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This study investigates whether baseline pain extent, extracted from an electronic pain drawing, is an independent predictive factor of pain and disability measured 1 year and 2 years later in people with chronic WAD. Participants completed questionnaires assessing neck pain intensity, disability via the Neck Disability Index (NDI), psychological features, and work ability. Participants also completed electronic pain drawings from which their pain extent was extracted. A two-step modelling approach was undertaken to identify the crude and adjusted association between pain extent and NDI measured at 1-year and 2-year follow-ups. A total of 205 participants were included in the analysis. The univariate analysis showed that pain extent was significantly associated with the NDI score at the 1-year (p = 0.006, 95% CI: 0.159–0.909) and 2-year (p = 0.029, 0.057–0.914) follow-ups. These associations were not maintained when we introduced perceived disability, psychological health, and work ability into the model after 1 year (p = 0.56, 95%CI: −0.28–0.499) and 2 years (p = 0.401, −0.226–0.544). Pain extent, as an independent factor, was significantly associated with perceived pain and disability in patients with chronic WAD for up to 2 years. This association was masked by neck disability, psychological health, and work ability.

BACKGROUND More than 40% of individuals with whiplash injury experience persistent neck pain and disability years later, called whiplash-associated disorders (WAD). A randomized controlled trial evaluated three exercise interventions in WAD and found that neck-specific exercise (NSE) and NSE with a behavioral approach (NSEB) significantly improve disability compared to prescribed physical activity (PPA). However, the relationship between neck-related function and disability is inconclusive and needs to be further investigated. AIM The present study compares the effect of NSE, NSEB, and PPA on neck muscle endurance (NME), active cervical range of motion (AROM), grip strength, and pain intensity immediately before and after the physical tests, and neck disability in individuals who are below or above the cut-off for normative reference values regarding NME, AROM, and grip strength. DESIGN Follow-up to a multicenter randomized clinical trial. SETTING Primary healthcare centers and hospital outpatient services. POPULATION The selected population of this study included 216 patients with persistent WAD grades II and III. METHODS This is a secondary analysis including 12 months' follow-up. NME, AROM, grip strength, pain, and self-reported disability were recorded at baseline, 3, 6, and 12 months. Linear mixed models were used, and sub-group analyses evaluated by non-parametric tests. RESULTS NSE and NSEB resulted in greater improvements compared to PPA (P

Background Neck and shoulder pain is common in the general population, but studies on factors related to the risk of neck and shoulder pain have produced inconclusive results. Known factors related to pain include general physical activity, exercise, sleep disorders, and lifestyle, but further research is needed to improve our ability to prevent neck and shoulder pain. The aim was to investigate whether neck and shoulder pain are associated with physical domains (i.e., aerobic physical activities, general physical activities, and sitting time), sleep disturbances, general health, job satisfaction, and/or working time. Methods This population-based, cross-sectional study was conducted in Sweden in 2017 and included 16,167 individuals, aged 18 to 63 years. We administered a questionnaire to determine neck and shoulder pain, the time spent in general physical activity or aerobic physical activity, the time spent sitting, sleep disturbances, general health, job satisfaction, and the time spent working. Factors associated with neck and shoulder pain were explored using logistic regression. Results Significant factors associated with neck and shoulder pain were: overall health, sleep quality, and aerobic exercise. The odds of sustaining neck and shoulder pain increased with moderate or poor health (odds ratios [ORs]: 2.3 and 2.8, respectively) and sleep disorders (OR: 1.7). Conversely, aerobic physical activity performed more than 60 min/week at a level that enhanced respiratory and heart rate was associated with a reduced risk of experiencing neck and shoulder pain (OR: 0.8). Conclusions Although no causal relationships could be determined in the present study, the results highlight important associations between aerobic exercise, undisturbed sleep, good health, and the absence of upper body pain. Exercises that enhance breathing and heart rate were associated with a reduced risk of experiencing neck or shoulder pain, but there was no association between general physical activity and upper body pain. Therefore, clinicians may not recommend low-intensity activities, such as walking, for preventing or improving neck and shoulder pain.

Objective The objective of this study was to evaluate an extended role for the physiotherapist in primary care in referring patients to plain X-ray. Methods This prospective cohort study was set in a single region in Sweden. It included 20 physiotherapists who were educated in a 1-day training in performing referral to X-ray, along with 107 patients with musculoskeletal disorders who were referred to X-ray. We evaluated referral quality and patient and physiotherapist satisfaction and calculated healthcare and patient costs. Results All referrals fulfilled the basic requirements of quality, and 78% were classified as good, fulfilling all criteria. Both patients and physiotherapists were satisfied with the extended role for the physiotherapist that decreased the waiting time to diagnosis and to adequate treatment. Costs were reduced for patients (by €53/patient) and healthcare (by €6286.2/107 patients). The cost to visit a physician was twice that of a physiotherapist visit. Conclusions An extended role for physiotherapists in primary care in referring patients to X-ray was effective and safe for patients and reduced costs for patients and for healthcare. Physiotherapists in primary care were able to refer patients to X-ray after a 1 day of training, and the extended role freed up 45 min of physician time for each patient with a musculoskeletal disorder in need of an X-ray.

Neck disorders are common in primary health care (PHC) physiotherapy. A neck-specific exercise program based on research findings was implemented among physiotherapists in Swedish PHC. The aim of the study was to evaluate the adoption of the program. We invited PHC physiotherapists to an educational session including theoretical information and practical training. Before the educational session the participants (n = 261) completed a baseline questionnaire. After 3 and 12 months, we distributed surveys to identify changes in practice and in confidence regarding diagnosis and treatment. We compared data from 3-months and 12-months follow-up, respectively, with baseline data. Self-reported frequency of most of the included assessment methods was unchanged after 12 months. Frequency of assessment of neck proprioception had increased significantly. Specific neck muscle exercise for treatment of whiplash associated disorders was applied more frequently after 3 and after 12 months than at baseline. Frequency of other treatment methods remained unchanged. Confidence in diagnosis and treatment increased significantly, particularly among women. The program was not adopted as expected, but resulted in increased confidence regarding diagnosis and treatment. The provision of a short educational session seemed not to be sufficient to obtain a sustained change in practice.

