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Survival analysis is a statistical approach used to study time to an event of interest. The approach is highly applicable to the manual therapy discipline, yet is rarely used. This masterclass aims to present a simple overview of survival analysis aimed at both clinicians and researchers in the manual therapy field. Specifically the masterclass aims to 1) describe situations where survival analysis is appropriate to use 2) describe unique characteristics of survival data including censoring of participants 3) describe analysis methods for survival data including log rank test and Cox regression 4) describe the interpretation of results from survival analyses including survival plots and hazard ratios., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Current treatments for low back pain have small effects. A research priority is to identify patient characteristics associated with larger effects for specific interventions., Objective: The aim of this study was to identify simple clinical characteristics of patients with chronic low back pain who would benefit more from either motor control exercises or graded activity., Design: This study was a secondary analysis of the results of a randomized controlled trial., Methods: One hundred seventy-two patients with chronic low back pain were enrolled in the trial, which was conducted in Australian physical therapy clinics. The treatment consisted of 12 initial exercise sessions over an 8-week period and booster sessions at 4 and 10 months following randomization. The putative effect modifiers (psychosocial features, physical activity level, walking tolerance, and self-reported signs of clinical instability) were measured at baseline. Measures of pain and function (both measured on a 0-10 scale) were taken at baseline and at 2, 6, and 12 months by a blinded assessor., Results: Self-reported clinical instability was a statistically significant and clinically important modifier of treatment response for 12-month function (interaction: 2.72; 95% confidence interval=1.39 to 4.06). Participants with high scores on the clinical instability questionnaire (≥9) did 0.76 points better with motor control exercises, whereas those who had low scores (<9) did 1.93 points better with graded activity. Most other effect modifiers investigated did not appear to be useful in identifying preferential response to exercise type., Limitations: The psychometric properties of the instability questionnaire have not been fully tested., Conclusions: A simple 15-item questionnaire of features considered indicative of clinical instability can identify patients who respond best to either motor control exercises or graded activity., (© 2014 American Physical Therapy Association.)

Background: Regular paracetamol is the recommended first-line analgesic for acute low-back pain; however, no high-quality evidence supports this recommendation. We aimed to assess the efficacy of paracetamol taken regularly or as-needed to improve time to recovery from pain, compared with placebo, in patients with low-back pain., Methods: We did a multicentre, double-dummy, randomised, placebo controlled trial across 235 primary care centres in Sydney, Australia, from Nov 11, 2009, to March 5, 2013. We randomly allocated patients with acute low-back pain in a 1:1:1 ratio to receive up to 4 weeks of regular doses of paracetamol (three times per day; equivalent to 3990 mg paracetamol per day), as-needed doses of paracetamol (taken when needed for pain relief; maximum 4000 mg paracetamol per day), or placebo. Randomisation was done according to a centralised randomisation schedule prepared by a researcher who was not involved in patient recruitment or data collection. Patients and staff at all sites were masked to treatment allocation. All participants received best-evidence advice and were followed up for 3 months. The primary outcome was time until recovery from low-back pain, with recovery defined as a pain score of 0 or 1 (on a 0-10 pain scale) sustained for 7 consecutive days. All data were analysed by intention to treat. This study is registered with the Australian and New Zealand Clinical Trial Registry, number ACTN 12609000966291., Findings: 550 participants were assigned to the regular group (550 analysed), 549 were assigned to the as-needed group (546 analysed), and 553 were assigned to the placebo group (547 analysed). Median time to recovery was 17 days (95% CI 14-19) in the regular group, 17 days (15-20) in the as-needed group, and 16 days (14-20) in the placebo group (regular vs placebo hazard ratio 0·99, 95% CI 0·87-1·14; as-needed vs placebo 1·05, 0·92-1·19; regular vs as-needed 1·05, 0·92-1·20). We recorded no difference between treatment groups for time to recovery (adjusted p=0·79). Adherence to regular tablets (median tablets consumed per participant per day of maximum 6; 4·0 [IQR 1·6-5·7] in the regular group, 3·9 [1·5-5·6] in the as-needed group, and 4·0 [1·5-5·7] in the placebo group), and number of participants reporting adverse events (99 [18·5%] in the regular group, 99 [18·7%] in the as-needed group, and 98 [18·5%] in the placebo group) were similar between groups., Interpretation: Our findings suggest that regular or as-needed dosing with paracetamol does not affect recovery time compared with placebo in low-back pain, and question the universal endorsement of paracetamol in this patient group., Funding: National Health and Medical Research Council of Australia and GlaxoSmithKline Australia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: The trapeziometacarpal (TMC) joint of the human thumb is the second most common joint in the hand affected by osteoarthritis. TMC arthroplasty is a common procedure used to alleviate symptoms. No randomized controlled trials have been published on the efficacy of different post-operative orthotic regimes., Method: Fifty six participants who underwent TMC arthroplasty were allocated to either rigid orthotic or semi-rigid orthotic groups. Both groups started an identical exercise program at two weeks following surgery. Outcome measures were assessed by an assessor blinded to group allocation. The primary outcome was the Patient Rated Wrist and Hand Evaluation (PRWHE) and secondary outcomes included the Michigan Hand Questionnaire (MHQ), thumb palmar abduction, first metacarpophalangeal extension and three point pinch grip. Measures were taken pre-operatively, at six weeks, three months and one year post-operatively. Between-group differences were analyzed with linear regression., Results: Both groups performed equally well. There was no significant between-group difference for PRWHE scores (0.47, CI -11.5 to 12.4), including subscales for pain and function, or for any of the secondary outcomes at one year follow-up., Conclusion: We found no difference in outcomes between using a rigid or semi-rigid orthosis after TMC arthroplasty. Patient comfort, cost and availability may determine choice between orthoses in clinical practice., Level of Evidence: 1b RCT., (Copyright © 2014 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.)

