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Objective: The ArmeD SerVices TrAuma RehabilitatioN OutComE (ADVANCE) study is investigating long-term combat-injury outcomes; this sub-study aims to understand the association of osteoarthritis (OA) biomarkers with knee radiographic OA (rOA), pain and function in this high-risk population for post-traumatic OA., Design: ADVANCE compares combat-injured participants with age, rank, deployment and job-role frequency-matched uninjured participants. Post-injury immunoassay-measured serum biomarkers, knee radiographs, Knee Injury and Osteoarthritis Outcome Scale, and six-minute walk tests are reported. The primary analysis, adjusted for age, body mass, socioeconomic status, and ethnicity, was to determine any differences in biomarkers between those with/without combat injury, rOA and pain. Secondary analyses were performed to compare post-traumatic/idiopathic OA, painful/painfree rOA and injury patterns., Results: A total of 1145 male participants were recruited, aged 34.1 ± 5.4, 8.9 ± 2.2 years post-injury (n = 579 trauma-exposed, of which, traumatic-amputation n = 161) or deployment (n = 566 matched). Cartilage oligomeric matrix protein (COMP) was significantly higher in the combat-injured group compared to uninjured (p = 0.01). Notably, COMP was significantly lower in the traumatic-amputation group compared to non-amputees (p < 0.001), decreasing relative to number of amputations (p < 0.001). Leptin was higher (p = 0.005) and adiponectin lower (p = 0.017) in those with v without knee pain, associated with an increased risk of 22% and 17% for pain, and 46% and 34% for painful rOA, respectively. There were no significant differences between trauma-exposed and unexposed participants with rOA., Conclusions: The most notable findings of this large, unique study are the similarities between those with rOA regardless of trauma-exposure, the injury-pattern and traumatic-amputation-associated differences in COMP, and the relationship between adipokines and pain., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Accurate monitoring of minimal residual disease (MRD) is crucial for effective management of patients with acute myeloid leukemia (AML). This study aims to validate MRD detection of the seven most common IDH1 and IDH2 mutations in patients with AML using a QuantStudio three-dimensional digital PCR platform. This assay demonstrated a high concordance for the variant allele frequencies between digital PCR and next-generation sequencing assays. Precision analysis revealed only small variation (<0.5 log10) for all mutations near or at the limit of detection level. This validation also showed a great reproducibility for interrun and intrarun comparisons (28 runs, variation ranges from 0 to 0.48 log10), ensuring comparable results for patient follow-ups. The limit of detection was determined to be 0.1% for all mutations, except the IDH2 R140Q mutation, which was 0.5%. Controls and acceptable ranges were also established for each mutation during validation. This study suggests that the QuantStudio three-dimensional digital PCR assay is a quantitative, sensitive, and reproducible platform for monitoring MRD in patients with AML., Competing Interests: Disclosure Statement The authors are previous or current employees of United Kingdom HealthCare genomics laboratory. This laboratory is a fee-for-service diagnostics laboratory using the platform in this study., (Copyright © 2024. Published by Elsevier Inc.)

Background: Immune checkpoint inhibitor (ICI) Kaplan-Meier (KM) curves often show delayed survival benefit followed by long-term survival in a subgroup of patients. Such outcomes can violate the proportional hazards assumption, leading to a loss of statistical power., Objective: We aimed to determine common trends in delayed separation to inform future ICI clinical trials., Patients and Methods: A literature search was performed using Trialtrove ® to identify phase III trials of antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) agents in locally advanced/metastatic solid tumors published between January 2010 and September 2021. The frequency of delayed separation of overall survival (OS) and progression-free survival (PFS) KM curves, correlation between duration of delayed separation in OS/PFS KM curves, and correlation between duration of delayed separation in OS/PFS KM curves with corresponding hazard ratios (HRs) were assessed in all-comer and PD-L1 enriched populations., Results: Eighty-five studies with OS/PFS KM curves were identified. Most studies showed delayed separation of OS (> 67.9%) and PFS (> 54.5%) KM curves. The correlation between the duration of delayed separation in OS/PFS KM curves was strongest in the PD-L1 enriched population (adjusted R 2 = 0.66). No correlation was seen between the duration of delayed separation of OS KM curves and OS HR. A modest correlation was seen between the duration of delayed separation of PFS KM curves and PFS HR in all-comer and PD-L1 enriched populations (adjusted R 2 = 0.24 and 0.31, respectively)., Conclusions: Delayed separation of KM curves was common in clinical trials of anti-PD-(L)1 agents. Understanding delayed separation is key to clinical study designs and assessing outcomes with ICIs., (© 2024. The Author(s).)