Background: Years after whiplash injury, more than 40 % of people experience persistent neck pain and disability, called whiplash-associated disorders (WAD). The relations between neck related function, neck pain and disability are inconclusive and need to be further investigated. The aims were; a) to compare the effect of three different exercise interventions – neck-specific exercise (NSE), NSE with a behavioral approach (NSEB) and prescribed physical activity (PPA) – on neck-muscle endurance (NME), active cervical range of motion (AROM), grip strength and pain intensity immediately before and after the tests, and b) to compare neck-disability in individuals who are below or above the cut-off for normative reference values of healthy individuals regarding NME, AROM and grip strength.Methods: This is a secondary analysis of a randomized controlled multicenter study including 12 months’ follow-up. A total of 216 individuals with chronic WAD grades II or III were recruited. Data were recorded at baseline, 3, 6, and 12 months. Linear mixed models were used and sub-group analyses were evaluated with non-parametric tests.Results: NSE and NSEB resulted in greater improvements compared to PPA (p < .01) and were maintained at 12 months’ follow-up in ventral (only males) and dorsal NME, AROM and pain intensity during testing. In grip strength, there were no significant between-group differences (p > 0.05). There were no significant differences between the NSE and NSEB groups (p > .05). Sub-group analyses revealed improvement in disability at 12 months follow-up in NSE and/or NSEB for individuals both below and above the cut-off reference value in NME and AROM. More severe disability was seen in individuals below the reference values both at baseline and 12 months’ follow-up. Individuals in the PPA group below the reference values in NME and AROM reported increasing disability at 12 months compared to baseline.Conclusion: The results suggest that neck-specific exercises (NSE, NSEB) improved clinical function and decreased disability in chronic WAD compared to PPA. The results may imply that higher neck-related clinical function can be important for reduced disability. Trial Registration: ClinicalTrials.gov: NCT01528579, date of registration: February 8, 2012, retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT0152857

Objective The aim of this study was to investigate and compare the mechanical responses of dorsal neck muscles in individuals with whiplash-associated disorders (WAD) versus healthy individuals. Design This study included 36 individuals with WAD (26 women and 10 men) and 36 healthy controls (26 women and 10 men). Ultrasound imaging with speckle tracking was used to measure deformation and deformation rate in five dorsal neck muscles during a neck extension task. Results Compared with controls, individuals with WAD showed higher deformations of the semispinalis cervicis (P = 0.02) and multifidus (P = 0.002) muscles and higher deformation rates (P = 0.03 and 0.0001, respectively). Among individuals with WAD, multifidus deformation and deformation rate were significantly associated with pain, disability, and fatigue (r = 0.31-0.46, P = 0.0001-0.01). Conclusions These findings indicate that the mechanical responses of the deep dorsal neck muscles differ between individuals with WAD and healthy controls, possibly reflecting that these muscles use altered strategies while performing a neck extension task. This finding provides new insight into neck muscles pathology in patients with chronic WAD and may help improve rehabilitation programs. To Claim CME Credits Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME Objectives Upon completion of this article, the reader should be able to: (1) Summarize the mechanical responses of dorsal neck muscles during loading of the neck muscles via an extension task in individuals with chronic whiplash associated disorders and healthy volunteers; (2) Differentiate mechanical responses between five dorsal neck muscles while loading the neck via an extension task; and (3) Describe the relationships between the mechanical responses of the dorsal neck muscles with the patients perception of neck pain, disability, and fatigue. Level Advanced Accreditation The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Funding Agencies|Swedish government; Swedish Social Insurance Agency through the REHSAM Foundation [RS2010/009]; Uppsala Orebro Regional Research Council Sweden; Swedish Research Council, Centre for Clinical Research Sormland at Uppsala University Sweden

Up to 90% of people with neurological deficits following whiplash injury report chronic symptoms. A recent unique study of neck-specific exercise showed positive results (post-intervention at 12 weeks), regarding arm pain and neurological deficits in people with chronic whiplash associated disorders (WAD). This 1-year follow-up of that randomised controlled study with assessor blinding aimed to examine whether neck-specific exercise with (NSEB) or without (NSE) a behavioural approach has long-term benefits over physical activity prescription (PPA) regarding arm pain and neurological deficits (n=171). Interventions were: NSE, NSEB, or PPA. Follow-up of arm pain, paraesthesia bothersomeness (questionnaires) and clinical neurological tests were performed after 3, 6 and 12 months and analysed with Linear Mixed Models and General Estimating Equations. The NSE and/or NSEB groups reported significantly less pain and paraesthesia bothersomeness as well as higher odds of normal key muscle arm strength and of normal upper limb neural tension over the year (all pFunding Agencies|Swedish government through the REHSAM Foundation [RS2010/009]; Swedish Research CouncilSwedish Research Council [521-2014-2982]; County Council of ostergotland [LIO-533041, LIO-439541, LIO-197631, LIO-276151, LIO-354241]; Centre for Clinical Research Sormland at Uppsala University [DLL-553281, DLL-465071, DLL-221851, DLL-112241, DLL-376711]; Medical Research Council of Southeast Sweden [FORSS-472691, FORSS-302601, FORSS-384421]; Uppsala-orebro Regional Research Council [RFR-384651, RFR-150591, RFR-297301, RFR-215571]; Linkoping University, Sweden; Linkoping University; regional Centre for Clinical Research [LIO-533041, LIO-439541, LIO-197631, LIO-276151, LIO-354241]

Objectives: Neck-specific exercise can reduce neck pain and increase function, but information on how different neck muscle layers are activated during neck exercises is scarce. The aim of this study was to investigate deformation and deformation rate in 5 dorsal neck muscles and the correlation among these muscles during a loaded dynamic exercise used in clinical practice. Methods: Deformation and deformation rate were investigated in 5 dorsal right-sided neck muscles in 20 individuals without neck pain using ultrasonography and speckle-tracking analyses. Repeated-measures analysis of variance was used to measure differences between the muscles, and correlations between neck muscles were analyzed with Kendalls tau. Results: Deformation in left (contralateral) rotation showed significant differences among the muscles (P = .01), with higher deformation of the semispinalis capitis muscle compared with the trapezius muscle (P = .02). There were no significant differences among the 5 neck muscles in right (unilateral) rotation (P = .46). There were significant differences in deformation rate among muscles in both right and left rotation (P < .01). The trapezius muscles have the lowest deformation rate in right rotation (P < .01). In left rotation, the trapezius and multifidus muscles showed lower deformation rates compared with most of the other muscles (P < .03). Almost all muscles were correlated in both deformation and deformation rate. Conclusion: The quadruped standing loaded dynamic neck exercise seemed to activate all the investigated neck muscles, with a tendency for more activation of the semispinalis capitis.

