Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

When Kinks Come to Life: An Exploration of Paraphilic Behaviors and Underlying Predictors.

Paraphilia is defined as a condition in which sexual excitement relies on fantasizing about and/or participating in unusual sexual behavior. Although recent studies have assessed the concordance between paraphilic interests and paraphilic behaviors, few studies have studied which individual traits and demographics predict engaging in paraphilic behaviors, or the level of concordance between arousal and behavior. The current study replicated and expanded Joyal and Carpentier's 2022 study. We assessed concordance between paraphilic arousal and behavior. Further, we assessed the impact of Dark Tetrad traits, impulsivity, social desirability and demographic variables on engaging in paraphilic behaviors using self-report questionnaires in a sample from the general population and FetLife. Finally, we were interested in whether these individual differences moderated the concordance between arousal and behavior. Results indicated high concordance between paraphilic arousal and behavior for all paraphilias except pedophilia and hebephilia. Younger, male participants were more likely to engage in various paraphilias than women and older participants. Machiavellianism was linked with lower paraphilic behavior, particularly impulsive or risky ones. Psychopathy predicted engaging in more deviant or illegal paraphilias, whereas sadism only showed an association for engaging in frotteurism and narcissism was not a predictor for engaging in any paraphilia. For several paraphilias, individual traits moderated the effect of arousal on behavior. Implications of these findings and future directions are discussed.

Automated EuroFlow approach for standardized in-depth dissection of human circulating B-cells and plasma cells.

Background: Multiparameter flow cytometry (FC) immunophenotyping is a key tool for detailed identification and characterization of human blood leucocytes, including B-lymphocytes and plasma cells (PC). However, currently used conventional data analysis strategies require extensive expertise, are time consuming, and show limited reproducibility. Objective: Here, we designed, constructed and validated an automated database-guided gating and identification (AGI) approach for fast and standardized in-depth dissection of B-lymphocyte and PC populations in human blood. Methods: For this purpose, 213 FC standard (FCS) datafiles corresponding to umbilical cord and peripheral blood samples from healthy and patient volunteers, stained with the 14-color 18-antibody EuroFlow BIgH-IMM panel, were used. Results: The BIgH-IMM antibody panel allowed identification of 117 different B-lymphocyte and PC subsets. Samples from 36 healthy donors were stained and 14 of the datafiles that fulfilled strict inclusion criteria were analysed by an expert flow cytometrist to build the EuroFlow BIgH-IMM database. Data contained in the datafiles was then merged into a reference database that was uploaded in the Infinicyt software (Cytognos, Salamanca, Spain). Subsequently, we compared the results of manual gating (MG) with the performance of two classification algorithms -hierarchical algorithm vs two-step algorithm- for AGI of the cell populations present in 5 randomly selected FCS datafiles. The hierarchical AGI algorithm showed higher correlation values vs conventional MG (r2 of 0.94 vs. 0.88 for the two-step AGI algorithm) and was further validated in a set of 177 FCS datafiles against conventional expert-based MG. For virtually all identifiable cell populations a highly significant correlation was observed between the two approaches (r2>0.81 for 79% of all B-cell populations identified), with a significantly lower median time of analysis per sample (6 vs. 40 min, p=0.001) for the AGI tool vs. MG, respectively and both intra-sample (median CV of 1.7% vs. 10.4% by MG, p<0.001) and inter-expert (median CV of 3.9% vs. 17.3% by MG by 2 experts, p<0.001) variability. Conclusion: Our results show that compared to conventional FC data analysis strategies, the here proposed AGI tool is a faster, more robust, reproducible, and standardized approach for in-depth analysis of B-lymphocyte and PC subsets circulating in human blood.

A vacuum-compatible cylindrical inertial rotation sensor with picoradian sensitivity.

We describe an inertial rotation sensor with a 30-cm cylindrical proof-mass suspended from a pair of 14 µm thick BeCu flexures. The angle between the proof-mass and support structure is measured with a pair of homodyne interferometers, which achieve a noise level of ∼5prad/Hz. The sensor is entirely made of vacuum compatible materials, and the center of mass can be adjusted remotely.