Medical exome sequencing pipelines consist of various preprocessing steps to prioritize credible causal variants before a pathologist or variant curation scientist manually interprets potential findings that are then reported to patients. The variant allele frequency (VAF), reported as the fraction of sequencing reads supporting a variant call, can be used to screen for technical artifacts, yet a specific filtering threshold has yet to be established. A total of 13,122 manually curated variants, sequenced from 289 patients using the Agilent SureSelect Focused Exome enrichment kit at the University of Kentucky Clinical Genomics laboratory from October 2019 to May 2023, were evaluated. Totals of 278 single-nucleotide polymorphisms (SNPs) and 3340 SNPs as technical artifacts are clinically reported. All reported variants had a VAF between 0.33 and 0.63, and 82% (2725/3340) of sequencing artifacts had a VAF of <0.33. It is proposed that removing SNPs in which the VAF is less than approximately 0.30 reduces manual curation time by approximately 20% while capturing all medically relevant variants in medical exome sequencing data sets., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Although the majority of RNAs are retained in the nucleus, their significance is often overlooked. However, it is now becoming clear that nuclear RNA forms a dynamic structure through interacting with various proteins that can influence the three-dimensional structure of chromatin. We review the emerging evidence for a nuclear RNA mesh or gel, highlighting the interplay between DNA, RNA and RNA-binding proteins (RBPs), and assessing the critical role of protein and RNA in governing chromatin architecture. We also discuss a proposed role for the formation and regulation of the nuclear gel in transcriptional control. We suggest that it may concentrate the transcriptional machinery either by direct binding or inducing RBPs to form microphase condensates, nanometre sized membraneless structures with distinct properties to the surrounding medium and an enrichment of particular macromolecules., (© 2024 The Author(s).)

Within the UK Armed Forces, musculoskeletal injuries account for over half of all medical downgrades and discharges. Data from other Armed Forces show that osteoarthritis (OA), more common in military personnel, is likely to contribute to this, both in its primary form and following injury (post-traumatic OA, PTOA), which typically presents in the third or fourth decade. OA is not a progressive 'wear and tear' disease, as previously thought, but a heterogenous condition with multiple aetiologies and modulators, including joint damage, abnormal morphology, altered biomechanics, genetics, low-grade inflammation and dysregulated metabolism. Currently, clinical diagnosis, based on symptomatic or radiological criteria, is followed by supportive measures, including education, exercise, analgesia, potentially surgical intervention, with a particular focus on exercise rehabilitation within the UK military. Developments in OA have led to a new paradigm of organ failure, with an emphasis on early diagnosis and risk stratification, prevention strategies (primary, secondary and tertiary) and improved aetiological classification using genotypes and phenotypes to guide management, with the introduction of biological markers (biomarkers) potentially having a role in all these areas. In the UK Armed Forces, there are multiple research studies focused on OA risk factors, epidemiology, biomarkers and effectiveness of different interventions. This review aims to highlight OA, especially PTOA, as an important diagnosis to consider in serving personnel, outline current and future management options, and detail current research trends within the Defence Medical Services., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: TAR DNA-binding protein 43 (TDP-43) is a highly prevalent proteinopathy that is involved in neurodegenerative processes, including axonal damage. To date, no ante mortem biomarkers exist for TDP-43, and few studies have directly assessed its impact on neuroimaging measures utilizing pathologic quantification., Methods: Ante mortem diffusion-weighted images were obtained from community-dwelling older adults. Regression models calculated the relationship between post mortem TDP-43 burden and ante mortem fractional anisotropy (FA) within each voxel in connection with the hippocampus, controlling for coexisting Alzheimer's disease and demographics., Results: Results revealed a significant negative relationship (false discovery rate [FDR] corrected p < .05) between post mortem TDP-43 and ante mortem FA in one cluster within the left medial