The development of methods of non-invasive measurement of neck muscle function remains a priority in the clinical sciences. In this study, dorsal neck muscle deformation vs time curves (deformation area) were evaluated against incremental force, recorded from non-invasive real-time ultrasound measurement. The results revealed subject-specific moderate to strong linear or non-linear relationships between deformation and force. Test-retest variability showed strong reliability for all five neck muscles summed together and fair to good reliability for the five muscles evaluated separately. Multivariate statistics were used to analyse the interactions between the dorsal neck muscles during different percentages of maximal voluntary contraction (MVC). Low force (10-20% MVC) was related to muscle shortening; higher force (40-80% MVC) showed combination of shortening and elongation deformation in the muscle interactions. The muscle interactions during isometric MVC test were subject-specific, with different combinations and deformations of the five neck muscles. Force amp;gt;= 40% MVC were associated with a forward movement of the cervical spine that affected the ultrasound measurement of the dorsal neck muscles. Ultrasound with speckle-tracking analyses may be best used to detect low levels (amp;lt;40% MVC) of neck muscle activity. Funding Agencies|Swedish government; Swedish Social Insurance Agency through the REHSAM foundation; Swedish Research CouncilSwedish Research Council; Centre for Clinical Research Sormland at Uppsala University Sweden; Swedish Society of Medicine

Patient enablement reflects patient's understanding of and coping with illness. The aim of this study was to investigate the content validity, construct validity, internal consistency and self-rated change (SRC) of the Patient Enablement Instrument (PEI) in patients with whiplash-associated disorders, cervical radiculopathy and mixed chronic pain treated in different settings.Psychometric analyses.Patients with disabling non-malignant chronic musculoskeletal pain.Participants answered questionnaires on disability (Neck Disability Index (NDI) or Functional Rating Index (FRI)), anxiety/depression (Hospital Anxiety and Depression Scale; HADS) and general health (EuroQol; EQ-5D). Content validity, construct validity (confirmatory factor analysis), internal consistency and cut-off for SRC were investigated for the PEI after treatment. The SRC value was the receiver operating characteristic (ROC) curve optimal cut-off point.After treatment all items were completed by 516 patients (mean standard deviation (SD) age 45.1 years (SD 10.1), women 75% (n = 385)). The 1-factor PEI model had approximate fit to the data. The internal consistency Cronbach's alpha was between 0.878 and 0.929 for the 3 groups. Correlations between the PEI and the NDI/FRI, HADS and EQ-5D were fair to good. The SRCROC for whiplash-associated disorders, cervical radiculopathy and mixed chronic pain groups was 5, 6 and 4 points in the PEI, respectively.The PEI showed fair content validity, construct validity and internal consistency. However, the scale needs further development to improve measurement of change.

Objectives: The present studys objective was to understand the causal mechanisms underpinning the recovery of individuals with whiplash-associated disorders (WAD). We applied Bayesian Networks (BN) to answer 2 study aims: (1) to identify the causal mechanism(s) of recovery underpinning neck-specific exercise (NSE), and (2) quantify if the cyclical pathway of the fear-avoidance model (FAM) is supported by the present data. Materials and Methods: We analyzed a prospective cohort data set of 216 individuals with chronic WAD. Fifteen variables were used to build a BN model: treatment group (NSE with or without a behavioral approach, or general physical activity), muscle endurance, range of motion, hand strength, neck proprioception, pain catastrophizing, fear, anxiety, depression, self-efficacy, perceived work ability, disability, pain intensity, sex, and follow-up time. Results: The BN model showed that neck pain reduction rate was greater after NSE compared with physical activity prescription (beta=0.59 points per month [Pamp;lt;0.001]) only in the presence of 2 mediators: global neck muscle endurance and perceived work ability. We also found the following pathway of variables that constituted the FAM: anxiety, followed by depressive symptoms, fear, catastrophizing, self-efficacy, and consequently pain. Conclusions: We uncovered 2 mediators that explained the mechanisms of effect behind NSE, and proposed an alternative FAM pathway. The present study is the first to apply BN modelling to understand the causal mechanisms of recovery in WAD. In doing so, it is anticipated that such analytical methods could increase the precision of treatment of individuals with chronic WAD. Funding Agencies|Swedish government through the REHSAM Foundation; Swedish Research Council; regional Center for Clinical Research; County Council of Ostergotland; Centre for Clinical Research Sormland at Uppsala University; Medical Research Council of Southeast Sweden; Uppsala-Orebro Regional Research Council, Sweden

Study Design Secondary analysis of a randomized clinical trial. Background Patient perception of the benefits gained from treatment is important, yet satisfaction with the outcome of treatment for chronic whiplash-associated disorders (WADs) has not been investigated. Objectives To investigate whether satisfaction with the outcome of treatment for chronic WAD changed over time, and whether there were group differences. Methods Two hundred sixteen people with chronic WAD (66% women; mean age, 40.4 years) participated in a 3-month program of physical therapist-led neck-specific exercises with or without a behavioral approach, or received a prescription of general physical activity. The main outcome was satisfaction with the outcome of treatment, assessed at baseline and 3, 6, and 12 months later. Additional outcomes were enablement and expectation fulfillment. Results Satisfaction improved over time in the 3 groups (odds ratio = 1.15; 95% confidence interval: 1.10, 1.20; P