Study Question: What are the best red flags to indicate the possibility of fracture or malignancy in patients presenting with low back pain in primary, secondary, or tertiary care?, Summary Answer: Older age, prolonged corticosteroid use, severe trauma, and presence of a contusion or abrasion increase the likelihood of spinal fracture (likelihood was higher with multiple red flags); a history of malignancy increases the likelihood of spinal malignancy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Clinical prediction rules can assist clinicians to identify patients with low back pain (LBP) who are likely to recover quickly with minimal treatment; however, there is a paucity of validated instruments to assist with this task., Method: We performed a pre-planned external validation study to assess the generalizability of a simple 3-item clinical prediction rule developed to estimate the probability of recovery from acute LBP at certain time points. The accuracy of the rule (calibration and discrimination) was determined in a sample of 956 participants enrolled in a randomized controlled trial., Results: The calibration of the rule was reasonable in the new sample with predictions of recovery typically within 5-10% of observed recovery. Discriminative performance of the rule was poor to moderate and similar to that found in the development sample., Conclusions: The results suggest that the rule can be used to provide accurate information about expected recovery from acute LBP, within the first few weeks of patients presenting to primary care. Impact analysis to determine if the rule influences clinical behaviours and patient outcomes is required., (© 2014 European Pain Federation - EFIC®)

Background and Objective: Magnetic resonance imaging (MRI) has the potential to identify pathology responsible for low back pain (LBP). However, the importance of findings on MRI remains controversial. We aimed to systematically review whether MRI findings of the lumbar spine predict future LBP in different samples with and without LBP., Databases and Data Treatment: MEDLINE, CINAHL and EMBASE databases were searched. Included were prospective cohort studies investigating the relationship between baseline MRI abnormalities of the lumbar spine and clinically important LBP outcome at follow-up. We excluded cohorts with specific diseases as the cause of their LBP. Associations between MRI findings and LBP pain outcomes were extracted from eligible studies., Results: A total of 12 studies met the inclusion criteria. Six studies presented data on participants with current LBP; one included a sample with no current LBP, three included a sample with no history of LBP and two included mixed samples. Due to small sample size, poor overall quality and the heterogeneity between studies in terms of participants, MRI findings and clinical outcomes investigated, it was not possible to pool findings. No consistent associations between MRI findings and outcomes were identified. Single studies reported significant associations for Modic changes type 1 with pain, disc degeneration with disability in samples with current LBP and disc herniation with pain in a mixed sample., Conclusions: The limited number, heterogeneity and overall quality of the studies do not permit definite conclusions on the association of MRI findings of the lumbar spine with future LBP (PROSPERO: CRD42012002342)., (© 2013 European Pain Federation - EFIC®)

Patient characteristics associated with the course and severity of low back pain (LBP) and disability have been the focus of extensive research, however, known characteristics do not explain much of the variance in outcomes. The relationship between anterior trunk pain (ATP) and LBP has not been explored, though mechanisms for visceral referred pain have been described. Study objectives were: (1) determine prevalence of ATP in chronic LBP patients, (2) determine whether ATP is associated with increased pain and disability in these patients, and (3) evaluate whether ATP predicts the course of pain and disability in these patients. In this study, spinal outpatient department patients mapped the distribution of their pain and patients describing pain in their chest, abdomen or groin were classified with ATP. Generalized estimating equations were performed to investigate the relationship between ATP and LBP outcomes. A total of 2974 patients were included and 19.6% of patients reported ATP. At all time points, there were significant differences in absolute pain intensity and disability in those with ATP compared with those without. The presence of ATP did not affect the clinical course of LBP outcomes. The results of this study suggest that patients who present with LBP and ATP have higher pain and disability levels than patients with localised LBP. Visceral referred pain mechanisms may help to explain some of this difference., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Many terms exist to describe radiating leg pain or symptoms associated with back pain (e.g., sciatica or radiculopathy) and it appears that these terms are used inconsistently. We examined the terms used to describe, and the eligibility criteria used to define, radiating leg pain in randomized controlled trials of conservative treatments, and evaluated how the eligibility criteria compared to an international pain taxonomy. Eligible studies were identified from two systematic reviews and an updated search of their search strategy. Studies were included if they recruited adults with radiating leg pain associated with back pain. Two independent reviewers screened the studies and extracted data. Studies were grouped according to the terms used to describe radiating leg pain. Thirty-one of the seventy-seven included studies used multiple terms to describe radiating leg pain; the most commonly used terms were sciatica (60 studies) and disc herniation (19 studies). Most studies that used the term sciatica included pain distribution in the eligibility criteria, but studies were inconsistent in including signs (e.g., neurological deficits) and imaging findings. Similarly, studies that used other terms to describe radiating leg pain used inconsistent eligibility criteria between studies and to the pain taxonomy, except that positive imaging findings were required for almost all studies that used disc herniation to describe radiating leg pain. In view of the varying terms to describe, and eligibility criteria to define, radiating leg pain, consensus needs to be reached for each of communication and comparison between studies., (© 2013 European Pain Federation - EFIC®)

Objective: To investigate whether kinesiotaping improves excessive foot pronation compared with sham kinesiotaping., Design: Quasi-randomised, double-blind study., Setting: One primary care centre., Participants: One hundred and thirty participants were screened for inclusion. Sixty-eight participants with pronated feet [Foot Posture Index (FPI)≥ 6] were enrolled, and the follow-up rate was 100%., Interventions: Participants were allocated into one of two groups: an experimental kinesiotaping group (KT1) and a sham taping group (KT2). Measures were collected by a blinded assessor at baseline, and 1 minute, 10 minutes, 60 minutes and 24 hours after taping., Main Outcome Measures: The primary outcome was total FPI score, and the secondary outcome was rear-foot FPI score., Results: There were no significant differences in total FPI score between kinesiotaping and sham taping at any time point. Similarly, there were no significant differences in rear-foot FPI score, apart from at 60-minute follow-up when the difference between groups was significant (P=0.04) but the effect size was very small (0.85 points on the rear-foot FPI score between -6 and +6)., Conclusions: Kinesiotaping does not correct foot pronation compared with sham kinesiotaping in people with pronated feet., (Copyright © 2013 Chartered Society of Physiotherapy. All rights reserved.)

Purpose: Little is known about what triggers an episode of low back pain (LBP) in those presenting to primary care. Previous studies of risk factors have focused on specific occupational settings and work conditions. No study has asked primary care clinicians to consider what triggers an episode of sudden-onset LBP in patients presenting to them for care. The purpose of this study, therefore, was to describe the short- and long-term factors that primary care clinicians consider important in triggering a sudden episode of acute LBP., Methods: One hundred and thirty-one primary care clinicians who were recruiting patients with LBP to a large observational study were invited to participate. A questionnaire was designed to obtain information about the clinician's characteristics, profession and clinical experience. We also asked clinicians to nominate the five short- and five long-term exposure factors, most likely to trigger a sudden episode of acute LBP, based on their experience. Descriptive statistics and frequency distributions were used to describe clinician's characteristics and the frequencies of the main risk factor categories were reported., Results: Based on the views of 103 primary care clinicians, biomechanical risk factors appear to be the most important short-term triggers (endorsed by 89.3% of clinicians) and long-term triggers (endorsed by 54.2% of clinicians) for a sudden episode of acute LBP. Individual risk factors were endorsed by 39% of clinicians as important long-term triggers, while only 6.4% of clinicians considered them important short-term triggers. Other risk factors, such as psychological/psychosocial and genetic factors, were not commonly endorsed as risk factors for an episode of LBP by primary care clinicians., Conclusions: This study shows that primary care clinicians believe that biomechanical risk factors are the most important short-term triggers, while biomechanical and individual risk factors are the most important long-term triggers for a sudden onset of LBP. However, other risk factors, such as psychological/psychosocial and genetic, were not commonly endorsed as risk factors for an episode of LBP by primary care clinicians. Results of this study are based on primary care clinicians' views and further investigation is needed to test the validity of these suggested risk factors.