The cost-effectiveness of an indicated blended care intervention in primary care compared to usual care in patients with moderate persistent somatic symptoms.

INTRODUCTION: Appropriate treatment for people with an increased risk for developing chronic Persistent Somatic Symptoms (PSS) is of great importance at an early stage to improve quality of life and prevent high costs for society. OBJECTIVE: To evaluate the cost-effectiveness of an integrated blended care intervention compared to usual care for QALYs, subjective symptom impact and physical and mental health status in patients with moderate PSS. METHODS: This economic evaluation was conducted alongside a 12-month prospective, multicenter cluster randomized controlled trial in Dutch primary care. 80 participants received the intervention and 80 participants received usual care. Seemingly unrelated regression analyzes were performed to estimate cost and effect differences. Missing data were imputed using multiple imputation. Bootstrapping techniques were used to estimate uncertainty. RESULTS: We found no significant difference in total societal costs. Intervention, primary and secondary healthcare and absenteeism costs were higher for the intervention group. The ICER for QALYs demonstrated the intervention was on average less costly and less effective compared to usual care. For the subjective symptom impact and physical health, the ICER indicated that the intervention group was on average less costly and more effective. For mental health, the intervention was on average more costly and less effective. CONCLUSION: We didn't find an integrated blended primary care intervention to be cost-effective compared to usual care. However, when looking on relevant, but specific outcome measures (subjective symptom impact and physical health) for this population, average costs are found to be lower and the effectiveness found to be higher.

Reducing control noise in gravitational wave detectors with interferometric local damping of suspended optics.

Control noise is a limiting factor in the low-frequency performance of the Advanced Laser Interferometer Gravitational-Wave Observatory (LIGO). In this paper, we model the effects of using new sensors called Homodyne Quadrature Interferometers (HoQIs) to control the suspension resonances. We show that if we were to use HoQIs, instead of the standard shadow sensors, we could suppress resonance peaks up to tenfold more while simultaneously reducing the noise injected by the damping system. Through a cascade of effects, this will reduce the resonant cross-coupling of the suspensions, allow for improved stability for feed-forward control, and result in improved sensitivity of the detectors in the 10-20 Hz band. This analysis shows that improved local sensors, such as HoQIs, should be used in current and future detectors to improve low-frequency performance.

The (cost-)effectiveness of combined lifestyle interventions for people with persistent low-back pain who are overweight or obese: A systematic review.

INTRODUCTION: Lifestyle factors are expected to contribute to the persistence and burden of low-back pain (LBP). However, there are no systematic reviews on the (cost-)effectiveness of combined lifestyle interventions for overweight or obese people with LBP. AIM: To assess whether combined lifestyle interventions are (cost-)effective for people with persistent LBP who are overweight or obese, based on a systematic review. DESIGN: Systematic review METHOD: PubMed, Cochrane, Embase, CINAHL, PsycINFO and the Wiley/Cochrane Library were searched from database inception till January 6th 2023. Two independent reviewers performed study selection, data-extraction and risk of bias scoring using the Cochrane RoB tool 2 and/or the Consensus Health Economic Criteria list. GRADE was used to assess the level of certainty of the evidence. RESULTS: In total 2510 records were screened, and 4 studies on 3 original RCTs with 216 participants were included. Low certainty evidence (1 study) showed that combined lifestyle interventions were not superior to usual care for physical functioning, pain and lifestyle outcomes. Compared to usual care, moderate certainty evidence showed that healthcare (-$292, 95%CI: 872; -33), medication (-$30, 95% CI -65; -4) and absenteeism costs (-$1000, 95%CI: 3573; -210) were lower for the combined lifestyle interventions. CONCLUSION: There is low certainty evidence from 3 studies with predominantly small sample sizes, short follow-up and low intervention adherence that combined lifestyle interventions are not superior to physical functioning, pain and lifestyle outcomes compared to usual care, but are likely to be cost-effective.

(Cost-)effectiveness of a personalized multidisciplinary eHealth intervention for knee arthroplasty patients to enhance return to activities of daily life, work and sports - rationale and protocol of the multicentre ACTIVE randomized controlled trial.