Introduction Patients suffering from remaining disability after anterior cervical decompression and fusion (ACDF) surgery for cervical disc disease may be prescribed physical activity (PPA) or neck-specific exercises (NSEs). Currently, we lack data for the success of either approach. There is also a knowledge gap concerning the use of internet-based care for cervical disc disease. The scarcity of these data, and the high proportion of patients with various degrees of incapacity following ACDF, warrant increased efforts to investigate and improve cost-effective rehabilitation. The objective is to compare the effectiveness of a structured, internet-based NSE programme, versus PPA following ACDF surgery. Methods and analysis This is a prospective, randomised, multicentre study that includes 140 patients with remaining disability (≥30% on the Neck Disability Index, NDI) following ACDF for radiculopathy due to cervical disc disease. Patient recruitment occurs following attendance at routine clinical appointments, scheduled at 3 months postsurgery. Patients are then randomised to one of two groups (70 patients/group) for a 3-month treatment programme/period of either internet-based NSE or PPA. Questionnaires on background data, pain and discomfort, physical and mental capacity, satisfaction with care, and health and workplace factors are completed, along with physical measures of neck-related function conducted by independent test leaders blinded to randomisation. Measures are collected at inclusion, after the 3-month treatments (end of treatment) and at a 2-year follow-up. Radiography will be completed at the 2-year follow-up. Preoperative data will be collected from the Swedish Spine Registry. Data on healthcare consumption, drug use and sick leave will be requested from the relevant national registers. Ethical considerations This study was approved by the Regional Ethical Review Board in Linköping Ref. 2016/283–31 and 2017/91– 32. The scientists are independent with no commercial ties. Patients are recruited after providing written informed consent. Patient data are presented at group level such that no connection to any individual can be made. All data are anonymised when reported, and subject to the Swedish Official Secrets Health Acts. The test leaders are independent and blinded for randomisation. Exercises, both general and neck-specific, have been used extensively in clinical practice and we anticipate no harm from their implementation other than a risk of muscle soreness. Both randomisation groups will receive care that is expected to relieve pain, although the group receiving NSE is expected to demonstrate a greater and more cost-effective improvement versu s the PPA group. Any significant harm or unintended effects in each group will be collected by the test leaders. All questionnaires and test materials are coded by the research group, with code lists stored in locked, fireproof file cabinets, housed at the university in a room with controlled (card-based) access. Only individuals in receipt of a unique website address posted by the researchers can access the programme; patients can neither communicate with each other nor with caregivers via the programme. Study participation might lead to improved rehabilitation versus non-participation, and might therefore be of benefit. The results of this study should also contribute to more effective and flexible rehabilitation, shorter waiting times, lower costs and the possibility to implement our findings on a wider level. Dissemination If effective, the protocols used in this study can be implemented in existing healthcare structures. The results of the study will be presented in scientific journals and popular science magazines of relevance to health. The findings will also be presented at local, regional, national and international conferences and meetings, as well as in the education of university students and at public lectures. Information about the results will be communicated to the general population in cooperation with patient organisations and the media. Trial registration NCT03036007.

Purpose The aim was to evaluate whether neck-specific exercise, with (NSEB) or without (NSE) a behavioural approach, improves health-related quality of life (HRQoL) compared to physical activity prescription (PPA) in chronic whiplash-associated disorders (WAD) grades 2 and 3. A secondary aim was to identify factors associated with HRQoL and HRQoL improvement following exercise interventions. Methods This is a secondary analysis of a multicentre randomized clinical trial. Participants (n = 216) with chronic WAD grades 2 and 3 were randomized to 12 weeks of PPA or physiotherapist-led NSE or NSEB. The EQ-5D 3L/EQ-VAS and SF-36v2 physical (PCS) and mental (MCS) component summaries were collected together with several neck-related and psychosocial outcomes at baseline, after 3, 6 and 12 months, and were analysed with linear mixed models (all time points) and multivariate linear regressions (baseline, 6 months). Results NSE/NSEB resulted in better outcomes than PPA (EQ-VAS and SF-36 PCS, both groups, p p p R2 = 0.38–0.59) were both neck-related and psychosocial (e.g. depression, work ability). Conclusion Neck-specific exercise, particularly with a behavioural approach, may have a more positive impact on HRQoL than physical activity prescription in chronic WAD grades 2 and 3. HRQoL is however complex, and other factors also need to be considered. Factors associated with HRQL and improvements in HRQoL following exercise are multidimensional. Trial registration number: ClinicalTrials.gov, No. NCT01528579.

To investigate the efficacy of exercise interventions and factors associated with changes in work ability for people with chronic whiplash-associated disorders.Secondary analysis of a single-blind, randomized multi-centre controlled trial.Interventions were conducted in Swedish primary care settings.A total of 165 individuals with chronic whiplash-associated disorders grade II-III.Participants were randomly allocated to neck-specific exercise, neck-specific exercise with a behavioural approach, or prescribed physical activity interventions. Work ability was evaluated with the Work Ability Index at baseline, 3, 6 and 12 months.The neck-specific exercise with a behavioural approach intervention significantly improved work ability compared with the prescribed physical activity intervention (3 months, p = 0.03; 6 months, p = 0.01; 12 months, p = 0.01), and neck-specific exercise at 12 months (p = 0.01). Neck-specific exercise was better than the prescribed physical activity intervention at 6 months (p = 0.05). An increase in work ability from baseline to one year for the neck-specific exercise with a behavioural approach group (p 0.01) was the only significant within-group difference. Higher self-rated physical demands at work, greater disability, greater depression and poorer financial situation were associated with poorer work ability (p0.01).This study found that neck-specific exercise with a behavioural approach intervention was better at improving self-reported work ability than neck-specific exercise or prescribed physical activity. Improvement in work ability is associated with a variety of factors.

Approximately 50% of people with Whiplash Associated Disorders (WAD) report longstanding symptoms. The upper trapezius is commonly painful yet its mechanical properties are not fully understood.This study examined the deformation of different depths of the upper trapezius muscle during a scapular elevation task (shoulder shrugging) before and following loaded arm abduction.A cross-sectional case-control study of 36 people (26 female and 10 male, mean age 38 (SD 11)) with chronic WAD and 36 controls, matched for age and gender. Real-time ultrasound recordings of upper trapezius were taken during both scapular elevation tasks. Post-process speckle tracking analysis was undertaken of three different sections of the upper trapezius muscle (superficial, middle, deep).The WAD group had lower deformation of the superficial section of the upper trapezius compared to the control group in both concentric and eccentric phases of scapular elevation (p 0.05) especially before the loaded arm abduction. After arm abduction, the deformation of the trapezius was reduced in both groups but only significantly in the WAD-group (p = 0.03). Within-group analysis revealed that the control group least engaged the deep section of upper trapezius during the task (p 0.01).This study, measuring mechanical deformation of the upper trapezius during a scapular elevation task indicates that persons with WAD may display different patterns in engagement of the muscle sections than those in the control group. Further research is needed to replicate and understand the reasons for and implications of this possible change in motor strategy within upper trapezius. Clinical Trials.gov, Number: NCT01547624.