Objectives: Expenditure on research has grown substantially; however, a major challenge for conducting successful clinical research is the efficient recruitment of participants. We investigated factors influencing the rate at which general practitioners (GPs) recruit participants to a randomized controlled trial., Study Design and Setting: We used data on 363 GPs recruiting participants for a randomized controlled trial of low back pain. Multivariate negative binomial regression was used to determine associations of characteristics of the GP and study operational aspects with the recruitment rate., Results: GPs recruited 1,195 participants at a rate of 0.013 participants/day. GPs located in a high socioeconomic area recruited at half the rate as those located in a low socioeconomic area [incident rate ratio (IRR), 0.52; 95% confidence interval (CI): 0.37, 0.74]. A follow-up within 2 weeks of training the GP and a higher number of face-to-face visits were operational procedures associated with a higher rate of recruitment (IRR, 2.15; 95% CI: 1.58, 2.94 and IRR, 1.17; 95% CI: 1.11, 1.24, respectively). Other contacts made with a GP were not associated with recruitment., Conclusion: The results suggested that the type of operational procedures used in clinical trial recruitment strategies are important aspects to consider. The ability to predict which GPs will recruit based on GP characteristics seems limited., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To examine the prognosis and prognostic factors for patients with chronic low back pain presenting to a private, community-based, group exercise program., Methods: A total of 118 consecutive patients with chronic LBP were recruited. Baseline assessments included socio-demographic characteristics, back pain history and clinical examination findings. Primary outcome measures were pain intensity and disability at 3, 6 and 12 months. Potential prognostic factors to predict pain intensity and disability at 12 months were assessed using a multivariate regression model., Results: 112 (95 %) participants were followed up at 12 months. The majority of participants were female (73 %), had high educational levels (82 %) and resided in suburbs with a high socio-economic status (99 %). Pain intensity improved markedly during the first 6 months (35 %) with further minimal reductions up to 12 months (39 %). Interestingly, disability improved to a greater degree than pain (48 % improvement at 6 months) and continued to improve throughout the 12 months (60 %). Baseline pain intensity accounted for 10 % of the variance in the 1 year pain outcomes. Duration of current episode, baseline disability and educational level accounted for 15 % of the variation in disability at 12 months., Conclusions: During a period of 12 months, patients with chronic LBP presenting to a private, community-based, group exercise program improved markedly, with greater improvements in disability than pain. The predictors investigated accounted for only 10 and 15 % of pain and disability outcomes, respectively.

Objective: To review the evidence on diagnostic accuracy of red flag signs and symptoms to screen for fracture or malignancy in patients presenting with low back pain to primary, secondary, or tertiary care., Design: Systematic review., Data Sources: Medline, OldMedline, Embase, and CINAHL from earliest available up to 1 October 2013., Inclusion Criteria: Primary diagnostic studies comparing red flags for fracture or malignancy to an acceptable reference standard, published in any language., Review Methods: Assessment of study quality and extraction of data was conducted by three independent assessors. Diagnostic accuracy statistics and post-test probabilities were generated for each red flag., Results: We included 14 studies (eight from primary care, two from secondary care, four from tertiary care) evaluating 53 red flags; only five studies evaluated combinations of red flags. Pooling of data was not possible because of index test heterogeneity. Many red flags in current guidelines provide virtually no change in probability of fracture or malignancy or have untested diagnostic accuracy. The red flags with the highest post-test probability for detection of fracture were older age (9%, 95% confidence interval 3% to 25%), prolonged use of corticosteroid drugs (33%, 10% to 67%), severe trauma (11%, 8% to 16%), and presence of a contusion or abrasion (62%, 49% to 74%). Probability of spinal fracture was higher when multiple red flags were present (90%, 34% to 99%). The red flag with the highest post-test probability for detection of spinal malignancy was history of malignancy (33%, 22% to 46%)., Conclusions: While several red flags are endorsed in guidelines to screen for fracture or malignancy, only a small subset of these have evidence that they are indeed informative. These findings suggest a need for revision of many current guidelines.

Objectives: The first aim of this study was to investigate whether kinesiotaping (KT) can increase the acromiohumeral distance (AHD) in asymptomatic subjects in the short term. The second aim was to investigate whether the direction of kinesiotaping application influences AHD., Background: In recent years, the use of KT has become increasingly popular for a range of musculoskeletal conditions and for sport injuries. To date, we are unaware of any research investigating the effect of kinesiotaping on AHD. Moreover, it is unknown whether the direction of kinesiotaping application for the shoulder is important., Methods: Forty nine participants were randomly assigned to one of three groups: kinesiotaping group 1 (KT1), kinesiotaping group 2 (KT2) and sham kinesiotaping (KT3). AHD ultrasound measurements at 0° and 60° of shoulder elevation were collected at baseline and immediately after kinesiotape application., Results: The results showed significant improvements in AHD after kinesiotaping, compared with sham taping. The mean difference in AHD between KT1 and KT3 groups was 1.28 mm (95% CI: 0.55, 2.03), and between KT2 and KT3 was 0.98 mm (95% CI: 0.23, 1.74). Comparison of KT1 and KT2 groups, which was performed to identify whether the direction of taping influences the AHD, indicated there were no significant differences., Conclusion: KT increases AHD in healthy individuals immediately following application, compared with sham kinesiotape. No differences were found with respect to the direction in which KT was applied., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Paracetamol (acetaminophen) is recommended in most clinical practice guidelines as the first choice of treatment for low back pain, however there is limited evidence to support this recommendation. The PACE trial is the first placebo controlled trial of paracetamol for acute low back pain. This article describes the statistical analysis plan., Results: PACE is a randomized double dummy placebo controlled trial that investigates and compares the effect of paracetamol taken in two regimens for the treatment of low back pain. The protocol has been published. The analysis plan was completed blind to study group and finalized prior to initiation of analyses. All data collected as part of the trial were reviewed, without stratification by group, and classified by baseline characteristics, process of care and trial outcomes. Trial outcomes were classified as primary and secondary outcomes. Appropriate descriptive statistics and statistical testing of between-group differences, where relevant, have been planned and described., Conclusions: A standard analysis plan was developed for the results of the PACE study. This plan comprehensively describes the data captured and pre-determined statistical tests of relevant outcome measures. The plan demonstrates transparent and verifiable use of the data collected. This a priori plan will be followed to ensure rigorous standards of data analysis are strictly adhered to., Trial Registration: Australia and New Zealand Clinical Trials Registry ACTRN12609000966291.

Background: Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica., Methods/design: PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant's optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives., Discussion: This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica., Trial Registration: ClinicalTrial.gov, ACTRN 12613000530729.