temporal lobe connecting to the parahippocampal cortex, entorhinal cortex, and cingulate, aligning with the ventral subdivision of the cingulum. FA within this cluster was associated with cognition., Discussion: Greater TDP-43 burden is associated with lower FA within the limbic system, which may contribute to impairment in learning and memory., Highlights: Post mortem TDP-43 pathological burden is associated with reduced ante mortem fractional anisotropy. Reduced FA located in the parahippocampal portion of the cingulum. FA in this area was associated with reduced episodic and semantic memory. FA in this area was associated with increased inward hippocampal surface deformation., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Individuals with behavioral-variant frontotemporal dementia (bvFTD) show changes in brain structure as assessed by MRI and brain function assessed by 18FDG-PET hypometabolism. However, current understanding of the spatial and temporal interplay between these measures remains limited., Methods: Here, we examined longitudinal atrophy and hypometabolism relationships in 15 bvFTD subjects with 2 to 4 follow-up MRI and PET scans (56 visits total). Subject-specific slopes of atrophy and hypometabolism over time were extracted across brain regions and correlated with baseline measures both locally, via Pearson correlations, and nonlocally, via sparse canonical correlation analyses (SCCA)., Results: Notably, we identified a robust link between initial hypometabolism and subsequent cortical atrophy rate changes in bvFTD subjects. Network-level exploration unveiled alignment between baseline hypometabolism and ensuing atrophy rates in the dorsal attention, language, and default mode networks. SCCA identified 2 significant and highly localized components depicting the connection between baseline hypometabolism and atrophy slope over time. The first centered around bilateral orbitofrontal, frontopolar, and medial prefrontal lobes, whereas the second concentrated in the left temporal lobe and precuneus., Conclusions: This study highlights 18FDG-PET as a dependable predictor of forthcoming atrophy in spatially adjacent brain regions for individuals with bvFTD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN)., Methods: Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach., Results: The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping., Conclusion: In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ma, Stocks, Rosen, Kantarci, Lockhart, Bateman, Craft, Gurcan, Popuri, Faisal Beg, Wang and on behalf of the ALLFTD consortium.)

Background: There is substantial evidence exploring the reliability of running distance self-reporting and GPS wearable technology, but there are currently no studies investigating the reliability of participant self-reporting in comparison to GPS wearable technology. There is also a critical sports science and medical research gap due to a paucity of reliability studies assessing self-reported running pace., Objective: The purpose of this study was to assess the reliability of weekly self-reported running distance and pace compared to a commercial GPS fitness watch, stratified by sex and age. These data will give clinicians and sports researchers insights into the reliability of runners' self-reported pace, which may improve training designs and rehabilitation prescriptions., Methods: A prospective study of recreational runners was performed. Weekly running distance and average running pace were captured through self-report and a fitness watch. Baseline characteristics collected included age and sex. Intraclass correlational coefficients were calculated for weekly running distance and running pace for self-report and watch data. Bland-Altman plots assessed any systemic measurement error. Analyses were then stratified by sex and age., Results: Younger runners reported improved weekly distance reliability (median 0.93, IQR 0.92-0.94). All ages demonstrated similar running pace reliability. Results exhibited no discernable systematic bias., Conclusions: Weekly self-report demonstrated good reliability for running distance and moderate reliability for running pace in comparison to the watch data. Similar reliability was observed for male and female participants. Younger runners demonstrated improved running distance reliability, but all age groups exhibited similar pace reliability. Running pace potentially should be monitored through technological means to increase precision., (©Garrett Bullock, Joanne Stocks, Benjamin Feakins, Zahra Alizadeh, Amelia Arundale, Stefan Kluzek. Originally published in JMIR Formative Research (https://formative.jmir.org), 04.01.2024.)