BackgroundSome studies support the prescription of exercise for people with whiplash-associated disorders (WAD); however, the response is highly variable. Further research is necessary to identify factors which predict response. MethodsThis is a secondary analysis of a randomized, multicentre controlled clinical trial of 202 volunteers with chronic WAD (grades 2 and 3). They received either neck-specific exercise with, or without a behavioural approach, or prescription of physical activity for 12weeks. Treatment response, defined as a clinical important reduction in pain or disability, was registered after 3 and 12months, and factors associated with treatment response were explored using logistic regression. ResultsParticipation in the neck-specific exercise group was the only significant factor associated with both neck pain and neck disability reduction both at 3 and 12months. Patients in this group had up to 5.3 times higher odds of disability reduction and 3.9 times higher odds of pain reduction compared to those in the physical activity group. Different baseline features were identified as predictors of response depending on the time point examined and the outcome measure selected (pain vs. disability). ConclusionFactors associated with treatment response after exercise interventions differ in the short and long term and differ depending on whether neck pain or disability is considered as the primary outcome. Participation in a neck-specific exercise intervention, in contrast to general physical activity, was the only factor that consistently indicated higher odds of treatment success. These results support the prescription of neck-specific exercise for individuals with chronic WAD. Funding Agencies|Swedish government through the REH-SAM Foundation; Clinical Research of Ostergotland Council; Clinical Research of Sormland County Council; Medical Research Council of Southeast Sweden; Uppsala-O rebro Regional Research Council Sweden; Swedish Research Council

Background: Fifty percent of people injured by whiplash still report neck pain after 1 year and costs associated with whiplash associated disorders (WAD) are mostly attributed to health service and sick-leave costs in chronic conditions. With increasing health care expenditures the economic impact of interventions needs to be considered. Objective: To analyze the cost-effectiveness of physiotherapist-led neck-specific exercise without (NSE) or with a behavioral approach (NSEB), or prescription of physical activity (PPA) in chronic WAD, grade 2 to 3. Methods: This is a secondary cost-effectiveness analysis of a multicenter randomized clinical trial of 216 participants with chronic WAD grade 2 to 3. The interventions were physiotherapist-led neck-specific exercise without or with a behavioral approach, or prescription of physical activity for 12 weeks. Incremental cost-effectiveness ratios (ICERs) were determined after 1 year and bootstrapped cost-effectiveness planes and sensitivity analyses of physiotherapy visits were performed. Health care and production loss costs were included and quality-adjusted life years (QALYs) were estimated, using the Euroqol-5D questionnaire. Comparisons with the Short Form-6D, and neck disability index (NDI) were also made. Results: The 1-year follow-up was completed by 170 participants (79%). Both physiotherapist-led groups improved in health related quality of life. The intervention cost alone, per quality-adjusted life year (QALY) gain in the NSE group was US$ 12,067. A trend for higher QALY gains were observed in the NSEB group but the costs were also higher. The ICERs varied depending on questionnaire used, but the addition of a behavioral approach to neck-specific exercise alone was not cost-effective from a societal perspective (ICER primary outcome $127,800 [95% confidence interval [CI], 37,816–711,302]). The sensitivity analyses confirmed the results. The prescription of physical activity did not result in any QALY gain and the societal costs were not lower. Conclusion: Neck-specific exercise was cost-effective from a societal perspective in the treatment of chronic WAD compared with the other exercise interventions. ICERS varied depending on health-related quality of life questionnaires used, but the addition of a behavioral approach was not cost-effective from a societal perspective. The prescription of physical activity did not result in any QALY gain and was thus not considered a relevant option.

Objective The purposes of this study were to examine whether any differences in function and health exist between patients with cervical radiculopathy (CR) due to disk disease scheduled for surgery and patients with chronic whiplash-associated disorders (WADs) and to compare measures of patients' physical function with those obtained from healthy volunteers. Methods This is a cross-sectional study of patients with CR (n = 198) and patients with chronic WAD (n = 215). Patient data were compared with raw data previously obtained from healthy people. Physical measures included cervical active range of motion, neck muscle endurance, and hand grip strength. Self-rated measures included pain intensity (visual analog scale), neck disability (Neck Disability Index), self-efficacy (Self-Efficacy Scale), and health-related quality of life (EuroQol 5-dimensional self-classifier). Results Patient groups exhibited significantly lower performance than the healthy group in all physical measures (P < .0005) except for neck muscle endurance in flexion for women (P > .09). There was a general trend toward worse results in the CR group than the WAD group, with significant differences in neck active range of motion, left hand strength for women, pain intensity, Neck Disability Index, EuroQol 5-dimensional self-classifier, and Self-Efficacy Scale (P < .0001). Conclusions Patients had worse values than healthy individuals in almost all physical measures. There was a trend toward worse results for CR than WAD patients.

Whiplash Associated Disorders (WAD) refers to the multifaceted and chronic burden that is common after a whiplash injury. Tools to assist in the diagnosis of WAD and an increased understanding of neck muscle behaviour are needed. We examined the multilayer dorsal neck muscle behaviour in nine women with chronic WAD versus healthy controls during the entire sequence of a dynamic low-loaded neck extension exercise, which was recorded using real-time ultrasound movies with high frame rates. Principal component analysis and orthogonal partial least squares were used to analyse mechanical muscle strain (deformation in elongation and shortening). The WAD group showed more shortening during the neck extension phase in the trapezius muscle and during both the neck extension and the return to neutral phase in the multifidus muscle. For the first time, a novel non-invasive method is presented that is capable of detecting altered dorsal muscle strain in women with WAD during an entire exercise sequence. This method may be a breakthrough for the future diagnosis and treatment of WAD.