BACKGROUND: With the worldwide rising obesity epidemic and the aging population, it is essential to deliver (cost-)effective care that results in enhanced societal participation among knee arthroplasty patients. The purpose of this study is to describe the development, content, and protocol of our (cost-)effectiveness study that assesses a perioperative integrated care program, including a personalized eHealth app, for knee arthroplasty patients aimed to enhance societal participation post-surgery compared to care as usual. METHODS: The intervention will be tested in a multicentre randomized controlled trial with eleven participating Dutch medical centers (i.e., hospitals and clinics). Working patients on the waiting-list for a total- or unicompartmental knee arthroplasty with the intention to return to work after surgery will be included. After pre-stratification on medical centre with or without eHealth as usual care, operation procedure (total- or unicompartmental knee arthroplasty) and recovery expectations regarding return to work, randomization will take place at the patient-level. A minimum of 138 patients will be included in both the intervention and control group, 276 in total. The control group will receive usual care. On top of care as usual, patients in the intervention group will receive an intervention consisting of three components: 1) a personalized eHealth intervention called ikHerstel ('I Recover') including an activity tracker, 2) goal setting using goal attainment scaling to improve rehabilitation and 3) a referral to a case-manager. Our main outcome is quality of life, based on patient-reported physical functioning (using PROMIS-PF). (Cost-)effectiveness will be assessed from a healthcare and societal perspective. Data collection has been started in 2020 and is expected to finish in 2024. DISCUSSION: Improving societal participation for knee arthroplasty is relevant for patients, health care providers, employers and society. This multicentre randomized controlled trial will evaluate the (cost-)effectiveness of a personalized integrated care program for knee arthroplasty patients, consisting of effective intervention components based on previous studies, compared to care as usual. TRIAL REGISTRATION: Trialsearch.who.int; reference no. NL8525, reference date version 1: 14-04-2020.

Poor association between tendon structure and self-reported symptoms following conservative management in active soldiers with mid-portion Achilles tendinopathy.

INTRODUCTION: Mid-portion Achilles tendinopathy (mid-AT) is currently the preferred term for persistent Achilles tendon pain, defined as located 2-7 cm proximal to the calcaneus, and with loss of function related to mechanical loading. Histologically, mid-AT is considered to represent a degenerative condition. Therefore, monitoring of tendon structure additional to pain and function may be warranted, to prevent progression of degeneration or even tendon rupture. The aim of this study was to determine the association between pain and function, relative to the Achilles tendon structure, in soldiers treated with a conservative programme for mid-AT. METHODS: A total of 40 soldiers (40 unilateral symptomatic tendons) were included in this study. Pain and function were evaluated with the Victorian Institute of Sports Assessment -Achilles (VISA-A) questionnaire. Tendon structure was quantified using ultrasound tissue characterisation (UTC). We quantified both the Achilles tendon mid-portion (2-7 cm) and the area of maximum degeneration (AoMD) within the tendon mid-portion. VISA-A and UTC measurements were taken at baseline and after 26 weeks of follow-up. Spearman's rho was used to determine the correlation between VISA-A and UTC. Correlations were calculated for baseline, follow-up and change score values. RESULTS: Negligible correlations were found for all analyses, ranging from -0.173 to 0.166 between mid-portion tendon structure and VISA-A, and from -0.137 to 0.150 between AoMD and VISA-A. While VISA-A scores improved, on average, from 59.4 points at baseline to 93.5 points at follow-up, no detectable improvement in aligned fibrillar structure was observed in our population. CONCLUSION: Pain and function are poorly associated with Achilles tendon structure in soldiers treated with a conservative programme for mid-AT. Therefore, we advise clinicians to use great caution in communicating relationships between both clinical entities. TRIAL REGISTRATION NUMBER: NL69527.028.19.

Niti-S Esophageal Covered stent (double anti-reflux type). An observational patient registry/post-market clinical follow-up study.