With the rapidly expanding number of studies reporting on treatment subgroups come new challenges in analyzing and interpreting this sometimes complex area of the literature. This article discusses 3 important issues regarding the analysis and interpretation of existing trials or systematic reviews that report on treatment effect modifiers (subgroups) for specific physical therapy interventions. The key messages are: (1) point estimates of treatment modifier effect size (interaction effect) and their confidence intervals can be calculated using group-level data when individual patient-level data are not available; (2) interaction effects do not define the total effect size of the intervention in the subgroup but rather how much more effective it is in the subgroup than in those not in the subgroup; (3) recommendations regarding the use of an intervention in a subgroup need to consider the size and direction of the main effect and the interaction effect; and (4) rather than simply judging whether a treatment modifier effect is clinically important based only on the interaction effect size, a better criterion is to determine whether the combined effect of the interaction effect and main effect makes the difference between an overall effect that is clinically important and one that is not clinically important.

Background: A treatment-based classification algorithm for low back pain (LBP) was created to help clinicians select treatments to which people are most likely to respond. To allow the algorithm to classify all people with LBP, additional criteria can help therapists make decisions for people who do not clearly fit into a subgroup (ie, unclear classifications). Recent studies indicated that classifications are unclear for approximately 34% of people with LBP., Objective: To guide improvements in the algorithm, it is imperative to determine whether people with unclear classifications are different from those with clear classifications., Design: This study was a secondary analysis of data from 3 previous studies investigating the algorithm., Methods: Baseline data from 529 people who had LBP were used (3 discrete cohorts). The primary outcome was type of classification, that is, clear or unclear. Univariate logistic regression was used to determine which participant variables were related to having an unclear classification., Results: People with unclear classifications had greater odds of being older (odds ratio [OR]=1.01, 95% confidence interval [CI]=1.003-1.033), having a longer duration of LBP (OR=1.001, 95% CI=1.000-1.001), having had a previous episode(s) of LBP (OR=1.61, 95% CI=1.04-2.49), having fewer fear-avoidance beliefs related to both work (OR=0.98, 95% CI=0.96-0.99) and physical activity (OR=0.98, 95% CI=0.96-0.996), and having less LBP-related disability (OR=0.98, 95% CI=0.96-0.99) than people with clear classifications., Limitations: Studies from which participant data were drawn had different inclusion criteria and clinical settings., Conclusions: People with unclear classifications appeared to be less affected by LBP (less disability and fewer fear avoidance beliefs), despite typically having a longer duration of LBP. Future studies should investigate whether modifying the algorithm to exclude such people or provide them with different interventions improves outcomes.

Background: Although low-back pain is a highly prevalent condition, its clinical course remains uncertain. Our main objective was to systematically review the literature on the clinical course of pain and disability in patients with acute and persistent low-back pain. Our secondary objective was to investigate whether pain and disability have similar courses., Methods: We performed a meta-analysis of inception cohort studies. We identified eligible studies by searching MEDLINE, Embase and CINAHL. We included prospective studies that enrolled an episode-inception cohort of patients with acute or persistent low-back pain and that measured pain, disability or recovery. Two independent reviewers extracted data and assessed methodologic quality. We used mixed models to determine pooled estimates of pain and disability over time., Results: Data from 33 discrete cohorts (11 166 participants) were included in the review. The variance-weighted mean pain score (out of a maximum score of 100) was 52 (95% CI 48-57) at baseline, 23 (95% CI 21-25) at 6 weeks, 12 (95% CI 9-15) at 26 weeks and 6 (95% CI 3-10) at 52 weeks after the onset of pain for cohorts with acute pain. Among cohorts with persistent pain, the variance-weighted mean pain score (out of 100) was 51 (95% CI 44-59) at baseline, 33 (95% CI 29-38) at 6 weeks, 26 (95% CI 20-33) at 26 weeks and 23 (95% CI 16-30) at 52 weeks after the onset of pain. The course of disability outcomes was similar to the time course of pain outcomes in the acute pain cohorts, but the pain outcomes were slightly worse than disability outcomes in the persistent pain cohorts., Interpretation: Patients who presented with acute or persistent low-back pain improved markedly in the first six weeks. After that time improvement slowed. Low to moderate levels of pain and disability were still present at one year, especially in the cohorts with persistent pain.

Unlabelled: Wrist pain is common. People with persistent pain commonly undergo arthroscopic investigation. Little is known about the prognosis or prognostic factors for these patients. The purpose of the study was to evaluate prognosis and prognostic factors for pain and functional disability in patients with persistent wrist pain who proceed to arthroscopic investigation. The study design used was a prospective cohort study. One hundred and five consecutive participants who underwent arthroscopic investigation for undiagnosed wrist pain for at least four-week duration were recruited. Patient-rated wrist and hand evaluation (PRWHE) scores were determined at baseline (before arthroscopy) and one year after arthroscopy. One-year follow-up data were obtained for 97 (92%) of 105 participants. Mean PRWHE total score declined from 49 of 100 (standard deviation [SD] 18.5) at baseline to 26 of 100 (SD 20.4) at one year. Two prognostic factors were identified: baseline PRWHE and duration of symptoms. These factors explained 19% and 5% of the variability in the final PRWHE score, respectively. Results of provocative wrist tests and arthroscopic findings did not significantly contribute to prognosis in this cohort. This study provides the first robust evidence of the prognosis of persistent wrist pain. Participants who underwent arthroscopic investigation for persistent wrist pain improved on average by approximately 50% at one year; however, most continued to have some pain and disability. Duration of pain and PRWHE at baseline explained 24% of the one-year PRWHE score., Level of Evidence: Level 2., (Copyright © 2012 Hanley & Belfus. All rights reserved.)

In Nature, directional surfaces on insect cuticle, animal fur, bird feathers, and plant leaves are comprised of dual micro-nanoscale features that tune roughness and surface energy. This feature article summarizes experimental and theoretical approaches for the design, synthesis and characterization of new bioinspired surfaces demonstrating unidirectional surface properties. The experimental approaches focus on bottom-up and top-down synthesis methods of unidirectional micro- and nanoscale films to explore and characterize their anomalous features. The theoretical component of the review focuses on computational tools to predict the physicochemical properties of unidirectional surfaces.