Background. Whiplash associated disorders (WAD) are a complex phenomenon associated with relevant social and economic burdens. Many people with chronic WAD show widespread pain which can be observed from the patient’s pain drawing. No studies have evaluated the relation of pain extent to perceived pain and disability, financial status, general health and psychological status in individuals with chronic WAD. Purpose. To evaluate the relation of pain extent to a number of variables related to the patients’ perceived pain and disability, their financial status, general health and psychological status. Methods. A total of 205 individuals with chronic WAD grade 2 or 3 were selected. The main outcome measure was pain extent, extracted from the pain drawing. Pain extent was evaluated in relation to sex, age, educational level, insurance status and financial status. Multiple linear regression analysis was then used to verify whether pain extent was significantly associated with the other health indicators including perceived pain intensity and disability, health-related quality of life, pain catastrophizing, anxiety, depression and self-efficacy. Results: Pain extent was influenced by the sex of the participant (p

BackgroundCompletion of a pain drawing is a familiar task in those presenting with whiplash-associated disorders (WAD). Some people report pain almost over their entire body. Yet the reasons for larger pain extent have not been fully explored. MethodsA novel method was applied to quantify pain extent from the pain drawings of 205 individuals with chronic WAD. Pain extent was evaluated in relation to sex, age, educational level, insurance status and financial status. Multiple linear regression analysis was used to verify whether pain extent was associated with other health indicators including perceived pain and disability, health-related quality of life, pain catastrophizing, anxiety, depression and self-efficacy. ResultsPain extent was influenced by sex ((2):10.392, pamp;lt;0.001) with larger pain extent in women compared to men (7.887.66% vs. 5.406.44%). People with unsettled insurance claims ((2): 7.500, pamp;lt;0.05) and those with a worse financial situation ((2):12.223, pamp;lt;0.01) also had larger pain extent. Multiple linear regression models revealed that, when accounting for age, sex, education, insurance status, financial status and neck pain intensity, pain extent remained associated with perceived disability (pamp;lt;0.01), depression (pamp;lt;0.05) and self-efficacy (pamp;lt;0.001). ConclusionBy utilizing a novel method for pain extent quantification, this study shows that widespread pain is associated with a number of factors including perceived disability, depression and self-efficacy in individuals with chronic WAD. Widespread pain should alert the clinician to consider more specific psychological screening, particularly for depression and self-efficacy, in patients with WAD. What does this study add?Women with chronic WAD, those with unsettled insurance claims and those with poorer financial status perceive more widespread pain. When controlling for these factors, larger pain areas remain associated with perceived pain and disability, depression and self-efficacy. The pain drawing is useful to support psychological screening in people with chronic WAD.

Gabriella Bernhoff,1 Maria Landén Ludvigsson,1,2 Gunnel Peterson,1,3 Bo Christer Bertilson,4,5 Madeleine Elf,6 Anneli Peolsson1 1Division of Physiotherapy, Department of Medical and Health Sciences, Linköping University, Linköping, 2Rehab Väst, County Council of Östergötland, Östergötland, 3Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, 4Musculoskeletal Functions and Pain, Division of Family Medicine, NVS, Karolinska Institutet, 5Academic Primary Health Care Center, Stockholm County Council, 6Kista Rygg and Idrottsklinik, Kista, Sweden Objective: The aim of the study was to investigate the psychometric properties of a standardized assessment of pain drawing with regard to clinical signs of cervical spine nerve root involvement.Design: This cross-sectional study included data collected in a randomized controlled study.Patients: Two hundred and sixteen patients with chronic (≥6months) whiplash-associated disorders, grade 2 or 3, were included in this study.Methods: The validity, sensitivity, and specificity of a standardized pain drawing assessment for determining nerve root involvement were analyzed, compared to the clinical assessment. In addition, we analyzed the interrater reliability with 50 pain drawings.Results: Agreement was poor between the standardized pain drawing assessment and the clinical assessment (kappa =0.11, 95% CI: −0.03 to 0.20). Sensitivity was high (93%), but specificity was low (19%). Interrater reliability was good (kappa =0.64, 95% CI: 0.53 to 0.76).Conclusion: The standardized pain drawing assessment of nerve root involvement in chronic whiplash-associated disorders was not in agreement with the clinical assessment. Further research is warranted to optimize the utilization of a pain/discomfort drawing as a supportive instrument for identifying nerve involvement in cervical spinal injuries. Keywords: pain drawing, cervical vertebrae, diagnostic self-evaluation, radiculopathy, reproducibility of results, whiplash injuries

Background: Dizziness and unsteadiness are common symptoms following a whiplash injury. Objective: To compare the effect of 3 exercise programs on balance, dizziness, proprioception and pain in patients with chronic whiplash complaining of dizziness. Design: A sub-analysis of a randomized study. Methods: One hundred and forty subjects were randomized to either a physiotherapist-guided neck-specific exercise (NSE), physiotherapist-guided neck-specific exercise, with a behavioural approach (NSEB) or prescription of general physical activity (PPA) group. Pre intervention, 3, 6 and 12 months post baseline they completed the University of California Los Angeles Dizziness Questionnaire (UCLA-DQ), Visual Analogue Scales (VAS) for, dizziness at rest and during activity and physical measures (static and dynamic clinical balance tests and head repositioning accuracy (HRA)). Results: There were significant time by group differences with respect to dizziness during activity and UCLA-Q favouring the physiotherapy led neck specific exercise group with a behavioural approach. Within group analysis of changes over time also revealed significant changes in most variables apart from static balance. Conclusion: Between and within group comparisons suggest that physiotherapist led neck exercise groups including a behavioural approach had advantages in improving measures of dizziness compared with the general physical activity group, although many still complained of dizziness and balance impairment. Future studies should consider exercises specifically designed to address balance, dizziness and cervical proprioception in those with persistent whiplash. Crown Copyright (C) 2015 Published by Elsevier Ltd. All rights reserved. Funding Agencies|Swedish government through the REHSAM foundation; regional Centres for Clinical Research of Ostergotland and Sormland County Councils; Medical Research Council of Southeast Sweden; Swedish government; Swedish Social Insurance Agency through the REHSAM foundation; Centre for Clinical Research Sormland at Uppsala University Sweden; Uppsala-Orebro Regional Research Council Sweden; Swedish Research Council; County Council of Ostergotland; County Council of Jonkoping