Background: Relieving dysphagia is the main goal of palliative care in advanced esophageal cancer. We aimed to evaluate the safety and clinical performance of the Niti-S esophageal double covered, anti-reflux stent (Taewoong Medical, Seoul, Korea) in inoperable carcinoma of the esophagus or gastric cardia. Methods: This was a retrospective patient registry/post-market clinical follow-up study of all patients with esophageal malignant strictures undergoing self-expandable metal stent (SEMS) placement with the Niti-S Esophageal covered stent, double antireflux in a community hospital (AZ St Maarten Mechelen, Belgium) between March 2013 and July 2021. Results: In twenty-nine patients, thirty self-expandable metal stents (SEMS) were placed. The median dysphagia score before stent placement was 3 and 0 after stent placement (p < 0.001). Stent migration did not occur. Two patients (7%) had new onset reflux symptoms. The most common adverse event was retrosternal pain (5 patients, 17%). One patient (3%) had recurrent dysphagia due to proximal tumoral overgrowth and two patients (7%) because of proximal benign tissue overgrowth. There were no perforations, fistula formations or episodes of food impaction. Conclusion: The Niti-S esophageal double covered, antireflux stent (Taewoong Medical, Seoul, Korea) is an effective and safe treatment option for malignant esophageal stenosis.

Effectiveness and cost-effectiveness of surgery versus casting for elderly patients with Displaced intra-Articular type C distal Radius fractures: protocol of a randomised controlled Trial with economic evaluation (the DART study).

INTRODUCTION: Current literature is inconclusive about the optimal treatment of elderly patients with displaced intra-articular distal radius fractures. Cast treatment is less invasive and less expensive than surgical treatment. Nevertheless, surgery is often the preferred treatment for this common type of distal radius fracture. Patients with a non-acceptable position after closed reduction are more likely to benefit from surgery than patients with an acceptable position after closed reduction. Therefore, this study aims to assess non-inferiority of functional outcomes after casting versus surgery in elderly patients with a non-acceptable position following a distal radius fracture. METHODS AND ANALYSIS: This study is a multicentre randomised controlled trial (RCT) with a non-inferiority design and an economic evaluation alongside. The population consists of patients aged 65 years and older with a displaced intra-articular distal radius fracture with non-acceptable radiological characteristics following either inadequate reduction or redisplacement after adequate reduction. Patients will be randomised between surgical treatment (open reduction and internal fixation) and non-operative treatment (closed reduction followed by cast treatment). We will use two age strata (65-75 and >75 years of age) and a web-based mixed block randomisation. A total of 154 patients will be enrolled and evaluated with the patient-rated wrist evaluation as the primary outcome at 1-year follow-up. Secondary outcomes include the Disabilities of the Arm, Shoulder and Hand questionnaire, quality of life (measured by the EQ-5D), wrist range of motion, grip strength and adverse events. In addition, we will perform a cost-effectiveness and cost-utility analysis from a societal and healthcare perspective. Incremental cost-effectiveness ratios, cost-effectiveness planes and cost-effectiveness acceptability curves will be presented. ETHICS AND DISSEMINATION: The Research and Ethics Committee approved this RCT (NL56858.100.16). The results of this study will be reported in a peer-reviewed journal. We will present the results of this study at (inter)national conferences and disseminate the results through guideline committees. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT03009890). Dutch Trial Registry (NTR6365).

Direct discharge of patients with simple stable musculoskeletal injuries as an alternative to routine follow-up: a systematic review of the current literature.