Post-traumatic OA (PTOA) can occur within 5 years after a significant injury and is a valuable paradigm for identifying biomarkers. This systematic review aims to summarise published literature in human studies on the associations of known serum and synovial fluid biomarkers at least a year from injury to structural, symptomatic changes and underlying PTOA processes. A systematic review was performed using PRISMA guidelines, prospectively registered on PROSPERO (CRD42022371838), for all 'wet' biomarkers a year or more post-injury in 18-45-year-old participants. Three independent reviewers screened search results, extracted data, and performed risk of bias assessments (Newcastle-Ottawa Scale). Study heterogeneity meant a narrative synthesis was undertaken, utilising SWiM guidelines. 952 studies were identified, 664 remaining after deduplication. Following first-round screening, 53 studies underwent second-round screening against pre-determined criteria. Eight studies, with 879 participants (49 ​% male), were included, measuring serum (n ​= ​7), synovial fluid (SF, n ​= ​6), or both (n ​= ​5). The pooled participant mean age was 29.1 (±4). 51 biomarkers were studied (serum ​= ​38, SF ​= ​13), with no correlation between paired serum and SF samples. One serum biomarker, cartilage oligomeric matrix protein (COMP), and four SF biomarkers, interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF), and COMP, were measured in multiple studies. Associations were described between 11 biomarkers related to catabolism (n ​= ​4), anabolism (n ​= ​2), inflammation (n ​= ​4) and non-coding RNA (n ​= ​1), with OA imaging changes (X-ray and MRI), pain, quality of life and function. Widespread differences in study design and methodology prevented meta-analysis, and evidence was generally weak. A unified approach is required before widespread research and clinical biomarker use., Competing Interests: There are no conflicts of interest for any authors., (© 2023 The Author(s).)

Background: While the integration of patient and public involvement (PPI) in clinical research is now widespread and recommended as standard practice, meaningful PPI in pre-clinical, discovery science research is more difficult to achieve. One potential way to address this is by integrating PPI into the training programmes of discovery science postgraduate doctoral students. This paper describes the development and formative evaluation of the Student Patient Alliance (SPA), a programme developed at the University of Birmingham that connects PPI partners with doctoral students., Methods: Following a successful pilot of the SPA by the Rheumatology Research Group at the University of Birmingham, the scheme was implemented across several collaborating Versus Arthritis / Medical Research Council (MRC) centres of excellence. Doctoral students were partnered with PPI partners, provided with initial information and guidance, and then encouraged to work together on research and public engagement activities. After six months, students, their PPI partners and the PPI coordinators at each centre completed brief surveys about their participation in the SPA., Results: Both doctoral students and their PPI partners felt that taking part in SPA had a positive impact on understanding, motivation and communication skills. Students reported an increased understanding of PPI and patient priorities and reported improved public engagement skills. Their PPI partners reported a positive impact of the collaboration with the students. They enjoyed learning about the student's research and contributing to the student's personal development. PPI coordinators also highlighted the benefits of the SPA, but noted some challenges they had experienced, such as difficulties matching students with PPI partners., Conclusions: The SPA was valued by students and PPI partners, and it is likely that initiatives of this kind would enhance students' PPI and public engagement skills and awareness of patients' experiences on a wider scale. However, appropriate resources are needed at an institutional level to support the implementation of effective programmes of this kind on a larger scale., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (β = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.