Objectives: The broad aim of this study was to assess the homogeneity of patients included in trials of non-specific low back pain (NSLBP). To do this, we investigated the consistency and clarity of criteria used to identify and exclude participants with serious pathologies and nerve root compromise in randomized controlled trials, investigating interventions for NSLBP., Methods: We searched Medline database for randomized controlled trials of low back pain (LBP). published between 2000 and 2009. We then randomly selected and screened trials for inclusion until we had 50 eligible trials. Data were extracted on the criteria used to identify cases of serious conditions (e.g. cancer, fracture) and nerve root involvement., Results: The majority of papers (35/50) explicitly excluded patients with serious pathology. However, the terminology used and examples given were highly variable. Nerve root involvement was an exclusion criterion in the majority but not all studies. The criteria used for excluding patients with nerve root involvement varied greatly between studies. The most common criteria were 'motor, sensory or reflex changes' (nine studies), followed by 'pain radiating below the knee' (five studies) and 'reduced straight leg raise which reproduces leg pain' (five studies). In half of the included studies, the criteria used, while alluding to nerve root involvement, were not explained adequately for us to determine the types of patients included or excluded., Discussion: The inconsistent and unclear criteria used to identify cases of serious pathology and nerve root compromise means that published trials of LBP likely include heterogeneous patient populations. This trait limits our ability to make comparisons across trials or pool studies. Standardization and consensus is important for future research.

This technical note describes a new bench-top method for producing anisotropic hydrogels composed of gradient layers of soluble factors, particles, polymer concentrations or material properties. Each gradient layer was produced by a previous gradient method in which a droplet of one precursor solution was added to a thin layer of a second solution. The ensuing rapid capillary flow along the open channel generated a gradient precursor solution, which was then crosslinked to form a gradient gel. Repeating these steps allowed a layered gel to be iteratively constructed with as many gradient layers as desired. This technique renders the synthesis of multi-layered gradient gels accessible to virtually any researcher and should help simplify the production of more biologically relevant cellular microenvironments.

A simple technique is presented for controlling the shapes of micro- and nanodrops by patterning surfaces with special hydrophilic regions surrounded by hydrophobic boundaries. Finite element method simulations link the shape of the hydrophilic regions to that of the droplets. Shaped droplets are used to controllably pattern planar surfaces and microwell arrays with microparticles and cells at the micro- and macroscales. Droplets containing suspended sedimenting particles, initially at uniform concentration, deposit more particles under deeper regions than under shallow regions. The resulting surface concentration is thus proportional to the local fluid depth and agrees well with the measured and simulated droplet profiles. A second application is also highlighted in which shaped droplets of prepolymer solution are crosslinked to synthesize microgels with tailored 3D geometry., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Developing biologically relevant models of human tissues and organs is an important enabling step for disease modeling and drug discovery. Recent advances in tissue engineering, biomaterials and microfluidics have led to the development of microscale functional units of such models also referred to as 'organs on a chip'. In this review, we provide an overview of key enabling technologies and highlight the wealth of recent work regarding on-chip tissue models. In addition, we discuss the current challenges and future directions of organ-on-chip development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: Over 20 years ago the term non-specific low back pain became popular to convey the limitations of our knowledge of the pathological source of most people's low back pain. Knowledge of underlying pathology has advanced little since then, despite limited improvements in outcomes for patients with low back pain., Methods: This paper discusses potential misunderstandings related to diagnostic studies in the field of low back pain and argues that future diagnostic studies should include and investigate pathological sources of low back pain., Results: Six potential misunderstandings are discussed. (1) Until diagnosis is shown to improve outcomes it is not worth investigating; (2) without a gold standard it is not possible to investigate diagnosis of low back pain; (3) the presence of pathology in some people without low back pain means it is not important; (4) dismissal of the ability to diagnose low back pain in clinical guidelines is supported by the same level of evidence as recommendations for therapy; (5) suggesting use of a diagnostic test in research is misinterpreted as endorsing its use in current clinical practice; (6) we seem to have forgotten the 'bio' in biopsychosocial low back pain., Conclusions: We believe the misunderstandings presented in this paper partly explain the lack of investigation into pathology as an important component of the low back pain experience. A better understanding of the biological component of low back pain in relation, and in addition, to psychosocial factors is important for a more rational approach to management of low back pain.

High-throughput preparation of multi-component solutions is an integral process in biology, chemistry and materials science for screening, diagnostics and analysis. Compact microfluidic systems enable such processing with low reagent volumes and rapid testing. Here we present a microfluidic device that incorporates two gradient generators, a tree-like generator and a new microfluidic active injection system, interfaced by intermediate solution reservoirs to generate diluted combinations of input solutions within an 8 × 8 or 10 × 10 array of isolated test chambers. Three input solutions were fed into the device, two to the tree-like gradient generator and one to pre-fill the test chamber array. The relative concentrations of these three input solutions in the test chambers completely characterized device behaviour and were controlled by the number of injection cycles and the flow rate. Device behaviour was modelled by computational fluid dynamics simulations and an approximate analytic formula. The device may be used for two-dimensional (2D) combinatorial dilution by adding two solutions in different relative concentrations to each of its three inputs. By appropriate choice of the two-component input solutions, test chamber concentrations that span any triangle in 2D concentration space may be obtained. In particular, explicit inputs are given for a coarse screening of a large region in concentration space followed by a more refined screening of a smaller region, including alternate inputs that span the same concentration region but with different distributions. The ability to probe arbitrary subspaces of concentration space and to control the distribution of discrete test points within those subspaces makes the device of potential benefit for high-throughput cell biology studies and drug screening.