Background: Neck pain and disability are common after whiplash injury. One year after the accident up to 50 % still have symptoms called whiplash associated disorders (WAD). Despite decades of research the cause of persistent pain and disability are largely unknown and effective treatment and diagnostic tools are lacking. Altered neck muscle function may cause pain and disability, and real-time non-invasive methods that investigate both superficial and deep neck muscle function need to be evaluated. Aim: The general aim of the work presented in this thesis was to investigate mechanical neck muscle function and evaluate effects of three different exercise interventions related to neck muscle function in individuals with persistent pain and disability after whiplash injury. Method: The thesis comprised two studies, reported in four papers. Study A was a prospective randomized controlled trail with 216 participants. The effects of three exercise interventions; neck-specific exercises, neck-specific exercises with behavioral approach and prescription of physical activity were evaluated. Neck muscle endurance, perceived pain following testing, kinesiophobia and satisfaction with treatment were compared between the three groups (paper I). Study B was an experimental case-control study with participants consecutively recruited from the randomized controlled trial. Deformation and deformation rates in the neck muscles were investigated with real-time ultrasound imaging during ten repetitive arm elevations (paper II-IV). To investigate ventral neck muscles, 26 individuals with WAD were compared with 26 healthy controls (paper II). The dorsal neck muscles were investigated in paper III, including 40 individuals with WAD and 40 controls. In total 46 individuals, 23 with WAD and 23 healthy controls were included in paper IV to develop ventral neck muscle interaction models. Results: Paper I: Participants in the two neck-specific exercise groups (with and without behavioral approach) showed increased dorsal neck muscle endurance (p = 0.003), decreased pain intensity following testing (p = 0.04) and were more satisfied with treatment (p < 0.001) than participants in the prescribed physical activity group. Kinesiophobia did not significantly differ between groups (p > 0.12). Paper II: Deformation and deformation rate showed linear positive relationship between ventral muscle pairs in healthy controls, especially between superficial and deep neck muscles. This relationship was weaker or absent in the WAD group. Paper III: The WAD group had higher deformation rates in the deepest dorsal neck muscles during the first and tenth (only women) arm elevations compared to the control group (p < 0.04). Women in the WAD group showed a weaker linear relationship between the two deepest dorsal neck muscles compared to women in the control group. Paper IV: The results revealed two different ventral neck muscle models in individuals with WAD and healthy controls (R2Y = 0.72, Q2Y = 0.59). The models were capable to detect different neck muscle interplay in people with WAD. Conclusion: Neck-specific exercise intervention with or without a behavioral approach appears to improve neck muscle endurance in individuals with persistent WAD. Decreased pain after the neck muscle endurance test also suggests improved tolerance of load in these two groups. Altered mechanical neck muscle function was revealed in individuals with WAD indicating decreased muscular support for maintain a stable cervical spine during repetitive arm elevations. The results show great promise for improved diagnosis of neck muscle function in WAD. The corrections in the errata list has been carried out in the electronic version.

Impaired neck muscle function leads to disability in individuals with chronic whiplash-associated disorder (WAD), but diagnostic tools are lacking. In this study, deformations and deformation rates were investigated in five dorsal neck muscles during 10 arm elevations by ultrasonography with speckle tracking analyses. Forty individuals with chronic WAD (28 women and 12 men, mean age = 37 y) and 40 healthy controls matched for age and sex were included. The WAD group had higher deformation rates in the multifidus muscle during the first (p < 0.04) and 10th (only women, p < 0.01) arm elevations compared with the control group. Linear relationships between the neck muscles for deformation rate (controls: R-2 = 0.24-0.82, WAD: R-2 = 0.05-0.74) and deformation of the deepest muscles (controls: R-2 = 0.61-0.32, WAD: R-2 = 0.15-0.01) were stronger for women in the control group versus women with WAD, indicating there is altered interplay between dorsal neck muscles in chronic WAD. (C) 2016 World Federation for Ultrasound in Medicine & Biology. Funding Agencies|Swedish government; Swedish Social Insurance Agency through the REHSAM Foundation [RS2010/009]; Swedish Research Council; Centre for Clinical Research Sormland at Uppsala University Sweden; Uppsala-Orebro Regional Research Council Sweden

Objective: To explore whether neck-specific exercise, with or without a behavioural approach, has benefits after 1 and 2 years compared with prescribed physical activity regarding pain, self-rated functioning/disability, and self-efficacy in management of chronic whiplash. Design: Follow-up of a randomized, assessor blinded, clinical trial. Patients: A total of 216 volunteers with chronic whiplash associated disorders, grades 2 or 3. Methods: Participants were randomized to 1 of 3 exercise interventions: neck-specific exercise with or without a behavioural approach, or physical activity prescription. Self-rated pain (visual analogue scale), disability/functioning (Neck Disability Index/Patient Specific Functional Scale) and self-efficacy (Self-Efficacy Scale) were evaluated after 1 and 2 years. Results: Both neck-specific exercise groups maintained more improvement regarding disability/functioning than the prescribed physical activity group at both time-points (p Funding Agencies|Swedish government through the REHSAM Foundation; Swedish Research Council; regional Center for Clinical Research; County Council of Ostergotland; Centre for Clinical Research Sormland at Uppsala University; Medical Research Council of Southeast Sweden; Uppsala-Orebro Regional Research Council, Sweden

Objective: To determine whether 3 months of neck-specific exercises (NSEs) could benefit individuals with chronic whiplash-associated disorder (WAD) who were on a waiting list (WL) for treatment. Design: A prospective, randomized controlled study. Setting: Primary health care. Participants: Individuals (N=41; 31 women, 10 men; mean age +/- SD, 38 +/- 11.2y) with chronic (6-36mo) WAD, grades 2 and 3, were analyzed. Interventions: Patients were randomly assigned to NSEs or no treatment for 3 months. Main Outcome Measures: Neck-specific disability (Neck Disability Index [NDI]), neck pain (visual analog scale), general pain-related disability (Pain Disability Index [PDI]), self-perceived performance ability (Self-Efficacy Scale [SES]), and health-related quality of life (EuroQol 5 dimensions [EQ-5D]) were measured. Results: NSEs significantly improved the NDI, SES, and EQ-5D compared with WL (P

Description of neck specific exercise program as used by Maria Landén Ludvigsson, Anneli Peolsson, Gunnel Peterson in a randomized study comparing exercise approaches in chronic whiplash “Effects of neck-specific exercise with or without a behavioural approach in addition to prescribed physical activity for individuals with chronic whiplash-associated disorders: a prospective randomised study” See also: Peolsson A, Landen Ludvigsson M, Overmeer T, Dedering A, Bernfort L, Johansson G, Kammerlind AS, Peterson G. Effects of neck-specific exercise with or without a behavioural approach in addition to prescribed physical activity for individuals with chronic whiplash-associated disorders: a prospective randomised study. BMC Musculoskelet Disord 2013;14:311. http://dx.doi.org/ 10.1186/1471-2474-14-311