Introduction: Osteoarthritis (OA) results from various aetiologies, including joint morphology, biomechanics, inflammation, and injury. The latter is implicated in post-traumatic OA, which offers a paradigm to identify potential biomarkers enabling early identification and intervention. This review aims to describe imaging features associated with structural changes or symptoms at least one year following injury., Methodology: A systematic review was conducted using PRISMA guidance, prospectively registered on PROSPERO (CRD42022371838). Three independent reviewers screened titles and abstracts, followed by full-texts, performed data extraction, and risk of bias assessments (Newcastle-Ottawa Scale). Inclusion criteria included imaging studies involving human participants aged 18-45 who had sustained a significant knee injury at least a year previously. A narrative synthesis was performed using synthesis without meta-analysis methodology., Results: Six electronic databases and conference proceedings were searched, identifying 11 studies involving 776 participants. All studies included participants suffering an anterior cruciate ligament (ACL) injury and utilised MRI. Different, and not directly comparable, techniques were used. MRI features could be broadly divided into structural, including joint position and morphology, and compositional. Promising biomarkers for diagnosing and predicting osteoarthritis include T1rho and T2 relaxation time techniques, bone morphology changes and radiomic modelling., Discussion: As early as 12 months after injury, differences in tibia position, bone morphology, presence of effusion and synovitis, and cartilage/subchondral bone composition can be detected, some of which are linked with worse patient-reported or radiological progression. Standardisation, including MR strength, position, sequence, scoring and comparators, is required to utilise clinical and research OA imaging biomarkers fully., Competing Interests: There are no conflicts of interest for any authors., (Crown Copyright © 2023 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International (OARSI).)

Background: The A/T/N framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined A/T/N groups is currently unclear., Objective: To determine the regions of association between atrophy and hypometabolism in A/T/N groups both within and across time points., Methods: We examined multivariate multimodal neuroimaging relationships between MRI and 18FDG-PET among suspected non-Alzheimer's disease pathology (SNAP) (A-T/N+; n = 14), Amyloid Only (A+T-N-; n = 24) and Probable AD (A+T+N+; n = 77) groups. Sparse canonical correlation analyses were employed to model spatially disjointed regions of association between MRI and 18FDG-PET data. These relationships were assessed at three combinations of time points -cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up., Results: In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12., Conclusion: These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration.

Neuroimaging-based brain-age estimation via machine learning has emerged as an important new approach for studying brain aging. The difference between one's estimated brain age and chronological age, the brain age gap (BAG), has been proposed as an Alzheimer's Disease (AD) biomarker. However, most past studies on the BAG have been cross-sectional. Quantifying longitudinal changes in an individual's BAG temporal pattern would likely improve prediction of AD progression and clinical outcome based on neurophysiological changes. To fill this gap, our study conducted predictive modeling using a large neuroimaging dataset with up to 8 years of follow-up to examine the temporal patterns of the BAG's trajectory and how it varies by subject-level characteristics (sex, APOEɛ4 carriership) and disease status. Specifically, we explored the pattern and rate of change in BAG over time in individuals who remain stable with normal cognition or mild cognitive impairment (MCI), as well as individuals who progress to clinical AD. Combining multimodal imaging data in a support vector regression model to estimate brain age yielded improved performance over single modality. Multilevel modeling results showed the BAG followed a linear increasing trajectory with a significantly faster rate in individuals with MCI who progressed to AD compared to cognitively normal or MCI individuals who did not progress. The dynamic changes in the BAG during AD progression were further moderated by sex and APOEɛ4 carriership. Our findings demonstrate the BAG as a potential biomarker for understanding individual specific temporal patterns related to AD progression., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2022. Published by Elsevier Inc.)