We present a simple bench-top technique to produce centimeter long concentration gradients in biomaterials incorporating soluble, material, and particle gradients. By patterning hydrophilic regions on a substrate, a stripe of prepolymer solution is held in place on a glass slide by a hydrophobic boundary. Adding a droplet to one end of this "pre-wet" stripe causes a rapid capillary flow that spreads the droplet along the stripe to generate a gradient in the relative concentrations of the droplet and pre-wet solutions. The gradient length and shape are controlled by the pre-wet and droplet volumes, stripe thickness, fluid viscosity and surface tension. Gradient biomaterials are produced by crosslinking gradients of prepolymer solutions. Demonstrated examples include a concentration gradient of cells encapsulated in three dimensions (3D) within a homogeneous biopolymer and a constant concentration of cells encapsulated in 3D within a biomaterial gradient exhibiting a gradient in cell spreading. The technique employs coated glass slides that may be purchased or custom made from tape and hydrophobic spray. The approach is accessible to virtually any researcher or student and should dramatically reduce the time required to synthesize a wide range of gradient biomaterials. Moreover, since the technique employs passive mechanisms it is ideal for remote or resource poor settings., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To cross-culturally adapt the Short Form of the McGill Pain Questionnaire (SF-MPQ) into Brazilian-Portuguese and test the clinimetric properties of the newly developed SF-MPQ and the previously cross-culturally adapted Brazilian-Portuguese Long Form of the McGill Pain Questionnaire (LF-MPQ)., Study Design and Setting: The SF-MPQ was translated and adapted into Brazilian-Portuguese following recommendations from current guidelines. Both SF-MPQ and LF-MPQ were administered in a prospective longitudinal design to 203 patients with a range of musculoskeletal conditions to evaluate their clinimetric properties., Results: Both questionnaires demonstrated high levels of internal consistency (Cronbach α range=0.70-0.79), reliability (intraclass correlation coefficient(2,1) range=0.69-0.85), and agreement (standard error of the measurement range=0.80-6.92). We observed positive and moderate-to-high correlations among the SF-MPQ, the LF-MPQ, and the Numerical Rating Scale (Pearson r ranging from 0.49 to 0.68). No ceiling or floor effects were detected. Both versions demonstrated acceptable levels of responsiveness (effect size range=0.30-0.60; correlations range=0.23-0.51; and area under the curve range=0.56-0.76)., Conclusions: The Brazilian-Portuguese versions of the MPQ were found to be reproducible, valid, and responsive for the assessment of pain in patients with musculoskeletal conditions., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A simple and inexpensive method is presented employing passive mechanisms to generate centimeters-long gradients of molecules and particles in under a second with only a coated glass slide and a micropipette. A drop of solution is pipetted onto a fluid stripe held in place on a glass slide by a hydrophobic boundary. The resulting difference in curvature pressure drives the flow and creates a concentration gradient by convection. Experiments and theoretical models characterize the flows and gradient profiles and their dependence on the fluid volumes, properties, and stripe geometry. A bench-top rapid prototyping method is outlined to allow the user to design and fabricate the coated slides using only tape and hydrophobic spray. The rapid prototyping method is compatible with microwell arrays, allowing soluble gradients to be applied to cells in shear-protected microwells. The method's simplicity makes it accessible to virtually any researcher or student and its use of passive mechanisms makes it ideal for field use and compatible with point-of-care and global health initiatives., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Several studies have investigated criteria for classifying patients with low back pain (LBP) into treatment-based subgroups. A comprehensive algorithm was created to translate these criteria into a clinical decision-making guide., Objective: This study investigated the translation of the individual subgroup criteria into a comprehensive algorithm by studying the prevalence of patients meeting the criteria for each treatment subgroup and the reliability of the classification., Design: This was a cross-sectional, observational study., Methods: Two hundred fifty patients with acute or subacute LBP were recruited from the United States and Australia to participate in the study. Trained physical therapists performed standardized assessments on all participants. The researchers used these findings to classify participants into subgroups. Thirty-one participants were reassessed to determine interrater reliability of the algorithm decision., Results: Based on individual subgroup criteria, 25.2% (95% confidence interval [CI]=19.8%-30.6%) of the participants did not meet the criteria for any subgroup, 49.6% (95% CI=43.4%-55.8%) of the participants met the criteria for only one subgroup, and 25.2% (95% CI=19.8%-30.6%) of the participants met the criteria for more than one subgroup. The most common combination of subgroups was manipulation + specific exercise (68.4% of the participants who met the criteria for 2 subgroups). Reliability of the algorithm decision was moderate (kappa=0.52, 95% CI=0.27-0.77, percentage of agreement=67%)., Limitations: Due to a relatively small patient sample, reliability estimates are somewhat imprecise., Conclusions: These findings provide important clinical data to guide future research and revisions to the algorithm. The finding that 25% of the participants met the criteria for more than one subgroup has important implications for the sequencing of treatments in the algorithm. Likewise, the finding that 25% of the participants did not meet the criteria for any subgroup provides important information regarding potential revisions to the algorithm's bottom table (which guides unclear classifications). Reliability of the algorithm is sufficient for clinical use.

Pain self-efficacy and fear of movement have been proposed to explain how pain can lead to disability for patients with chronic low back pain. However the extent to which pain self-efficacy and fear of movement mediate the relationship between pain and disability over time has not been investigated. This study aimed to investigate whether pain self-efficacy and/or fear of movement mediate the relationship between pain intensity and disability in patients with recent onset chronic low back pain. In a two-wave longitudinal design, 184 chronic low back pain patients completed measures for pain intensity, disability, pain self-efficacy and fear of movement at baseline and 12months after the onset of chronic low back pain. Regression analyses were used to test the mediational hypothesis. We found that, when measured at the same time, both pain self-efficacy and fear of movement beliefs partially mediated the effects of pain intensity on disability at the onset of chronic low back pain. However, in the longitudinal analyses, only improvements in self-efficacy beliefs partially mediated the relationship between changes in pain and changes in disability over a 12months period. We found no support for the theory that fear of movement beliefs mediate this relationship. Therefore, we concluded that pain self-efficacy may be a more important variable than fear of movement beliefs in terms of understanding the relationship between pain and disability., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Combinatorial material synthesis is a powerful approach for creating composite material libraries for the high-throughput screening of cell-material interactions. Although current combinatorial screening platforms have been tremendously successful in identifying target (termed "hit") materials from composite material libraries, new material synthesis approaches are needed to further optimize the concentrations and blending ratios of the component materials. Here we employed a microfluidic platform to rapidly synthesize composite materials containing cross-gradients of gelatin and chitosan for investigating cell-biomaterial interactions. The microfluidic synthesis of the cross-gradient was optimized experimentally and theoretically to produce quantitatively controllable variations in the concentrations and blending ratios of the two components. The anisotropic chemical compositions of the gelatin/chitosan cross-gradients were characterized by Fourier transform infrared spectrometry and X-ray photoelectron spectrometry. The three-dimensional (3D) porous gelatin/chitosan cross-gradient materials were shown to regulate the cellular morphology and proliferation of smooth muscle cells (SMCs) in a gradient-dependent manner. We envision that our microfluidic cross-gradient platform may accelerate the material development processes involved in a wide range of biomedical applications., (© 2010 Wiley Periodicals, Inc.)

During tissue morphogenesis and homeostasis, cells experience various signals in their environments, including gradients of physical and chemical cues. Spatial and temporal gradients regulate various cell behaviours such as proliferation, migration, and differentiation during development, inflammation, wound healing, and cancer. One of the goals of functional tissue engineering is to create microenvironments that mimic the cellular and tissue complexity found in vivo by incorporating physical, chemical, temporal, and spatial gradients within engineered three-dimensional (3D) scaffolds. Hydrogels are ideal materials for 3D tissue scaffolds that mimic the extracellular matrix (ECM). Various techniques from material science, microscale engineering, and microfluidics are used to synthesise biomimetic hydrogels with encapsulated cells and tailored microenvironments. In particular, a host of methods exist to incorporate micrometer to centimetre scale chemical and physical gradients within hydrogels to mimic the cellular cues found in vivo. In this review, we draw on specific biological examples to motivate hydrogel gradients as tools for studying cell-material interactions. We provide a brief overview of techniques to generate gradient hydrogels and showcase their use to study particular cell behaviours in two-dimensional (2D) and 3D environments. We conclude by summarizing the current and future trends in gradient hydrogels and cell-material interactions in context with the long-term goals of tissue engineering.

