic rhinitis and healthy non-allergic volunteers, nasal lavage (NAL), peripheral blood and bone marrow were sampled before and during the pollen season. TLR2 and TLR4 expression was determined flow cytometrically. Changes in the TLR receptor expression pattern were evaluated by a nasal challenge with allergen followed by LPS, or vice versa. Symptoms along with cells and cytokines in NAL were analyzed. RESULTS: TLR4 expression increased in leukocytes in NAL, peripheral blood and bone marrow during symptomatic allergic rhinitis. A similar increase was seen for TLR2 in neutrophils in blood. Nasal challenge with allergen followed by LPS augmented the release of IL-4, IL-5, IL-10, IL-13, IFN-γ and TNF-α. CONCLUSION: A systemic up-regulation of TLR4 in symptomatic allergic rhinitis may explain why LPS preceded by allergen increases nasal cytokine release.

Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor.

BACKGROUND: The existence of a link between inflammation in upper and lower airways is well established. It may therefore be assumed that the nose could be used to study inflammatory events in the lower airways. OBJECTIVE: This study aimed to evaluate a lipopolysaccharide (LPS) nasal challenge model by investigating the effect of the CXCR2 inhibitor AZD8309 on neutrophilic inflammation. METHODS: A total of 18 healthy volunteers were randomized in a placebo-controlled, double-blind, cross-over study. AZD8309 or placebo was dosed for 3 days. Subjects were challenged nasally with LPS (50 µg/nostril), and nasal lavage was performed 6 and 24 h later. Leucocytes, neutrophils and inflammatory mediators were assessed in the lavage fluid. The outcome was compared with data from analogous experiments performed in a model of inhaled LPS followed by induced sputum. This trial was registered in the Current Controlled Trials register (ISRCTN trial number: ISRCTN46666382). RESULTS: The leucocytes in nasal lavage consisted to 99% of neutrophils on average. Treatment with AZD8309 reduced the leucocyte count to 48% of placebo 6 h after the LPS challenge. There was also a reduction in LTB4 levels to 45% of placebo after 6 h and in the neutrophil elastase activity after 24 h. No major adverse events were seen with either AZD8309 or placebo. The nasal LPS model induced only minimal local irritation and no signs of systemic inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: LPS-induced neutrophil recruitment was reduced by inhibition of CXCR2. This outcome mimicked the response previously seen in a lower airway LPS model. Hence, the nasal model offers a convenient and well-tolerated alternative for pharmacological evaluation of anti-inflammatory drugs affecting neutrophilic migration and activity.

Pain-related fear: a critical review of the related measures.

OBJECTIVES: In regards to pain-related fear, this study aimed to: (1) identify existing measures and review their measurement properties, and (2) identify the optimum measure for specific constructs of fear-avoidance, pain-related fear, fear of movement, and kinesiophobia. DESIGN: Systematic literature search for instruments designed to measure fear of pain in patients with persistent musculoskeletal pain. Psychometric properties were evaluated by adjusted Wind criteria. RESULTS: Five questionnaires (Fear-Avoidance Beliefs Questionnaire (FABQ), Fear-Avoidance of Pain Scale (FAPS), Fear of Pain Questionnaire (FPQ), Pain and Anxiety Symptoms Scale (PASS), and the Tampa Scale for Kinesiophobia (TSK)) were included in the review. The main findings were that for most questionnaires, there was no underlying conceptual model to support the questionnaire's construct. Psychometric properties were evaluated by diverse methods, which complicated comparisons of different versions of the same questionnaires. Construct validity and responsiveness was generally not supported and/or untested. CONCLUSION: The weak construct validity implies that no measure can currently identify who is fearful. The lack of evidence for responsiveness restricts the current use of the instruments to identify clinically relevant change from treatment. Finally, more theoretically driven research is needed to support the construct and thus the measurement of pain-related fear.

Genetic variability within the innate immune system influences personality traits in women.

Raised levels of inflammation markers have been associated with several mental disorders; however, studies regarding the relationship between inflammation or the immune system and various aspects of human behaviour are not numerous. The aim of the present study was to investigate whether an association exists between personality traits and two single nucleotide polymorphisms located in genes that are associated with the innate immune system. The studied population consisted of 42-year-old women recruited from the population registry that had been assessed by means of Karolinska Scales of Personality, a self-reported inventory. The first polymorphism, +1444C>T (rs1130864), is located in the gene coding for C-reactive protein (CRP), a marker of low-grade inflammation. The T-allele has previously been suggested to be linked to raised serum levels of CRP. The second polymorphism, Y402H (1277T>C, rs1061170), is located in the gene coding for complement factor H, an important regulator of the complement system. The C-allele has consistently been associated with age-related macular degeneration. While the +1444T allele was associated with higher scores in the personality traits impulsiveness, monotony avoidance and social desirability, the 1277C polymorphism was associated with higher scores in verbal aggression and lower scores in social desirability. In conclusion, the associations between the personality traits and the studied polymorphisms further support the possible influence of the immune system on mental functions.

Stable serum levels of relaxin throughout the menstrual cycle: a preliminary comparison of women with premenstrual dysphoria and controls.

Serum levels of relaxin in 25 women with premenstrual dysphoria and 25 age-matched controls were determined at three time points during the menstrual cycle. At the same time, levels of estradiol, progesterone, 17-beta-OH-progesterone, free testosterone, total testosterone, sex hormone binding hormone, androstenedione, dehydroepiandrosterone sulphate, and 3-alpha-androstanediol glucuronide were determined. Detectable levels of relaxin were found in all women in both the follicular and luteal phase as well as around ovulation, the inter-individual variations being larger than intra-individual differences. The levels of relaxin were not influenced by the fluctuation of the other reproductive hormones. A significant difference between the two groups of women was observed, subjects with premenstrual dysphoria displaying reduced levels of relaxin (p < 0.05) compared to controls. Also, when analysed with respect to a variable number of tandem repeats polymorphism (CT repeats followed by GT repeats) in the promotor region of the relaxin H2 gene, women with premenstrual dysphoria (n = 29) were found to display significantly longer GT repeats than controls (n = 35).

A comparison of bispectral index and rapidly extracted auditory evoked potentials index responses to noxious stimulation during sevoflurane anesthesia.

In 21 patients given sevoflurane anesthesia, we simultaneously compared the abilities of Bispectral Index (BIS) and rapidly extracted auditory evoked potentials index (AAI) to display the effect of an increasing cerebral concentration of sevoflurane, with and without noxious stimulation. In addition to BIS/AAI, hemodynamic variables were monitored. After titrating sevoflurane to BIS = 50-55 during 15 min, the end-tidal concentration of sevoflurane (1.46% +/- 0.20%) was doubled followed by a noxious stimulus, laryngoscopy, applied at random time points within the following 15 min. After the end-tidal concentration of sevoflurane was doubled, a substantial reduction in BIS was observed, whereas only a slight reduction in AAI was seen (P < 0.0001). BIS/AAI responses to laryngoscopy were not attenuated with increasing wash-in of sevoflurane. After noxious stimulation, AAI exceeded the highest recommended value, 25, in 3 cases, whereas BIS did not exceed the recommended threshold, 60, in any of the patients. Response times for BIS and AAI were 44.5 +/- 26 and 47 +/- 31 s, respectively. These results suggest that, at a hypnotic level associated with surgical sevoflurane anesthesia, BIS better displays drug-related alterations in the level of hypnosis than AAI or hemodynamic variables but there is no difference between BIS and AAI in the time to response to a noxious stimulus.