Chronic whiplash-associated disorder (WAD) is common after whiplash injury, with considerable personal, social, and economic burden. Despite decades of research, factors responsible for continuing pain and disability are largely unknown, and diagnostic tools are lacking. Here, we report a novel model of mechanical ventral neck muscle function recorded from non-invasive, real-time, ultrasound measurements. We calculated the deformation area and deformation rate in 23 individuals with persistent WAD and compared them to 23 sex-and age-matched controls. Multivariate statistics were used to analyse interactions between ventral neck muscles, revealing different interplay between muscles in individuals with WAD and healthy controls. Although the cause and effect relation cannot be established from this data, for the first time, we reveal a novel method capable of detecting different neck muscle interplay in people with WAD. This non-invasive method stands to make a major breakthrough in the assessment and diagnosis of people following a whiplash trauma. Funding Agencies|Swedish government; Swedish Social Insurance Agency through the REHSAM foundation; Swedish Research Council; Centre for Clinical Research Sormland at Uppsala University Sweden; Uppsala-Orebro Regional Research Council Sweden

Objective: To investigate the factors related to self-perceived work ability in patients with chronic whiplash-associated disorder grades II-III. Design: Cross-sectional analysis. Patients: A total of 166 working age patients with chronic whiplash-associated disorder. Methods: A comprehensive survey collected data on work ability (using the Work Ability Index); demographic, psychosocial, personal, work- and condition-related factors. Forward, stepwise regression modelling was used to assess the factors related to work ability. Results: The proportion of patients in each work ability category were as follows: poor (12.7%); moderate (39.8%); good (38.5%); excellent (9%). Seven factors explained 65% (adjusted R-2 = 0.65, p less than 0.01) of the variance in work ability. In descending order of strength of association, these factors are: greater neck disability due to pain; reduced self-rated health status and health-related quality of life; increased frequency of concentration problems; poor workplace satisfaction; lower self-efficacy for performing daily tasks; and greater work-related stress. Conclusion: Condition-specific and psychosocial factors are associated with self-perceived work ability of individuals with chronic whiplash-associated disorder. Funding Agencies|Swedish government; Swedish Social Insurance Agency through the REHSAM Foundation

OBJECTIVES:: The aim of this study was to compare the effect on self-rated pain, disability and self-efficacy of three interventions for the management of chronic Whiplash Associated Disorders (WAD): physiotherapist-led neck-specific exercise, physiotherapist-led neck-specific exercise with the addition of a behavioral approach, or prescription of physical activity. METHODS:: Two hundred and sixteen volunteers with chronic WAD participated in this randomized, assessor blinded, clinical trial of three exercise interventions. Self-rated pain/pain bothersomeness (Visual Analogue Scale), disability (Neck Disability Index) and self-efficacy (Self-Efficacy Scale) were evaluated at baseline and at three and six months. RESULTS:: The proportion of patients reaching substantial reduction in pain bothersomness (at least 50% reduction) was more evident (PThis is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

Previous studies have shown altered neck muscle function in individuals with chronic whiplash associated disorder (WAD). However, we lack real-time investigations with non-invasive methods that can distinguish between the different ventral neck muscle layers. This study investigated deformations and deformation rates in the sternocleidomastoid (SCM), longus capitis (Lcap), and longus colli (Lco) muscles with real-time ultrasonography. Twenty-six individuals with WAD were compared with 26 controls, matched for age and sex. Ultrasound imaging of the SCM, Lcap, and Lco were recorded during 10 repetitive arm elevations. The first and tenth arm elevations were post-process analyzed with speckle tracking. There were few significant differences in the deformations or deformation rates in the SCM, Lcap, and Lco between the WAD and control group. In controls, deformations and deformation rates showed linear positive relationships between SCM/Lcap, SCM/Lco, and Lcap/Lco which increased from the first arm elevation (R(2) = 0.14-0.70); to the tenth arm elevation (R(2) = 0.51-0.71). The WAD group showed similar or weaker linear relationship (R(2)

Background: Up to 50% of chronic whiplash associated disorders (WAD) patients experience considerable pain and disability and remain on sick-leave. No evidence supports the use of physiotherapy treatment of chronic WAD, although exercise is recommended. Previous randomised controlled studies did not evaluate the value of adding a behavioural therapy intervention to neck-specific exercises, nor did they compare these treatments to prescription of general physical activity. Few exercise studies focus on patients with chronic WAD, and few have looked at patients ability to return to work and the cost-effectiveness of treatments. Thus, there is a great need to develop successful evidence-based rehabilitation models. The study aim is to investigate whether neck-specific exercise with or without a behavioural approach (facilitated by a single caregiver per patient) improves functioning compared to prescription of general physical activity for individuals with chronic WAD. less thanbrgreater than less thanbrgreater thanMethods/Design: The study is a prospective, randomised, controlled, multi-centre study with a 2-year follow-up that includes 216 patients with chronic WAD (andgt;6 months and andlt;3 years). The patients (aged 18 to 63) must be classified as WAD grade 2 or 3. Eligibility will be determined with a questionnaire, telephone interview and clinical examination. The participants will be randomised into one of three treatments: (A) neck-specific exercise followed by prescription of physical activity; (B) neck-specific exercise with a behavioural approach followed by prescription of physical activity; or (C) prescription of physical activity alone without neck-specific exercises. Treatments will be performed for 3 months. We will examine physical and psychological function, pain intensity, health care consumption, the ability to resume work and economic health benefits. An independent, blinded investigator will perform the measurements at baseline and 3, 6, 12 and 24 months after inclusion. The main study outcome will be improvement in neck-specific disability as measured with the Neck Disability Index. All treatments will be recorded in treatment diaries and medical records. less thanbrgreater than less thanbrgreater thanDiscussion: The study findings will help improve the treatment of patients with chronic WAD. Funding Agencies|Swedish government||Swedish Social Insurance Agency through the REHSAM foundation||Research Council of Southeast Sweden||Uppsala-Orebro Regional Research Council, Sweden||Centre for Clinical Research Sormland: Uppsala University, Sweden||County Council of Ostergotland, Sweden