Anisotropic textured surfaces allow water striders to walk on water, butterflies to shed water from their wings and plants to trap insects and pollen. Capturing these natural features in biomimetic surfaces is an active area of research. Here, we report an engineered nanofilm, composed of an array of poly(p-xylylene) nanorods, which demonstrates anisotropic wetting behaviour by means of a pin-release droplet ratchet mechanism. Droplet retention forces in the pin and release directions differ by up to 80 μN, which is over ten times greater than the values reported for other engineered anisotropic surfaces. The nanofilm provides a microscale smooth surface on which to transport microlitre droplets, and is also relatively easy to synthesize by a bottom-up vapour-phase technique. An accompanying comprehensive model successfully describes the film's anisotropic wetting behaviour as a function of measurable film morphology parameters.

Epidemiological and clinical studies of people with low back pain (LBP) commonly measure the incidence of recovery. The pain numerical rating scale (NRS), scores from 0 to 10, and Roland Morris disability questionnaire (RMDQ), scores from 0 to 24, are two instruments often used to define recovery. On both scales higher scores indicate greater severity. There is no consensus, however, on the cutoff scores on these scales that classify people as having recovered. The aim of this study was to determine which cutoff scores most accurately classify those who had recovered from LBP. Subjects from four clinical studies were categorized as 'recovered' or 'unrecovered' according to their self-rating on a global perceived effect scale. Odd ratios were calculated for scores of 0, 1, 2, 3 and 4 on the NRS and RMDQ to predict perceived recovery. Scores of 0 on the NRS and

Background: Clinical practice guidelines recommend that the initial treatment of acute low back pain (LBP) should consist of advice to stay active and regular simple analgesics such as paracetamol 4 g daily. Despite this recommendation in all international LBP guidelines there are no placebo controlled trials assessing the efficacy of paracetamol for LBP at any dose or dose regimen. This study aims to determine whether 4 g of paracetamol daily (in divided doses) results in a more rapid recovery from acute LBP than placebo. A secondary aim is to determine if ingesting paracetamol in a time-contingent manner is more effective than paracetamol taken when required (PRN) for recovery from acute LBP., Methods/design: The study is a randomised double dummy placebo controlled trial. 1650 care seeking people with significant acute LBP will be recruited. All participants will receive advice to stay active and will be randomised to 1 of 3 treatment groups: time-contingent paracetamol dose regimen (plus placebo PRN paracetamol), PRN paracetamol (plus placebo time-contingent paracetamol) or a double placebo study arm. The primary outcome will be time (days) to recovery from pain recorded in a daily pain diary. Other outcomes will be pain intensity, disability, function, global perceived effect and sleep quality, captured at baseline and at weeks 1, 2, 4 and 12 by an assessor blind to treatment allocation. An economic analysis will be conducted to determine the cost-effectiveness of treatment from the health sector and societal perspectives., Discussion: The successful completion of the trial will provide the first high quality evidence on the effectiveness of the use of paracetamol, a guideline endorsed treatment for acute LBP.

Objective: The study investigated the test-retest reliability and construct validity of the Global Perceived Effect (GPE) scale in patients with musculoskeletal disorders., Study Design and Setting: Data from seven clinical studies including 861 subjects were used for the analyses. Repeat measures taken at the same attendance and from attendances separated by 24 hours were compared to estimate test-retest reliability. Construct validity was evaluated by examining relationships between pre, post, and change scores in pain and disability measures with GPE measures., Results: Intraclass correlation coefficient values of 0.90-0.99 indicate excellent reproducibility of the GPE scale. In all but one data set, change scores on pain and disability measures correlated well (r=0.40-0.74) with GPE; however, post scores nearly always correlated even more strongly (r=0.58-0.84), and pre scores showed much weaker association (r=0.00-0.28). Pre scores accounted for only a small amount of additional R(2) when added to regression models including post score., Conclusions: Test-retest reliability of the GPE is excellent. GPE ratings are strongly influenced by current status, with the effect more obvious as transition time lengthens. This result questions whether transition ratings truly reflect change, or rather just current state. This finding also has implications for the use of GPE ratings as an external criterion of change in clinimetric studies., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Clinical prediction rules (CPRs) for treatment selection in musculoskeletal conditions have become increasingly popular., Purpose: The purposes of this review are: (1) to critically appraise studies evaluating CPRs and (2) to consider the clinical utility and stage of development of each CPR., Data Sources: Pertinent databases were searched up to April 2009. Studies aiming to develop or evaluate a CPR for treatment response in musculoskeletal conditions were included. Two independent reviewers assessed eligibility and extracted methodological data, stage of development, and effect size information. STUDY SELECTION/DATA EXTRACTION AND SYNTHESIS: Eighteen studies, evaluating 15 separate CPRs, were included. Fourteen CPRs were at the derivation stage, and all CPRs had been evaluated using a single-arm trial design, thus it is not possible to determine whether the CPRs identify prognosis (regardless of treatment) or specifically response to treatment. The CPR at the validation stage investigated spinal manipulative therapy (SMT) for low back pain and had been evaluated in 2 separate well-conducted randomized controlled trials. The first trial demonstrated a clinically meaningful effect of the SMT CPR; the additional effect from SMT in patients "positive-on-the-rule" was 15 Oswestry disability units at week 1 and 9 units at week 4. The second trial showed that the CPR did not generalize to a different clinical setting, including a modified treatment., Limitations: Due to differences in methods of reporting and journal publication restraints (eg, word count restrictions), some quality assessment items may have been completed in the included studies, but not captured in this review., Conclusions: There is, at present, little evidence that CPRs can be used to predict effects of treatment for musculoskeletal conditions. The principal problem is that most studies use designs that cannot differentiate between predictors of response to treatment and general predictors of outcome. Only 1 CPR has been evaluated within an RCT designed to predict response to treatment. Validation of these rules is imperative to allow clinical application.

Cell patterning is useful for a variety of biological applications such as tissue engineering and drug discovery. In particular, the ability to localize cells within distinct fluids is beneficial for a variety of applications ranging from microencapsulation to high-throughput analysis. However, despite much progress, cell immobilization and maintenance within patterned microscale droplets remains a challenge. In particular, no method currently exists to rapidly seed cells into microwell arrays in a controllable and reliable manner. In this study, we present a simple wiping technique to localize cells within arrays of polymeric microwells. This robust method produces cell seeding densities that vary consistently with microwell geometry and cell concentration. Moreover, we develop a simple theoretical model to accurately predict cell seeding density and seeding efficiency in terms of the design parameters of the microwell array and the cell density. This short-term cell patterning approach is an enabling tool to develop new high-throughput screening technologies that utilize microwell arrays containing cells for screening applications., (Copyright 2009 Wiley Periodicals, Inc.)