Background: We previously reported relatively normal pulmonary function (2 years of age) and computed tomography (CT, 1 year of age) in cystic fibrosis (CF) newborn screened (NBS) infants. We now report follow up of these children to preschool age., Methods: 67 NBS children with CF and 41 healthy controls underwent pulmonary function tests in infancy (∼3 months, 1 year and 2 years) and at preschool (3-6 years). Broncho-alveolar lavage (BAL) and CT were undertaken in those with CF at 1 year. Primary outcomes at preschool were lung clearance index (LCI) and forced expired volume (FEV 0.75 ). Risk factors for lung function impairment were identified by regression modelling, emphasising factors that could be identified or measured in the first 2 years of life., Results: At preschool age children with CF had poorer lung function than controls, mean(95% CI) difference in LCI z-score: 1.47(0.96;1.97) and FEV 0.75 z-score -0.54(-0.98; -0.10). Isolation of Pseudomonas aeruginosa before 6 months was a highly significant predictor of raised (abnormal) preschool LCI, associated with a mean (95%CI) increase of 1.69(0.43, 2.95) z-scores, compared to those with no Pseudomonas aeruginosa during the first 2 years of life. Including 2 year LCI and 1 year CT data in the predictive model increased the r 2 from 13% to 61%., Conclusions: Lung function deteriorates after 2 years in NBS children with CF. Isolation of Pseudomonas aeruginosa before 6 months and minor abnormalities of infant lung function tests and CT in infancy are associated with higher preschool LCI., Competing Interests: Declaration of Competing Interest Dr Aurora received grant funding from Action Medical Research, The Henry Smith Charity and the Cystic Fibrosis Trust for this work. Other authors have no conflicts of interests to declare., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Background: Mobile phone ownership among women of reproductive age in western Kenya is not well described, and our understanding of its link with care-seeking behaviors is nascent. Understanding access to and use of mobile phones among this population as well as willingness to participate in mobile health interventions are important in improving and more effectively implementing mobile health strategies., Objective: This study aims to describe patterns of mobile phone ownership and use among women attending cervical cancer screening and to identify key considerations for the use of SMS text message-guided linkage to treatment strategies and other programmatic implications for cervical cancer screening in Kenya., Methods: This analysis was nested within a cluster randomized trial evaluating various strategies for human papillomavirus (HPV)-based cervical cancer screening and prevention in a rural area in western Kenya between February and November 2018. A total of 3299 women were surveyed at the time of screening and treatment. Questionnaires included items detailing demographics, health history, prior care-seeking behaviors, and patterns of mobile phone ownership and use. We used bivariate and multivariable log-binomial regression to analyze associations between independent variables and treatment uptake among women testing positive for high-risk HPV., Results: Rates of mobile phone ownership (2351/3299, 71.26%) and reported daily use (2441/3299, 73.99%) were high among women. Most women (1953/3277, 59.59%) were comfortable receiving their screening results via SMS text messages, although the most commonly preferred method of notification was via phone calls. Higher levels of education (risk ratio 1.23, 95% CI 1.02-1.50), missing work to attend screening (risk ratio 1.29, 95% CI 1.10-1.52), and previous cervical cancer screening (risk ratio 1.27, 95% CI 1.05-1.55) were significantly associated with a higher risk of attending treatment after testing high-risk HPV-positive, although the rates of overall treatment uptake remained low (278/551, 50.5%) among this population. Those who shared a mobile phone with their partner or spouse were less likely to attend treatment than those who owned a phone (adjusted risk ratio 0.69, 95% CI 0.46-1.05). Treatment uptake did not vary significantly according to the type of notification method, which were SMS text message, phone call, or home visit., Conclusions: Although the rates of mobile phone ownership and use among women in western Kenya are high, we found that individual preferences for communication of messages about HPV results and treatment varied and that treatment rates were low across the entire cohort, with no difference by modality (SMS text message, phone call, or home visit). Therefore, although text-based results performed as well as phone calls and home visits, our findings highlight the need for more work to tailor communication about HPV results and support women as they navigate the follow-up process., (©Jacob Stocks, Saduma Ibrahim, Lawrence Park, Megan Huchko. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 07.06.2022.)