PURPOSE: There is growing evidence that patients with certain simple stable musculoskeletal injuries can be discharged directly from the Emergency Department (ED), without compromising patient outcome and experience. This study aims to review the literature on the effects of direct discharge (DD) of simple stable musculoskeletal injuries, regarding healthcare utilization, costs, patient outcome and experience. METHODS: A systematic review was performed in Medline, Embase, CINAHL, Cochrane Library and Web of Science using PRISMA guidelines. Comparative and non-comparative studies on DD of simple stable musculoskeletal injuries from the ED in an adult/paediatric/mixed population were included if reporting ≥ 1 of: (1) logistic outcomes: DD rate (proportion of patients discharged directly); number of follow-up appointments; DD return rate; (2) costs; (3) patient outcomes/experiences: functional outcome; treatment satisfaction; adverse outcomes; other. RESULTS: Twenty-six studies were included (92% conducted in the UK). Seven studies (27%) assessed functional outcome, nine (35%) treatment satisfaction, and ten (38%) adverse outcomes. A large proportion of studies defined DD eligibility criteria as injuries being minor/simple/stable, without further detail. ED DD rate was 26.7-59.5%. Mean number of follow-up appointments was 1.00-2.08 pre-DD, vs. 0.00-0.33 post-DD. Return rate was 0.0-19.4%. Costs per patient were reduced by €69-€210 (ranging from - 38.0 to - 96.6%) post-DD. Functional outcome and treatment satisfaction levels were 'equal' or 'better' (comparative studies), and 'high' (non-comparative studies), post-DD. Adverse outcomes were low and comparable. CONCLUSIONS: This systematic review supports the idea that DD of simple stable musculoskeletal injuries from the ED provides an opportunity to reduce healthcare utilization and costs without compromising patient outcomes/experiences. To improve comparability and facilitate implementation/external validation of DD, future studies should provide detailed DD eligibility criteria, and use a standard set of outcomes. Systematic review registration number: 120779, date of first registration: 12/02/2019.

Impact analysis of rotavirus vaccination in various geographic regions in Western Europe.

BACKGROUND: Universal mass vaccination (UMV) against rotavirus has been implemented in many but not all European countries. This study investigated the impact of UMV on rotavirus incidence trends by comparing European countries with UMV: Belgium, England/Wales and Germany versus countries without UMV: Denmark and the Netherlands. METHODS: For this observational retrospective cohort study, time series data (2001-2016) on rotavirus detections, meteorological factors and population demographics were collected. For each country, several meteorological and population factors were investigated as possible predictors of rotavirus incidence. The final set of predictors were incorporated in negative binomial models accounting for seasonality and serial autocorrelation, and time-varying incidence rate ratios (IRR) were calculated for each age group and country separately. The overall vaccination impact two years after vaccine implementation was estimated by pooling the results using a random effects meta-analyses. Independent t-tests were used to compare annual epidemics in the pre-vaccination and post-vaccination era to explore any changes in the timing of rotavirus epidemics. RESULTS: The population size and several meteorological factors were predictors for the rotavirus epidemiology. Overall, we estimated a 42% (95%-CI 23;56%) reduction in rotavirus incidence attributable to UMV. Strongest reductions were observed for age-groups 0-, 1- and 2-years (IRR 0.47, 0.48 and 0.63, respectively). No herd effect induced by UMV in neighbouring countries was observed. In all UMV countries, the start and/or stop and corresponding peak of the rotavirus season was delayed by 4-7 weeks. CONCLUSIONS: The introduction of rotavirus UMV resulted in an overall reduction of 42% in rotavirus incidence in Western European countries two years after vaccine introduction and caused a change in seasonal pattern. No herd effect induced by UMV neighbouring countries was observed for Denmark and the Netherlands.

Virus removal from semen with a pinched flow fractionation microfluidic chip.

Nowadays pigs are bred with artificial insemination to reduce costs and transportation. To prevent the spread of diseases, it is important to test semen samples for viruses. Screening techniques applied are enzyme-linked immunosorbent assays and/or polymerase chain reaction, which are labor-intensive and expensive methods. In contrast to the current used screening techniques, it is possible to remove viruses physically from semen. However, existing methods for virus removal techniques have a low yield of spermatozoa. Therefore, we have developed a microfluidic chip that performs size-based separation of viruses and spermatozoa in boar semen samples, thereby having the potential to reduce the risk of disease spreading in the context of artificial insemination in the veterinary industry. As the head of a spermatozoon is at least twenty times larger than a virus particle, the particle size can be used to achieve separation, resulting in a semen sample with lower viral load and of higher quality. To achieve the size separation, our microfluidic device is based on pinched-flow fractionation. A model virus, cowpea chlorotic mottle virus, was used and spiked to porcine semen samples. With the proposed microfluidic chip and the optimized flow parameters, at least 84 ± 4% of the model viruses were removed from the semen. The remaining virus contamination is caused by the model virus adhering to spermatozoa instead of the separation technique. The spermatozoa recovery was 86 ± 6%, which is an enormous improvement in yield compared to existing virus removal techniques.