Cell-laden hydrogels show great promise for creating engineered tissues. However, a major shortcoming with these systems has been the inability to fabricate structures with controlled micrometer-scale features on a biologically relevant length scale. In this Full Paper, a rapid method is demonstrated for creating centimeter-scale, cell-laden hydrogels through the assembly of shape-controlled microgels or a liquid-air interface. Cell-laden microgels of specific shapes are randomly placed on the surface of a high-density, hydrophobic solution, induced to aggregate and then crosslinked into macroscale tissue-like structures. The resulting assemblies are cell-laden hydrogel sheets consisting of tightly packed, ordered microgel units. In addition, a hierarchical approach creates complex multigel building blocks, which are then assembled into tissues with precise spatial control over the cell distribution. The results demonstrate that forces at an air-liquid interface can be used to self-assemble spatially controllable, cocultured tissue-like structures.

There has been a recent increase in research evaluating treatment-based subgroups of non-specific low back pain. The aim of these sub-classification schemes is to identify subgroups of patients who will respond preferentially to one treatment as opposed to another. Our article provides accessible guidance on to how to interpret this research and determine its implications for clinical practice. We propose that studies evaluating treatment-based subgroups can be interpreted in the context of a three-stage process: (1) hypothesis generation-proposal of clinical features to define subgroups; (2) hypothesis testing-a randomised controlled trial (RCT) to test that subgroup membership modifies the effect of a treatment; and (3) replication-another RCT to confirm the results of stage 2 and ensure that findings hold beyond the specific original conditions. At this point, the bulk of research evidence in defining subgroups of patients with low back pain is in the hypothesis generation stage; no classification system is supported by sufficient evidence to recommend implementation into clinical practice., (Copyright 2009 Elsevier Ltd. All rights reserved.)

In conventional hanging drop (HD) methods, embryonic stem cell aggregates or embryoid bodies (EBs) are often maintained in small inverted droplets. Gravity limits the volumes of these droplets to less than 50 microL, and hence such cell cultures can only be sustained for a few days without frequent media changes. Here we present a new approach to performing long-term HD methods (10-15 days) that can provide larger media reservoirs in a HD format to maintain more consistent culture media conditions. To implement this approach, we fabricated hollow sphere (HS) structures by injecting liquid drops into noncured poly(dimethylsiloxane) mixtures. These structures served as cell culture chambers with large media volumes (500 microL in each sphere) where EBs could grow without media depletion. The results showed that the sizes of the EBs cultured in the HS structures in a long-term HD format were approximately twice those of conventional HD methods after 10 days in culture. Further, HS cultures showed multilineage differentiation, similar to EBs cultured in the HD method. Due to its ease of fabrication and enhanced features, this approach may be of potential benefit as a stem cell culture method for regenerative medicine.

Natural materials exhibit anisotropy with variations in soluble factors, cell distribution, and matrix properties. The ability to recreate the heterogeneity of the natural materials is a major challenge for investigating cell-material interactions and for developing biomimetic materials. Here we present a generic fluidic approach using convection and alternating flow to rapidly generate multi-centimeter gradients of biomolecules, polymers, beads and cells and cross-gradients of two species in a microchannel. Accompanying theoretical estimates and simulations of gradient growth provide design criteria over a range of material properties. A poly(ethylene-glycol) hydrogel gradient, a porous collagen gradient and a composite material with a hyaluronic acid/gelatin cross-gradient were generated with continuous variations in material properties and in their ability to regulate cellular response. This simple yet generic fluidic platform should prove useful for creating anisotropic biomimetic materials and high-throughput platforms for investigating cell-microenvironment interactions., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Objectives: To describe the course of chronic low back pain in an inception cohort and to identify prognostic markers at the onset of chronicity., Design: Inception cohort study with one year follow-up., Setting: Primary care clinics in Sydney, Australia., Participants: The study sample was a subcohort of an inception cohort of 973 consecutive patients presenting to primary care with acute low back pain (<2 weeks' duration). 406 participants whose pain persisted for three months formed the inception cohort of patients with chronic low back pain., Main Outcome Measures: Outcomes and putative predictors measured at initial presentation, onset of chronicity (study entry), and follow-up at nine and 12 months. Recovery was determined from measures of pain intensity, disability, and work status. The association between potential prognostic factors and time to recovery was modelled with Cox regression., Results: Completeness of follow-up was 97% of total person time for all outcomes. The cumulative probability of being pain-free was 35% at nine months and 42% at 12 months and for complete recovery was 35% at nine months and 41% at 12 months. Of the 259 participants who had not recovered from pain related disability at entry to the chronic study, 47% had recovered by 12 months. Previous sick leave due to low back pain, high disability levels or high pain intensity at onset of chronicity, low levels of education, greater perceived risk of persistent pain, and being born outside Australia were associated with delayed recovery., Conclusion: More than one third of patients with recent onset, non-radicular chronic low back pain recover within 12 months. The prognosis is less favourable for those who have taken previous sick leave for low back pain, have high disability levels or high pain intensity at onset of chronic low back pain, have lower education, perceive themselves as having a high risk of persistent pain, and were born outside Australia.

Microstructures that generate shear-protected regions in microchannels can rapidly immobilize cells for cell-based biosensing and drug screening. Here, a two-step fabrication method is used to generate double microgrooves with various depth ratios to achieve controlled double-level cell patterning while still providing shear protection. Six microgroove geometries are fabricated with different groove widths and depth ratios. Two modes of cell docking are observed: cells docked upstream in sufficiently deep and narrow grooves, and downstream in shallow, wide grooves. Computational flow simulations link the groove geometry and bottom shear stress to the experimental cell docking patterns. Analysis of the experimental cell retention in the double grooves demonstrates its linear dependence on inlet flow speed, with slope inversely proportional to the sheltering provided by the groove geometry. Thus, double-grooved microstructures in microfluidic channels provide shear-protected regions for cell docking and immobilization and appear promising for cell-based biosensing and drug discovery.

The ability to rapidly generate concentration gradients of diffusible molecules has important applications in many chemical and biological studies. Here we established spatially and temporally controllable concentration gradients of molecules (i.e. proteins or toxins) in a portable microfluidic device in an easy and rapid manner. The formation of the concentration gradients was initiated by a passive-pump-induced forward flow and further optimized during an evaporation-induced backward flow. The centimeter-long gradients along the microfluidic channel were shown to be spatially and temporally controlled by the backward flow. The gradient profile was stabilized by stopping the flow. Computational simulations of this dynamic process illustrated the combined effects of convection and diffusion on the gradient generation, and fit well with the experimental data. To demonstrate the applications of this methodology, a stabilized concentration gradient of a cardiac toxin, alpha-cypermethrin, along the microchannel was used to test the response of HL-1 cardiac cells in the micro-device, which correlated with toxicity data obtained from multi-well plates. The approach presented here may be useful for many biological and chemical processes that require rapid generation of long-range gradients in a portable microfluidic device.