Background: Concordance between cortical atrophy and cortical glucose hypometabolism within distributed brain networks was evaluated among cerebrospinal fluid (CSF) biomarker-defined amyloid/tau/neurodegeneration (A/T/N) groups., Method: We computed correlations between cortical thickness and fluorodeoxyglucose metabolism within 12 functional brain networks. Differences among A/T/N groups (biomarker normal [BN], Alzheimer's disease [AD] continuum, suspected non-AD pathologic change [SNAP]) in network concordance and relationships to longitudinal change in cognition were assessed., Results: Network-wise markers of concordance distinguish SNAP subjects from BN subjects within the posterior multimodal and language networks. AD-continuum subjects showed increased concordance in 9/12 networks assessed compared to BN subjects, as well as widespread atrophy and hypometabolism. Baseline network concordance was associated with longitudinal change in a composite memory variable in both SNAP and AD-continuum subjects., Conclusions: Our novel study investigates the interrelationships between atrophy and hypometabolism across brain networks in A/T/N groups, helping disentangle the structure-function relationships that contribute to both clinical outcomes and diagnostic uncertainty in AD., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: To achieve the World Health Organization targets for cervical cancer elimination, low- and middle-income countries will need to develop innovative strategies to provide human papillomavirus (HPV)-based screening at a population level. Although mobile health (mHealth) interventions may help realize these goals by filling gaps in electronic specimen tracking and patient education, effective implementation of mHealth interventions is dependent upon context-specific development that is acceptable and usable by the target population. Detailed feedback should be gathered at the design and development stages to yield final products that reflect the needs, desires, and capabilities of target users., Objective: The aim of this study is to develop an mHealth app (mSaada) to support HPV-based screening in partnership with community health volunteers (CHVs) and program planners in western Kenya., Methods: A team of student programmers developed a prototype to meet previously identified gaps in screening: patient education, protocol support, data capture, and specimen tracking. The prototype was iteratively developed through 2 waves of in-person working sessions with quantitative (survey) and qualitative (in-depth interview) feedback. Research staff engaged key stakeholders from both urban and rural locations and with varying levels of experience in delivering screening services. During the sessions, participants completed simulation exercises and role-play activities to become familiar with the platform. Once feedback was gathered and synthesized after each wave of in-person data collection, developers implemented changes to improve mSaada functionality., Results: A total of 18 CHVs and clinicians participated in the in-person sessions. Participants found mSaada useful, easy to use, and would meet the needs of CHVs to provide HPV-based cervical cancer screening (electronic data capture, client education resources, and specimen tracking). They provided key feedback to enhance user experience, workflow, and sustainability. Key changes included altering the appearance of the wireframes, adding translation in additional local languages, changing potentially insensitive figures, alphabetizing lengthy dropdown menus, adding clinically relevant logic checks when entering data, and incorporating the ability to make real time edits to client records. They also made recommendations for additional features that might enhance mSaada's impact at the facility and health system levels, specifically the inclusion of a report-generating tool consistent with the Ministry of Health standards., Conclusions: Using a process of iterative feedback with key stakeholders and rapid response from developers, we have developed a mobile app ready for pilot testing in HPV-based screening programs led by CHVs., (©Jacob Stocks, Yujung Choi, Saduma Ibrahim, Megan Huchko. Originally published in JMIR Formative Research (https://formative.jmir.org), 24.02.2022.)

Although neuroimaging studies of collision (COLL) sport athletes demonstrate alterations in brain structure and function from pre- to post-season, reliable tools to detect behavioral/cognitive change relevant to functional networks associated with participation in collision sports are lacking. This study evaluated the use of eye-movement testing to detect change in cognitive and sensorimotor processing among male club collegiate athletes after one season of participation in collision sports of variable exposure. We predicted that COLL (High Dose [hockey], n  = 8; Low Dose [rugby], n  = 9) would demonstrate longer reaction times (antisaccade and memory-guided saccade [MGS] latencies), increased inhibitory errors (antisaccade error rate), and poorer spatial working memory (MGS spatial accuracy) at post-season, relative to pre-season, whereas non-collision collegiate athletes (NON-COLL; n  = 17) would remain stable. We also predicted that whereas eye-movement performance would detect pre- to post-season change, ImPACT (Immediate Post-Concussion Assessment and Cognitive Test) performance would remain stable. Our data showed that NON-COLL had shorter (improved performance) post- versus pre-season antisaccade and MGS latencies, whereas COLL groups showed stable, longer, or attenuated reduction in latency ( p s ≤ 0.001). Groups did not differ in antisaccade error rate. On the MGS task, NON-COLL demonstrated improved spatial accuracy over time, whereas COLL groups showed reduced spatial accuracy ( p  < 0.05, uncorrected). No differential change was observed on ImPACT. This study provides preliminary evidence for eye-movement testing as a sensitive marker of subtle changes in attentional control and working memory resulting from participation in sports with varying levels of subconcussive exposure., Competing Interests: No competing financial interests exist., (© Virginia T. Gallagher et al., 2021; Published by Mary Ann Liebert, Inc.)