Reduction of routine use of radiography in patients with ankle fractures leads to lower costs and has no impact on clinical outcome: an economic evaluation.

BACKGROUND: To evaluate the cost-effectiveness of a reduction in the number of routine radiographs in the follow-up of patients with ankle fractures. METHODS: We performed an economic evaluation alongside the multicentre, randomised WARRIOR trial. Participants were randomised to a reduced imaging follow-up protocol (i.e. radiographs at week 6 and 12 follow-up obtained on clinical indication) or usual care (i.e. routine radiography at weeks 6 and 12). The Olerud & Molander Ankle Score (OMAS) was used to assess ankle function and the EQ-5D-3L was used to estimate Quality-Adjusted Life Years (QALYs). Costs and resource use were assessed using self-reported questionnaires and medical records, and analysed from a societal perspective. Multiple imputation was used for missing data, and data were analysed using seemingly unrelated regression analysis and bootstrapping. RESULTS: In total, 246 patients had data available for analysis (reduced imaging = 118; usual care = 128). Fewer radiographs were obtained in the reduced imaging group (median = 4) compared with the usual-care group (median = 5). Functional outcome was comparable in both groups. The difference in QALYs was - 0.008 (95% CI:-0.06 to 0.04) and the difference in OMAS was 0.73 (95% CI:-5.29 to 6.76). Imaging costs were lower in the reduced imaging group (-€48; 95% CI:- €72 to -€25). All other cost categories did not statistically differ between the groups. The probability of the reduced imaging protocol being cost-effectiveness was 0.45 at a wiliness-to-pay of €20,000 per QALY. CONCLUSIONS: Reducing the number of routine follow-up radiographs has a low probability of being cost-effective compared with usual care. Functional outcome, health-related quality of life and societal costs were comparable in both groups, whereas imaging costs were marginally lower in the reduced imaging group. Given this, adherence to a reduced imaging follow-up protocol for those with routine ankle fractures can be followed without sacrificing quality of care, and may result in reduced costs. TRIAL REGISTRATION: The trial was registered on 26-05-2014 in the Netherlands Trial Registry, with reference number NL4477 ( www.trialregister.nl/trial/4477 ).

Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The longitudinal relationships between pain severity and disability versus health-related quality of life and costs among chronic low back pain patients.

PURPOSE: Previous studies found higher levels of pain severity and disability to be associated with higher costs and lower health-related quality of life. However, these findings were based on cross-sectional data and little is known about the longitudinal relationships between pain severity and disability versus health-related quality of life and costs among chronic low back pain patients. This study aims to cover this knowledge gap by exploring these longitudinal relationships in a consecutive cohort. METHODS: Data of 6316 chronic low back pain patients were used. Measurements took place at 3, 6, 9, and 12 months. Pain severity (Numeric pain rating scale; range: 0-100), disability (Oswestry disability index; range: 0-100), health-related quality of life (EQ-5D-3L: range: 0-1), societal and healthcare costs (cost questionnaire) were measured. Using linear generalized estimating equation analyses, longitudinal relationships were explored between: (1) pain severity and health-related quality of life, (2) disability and health-related quality of life, (3) pain severity and societal costs, (4) disability and societal costs, (5) pain severity and healthcare costs, and (6) disability and healthcare costs. RESULTS: Higher pain and disability levels were statistically significantly related with poorer health-related quality of life (pain intensity: - 0.0041; 95% CI - 0.0043 to - 0.0039; disability: - 0.0096; 95% CI - 0.0099 to - 0.0093), higher societal costs (pain intensity: 7; 95% CI 5 to 8; disability: 23; 95% CI 20 to 27) and higher healthcare costs (pain intensity: 3; 95% CI 2 to 4; disability: 9; 95% CI 7 to 11). CONCLUSION: Pain and disability were longitudinally related to health-related quality of life, societal costs, and healthcare costs. Disability had a stronger association with all outcomes compared to pain.