We investigated differences due to sex in brain structural volume and cortical thickness in older cognitively normal (N=742), cognitively impaired (MCI; N=540) and Alzheimer's Dementia (AD; N=402) individuals from the ADNI and AIBL datasets (861 Males and 823 Females). General linear models were used to control the effect of relevant covariates including age, intracranial volume, magnetic resonance imaging (MRI) scanner field strength and scanner types. Significant volumetric differences due to sex were observed within different cortical and subcortical regions of the cognitively normal group. The number of significantly different regions was reduced in the MCI group, and no region remained different in the AD group. Cortical thickness was overall thinner in males than females in the cognitively normal group, and likewise, the differences due to sex were reduced in the MCI and AD groups. These findings were sustained after including cerebrospinal fluid (CSF) Tau and phosphorylated tau (pTau) as additional covariates., Competing Interests: Declaration of Competing Interest There is no conflict of interest to declare from all authors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for clinicians, researchers, policy- and decision-makers, funders, publishers, public health experts, disaster preparedness and response experts, infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations), and other potential users. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Austin CC et al.)

Objectives: To determine individual responses to ibuprofen gel or capsaicin cream for painful, radiographic knee OA using a series of n-of-1 trials., Methods: Twenty-two participants were allocated 5% ibuprofen gel (A) and 0.025% capsaicin cream (B) in random sequence (AB or BA). Patients underwent up to 3 treatment cycles, each comprising one treatment for 4 weeks, an individualized washout period (maximum 4 weeks), then the other treatment for 4 weeks. Differential (ibuprofen or capsaicin) response was defined when change-from-baseline pain intensity scores (0-10 NRS) differed by ≥1 between treatments in ≥2 cycles within a participant., Results: A total of 104 treatment periods were aggregated. Mean pain reduction was 1.2 (95% CI: 0.5, 1.8) on ibuprofen and 1.6 (95% CI: 0.9, 2.4) on capsaicin (P = 0.221). Of 22 participants, 4 (18%) had a greater response to ibuprofen, 9 (41%) to capsaicin, 4 (18%) had similar responses, and 5 (23%) were undetermined., Conclusion: Irrespective of equal efficacy overall, 59% of people displayed a greater response to one treatment over the other. Patients who do not benefit from one type of topical treatment should be offered to try another, which may be more effective. N-of-1 trials are useful to identify individual response to treatment., Clinical Trial Registration: https://clinicaltrials.gov, NCT03146689., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dementia of Alzheimer's type (DAT) is associated with devastating and irreversible cognitive decline. Predicting which patients with mild cognitive impairment (MCI) will progress to DAT is an ongoing challenge in the field. We developed a deep learning model to predict conversion from MCI to DAT. Structural magnetic resonance imaging scans were used as input to a 3-dimensional convolutional neural network. The 3-dimensional convolutional neural network was trained using transfer learning; in the source task, normal control and DAT scans were used to pretrain the model. This pretrained model was then retrained on the target task of classifying which MCI patients converted to DAT. Our model resulted in 82.4% classification accuracy at the target task, outperforming current models in the field. Next, we visualized brain regions that significantly contribute to the prediction of MCI conversion using an occlusion map approach. Contributory regions included the pons, amygdala, and hippocampus. Finally, we showed that the model's prediction value is significantly correlated with rates of change in clinical assessment scores, indicating that the model is able to predict an individual patient's future cognitive decline. This information, in conjunction with the identified anatomical features, will aid in building a personalized therapeutic strategy for individuals with MCI., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Sensitive and reliable tools are needed to evaluate potential behavioral and cognitive changes following head impact exposure in contact and collision sport participation. We evaluated change in oculomotor testing performance among female, varsity, collegiate athletes following variable exposure to head impacts across a season. Female, collegiate, contact sport (soccer, CONT) and non-contact sport (NON-CONT) athletes were assessed pre-season and post-season. Soccer athletes were grouped according to total season game headers into low dose (≤40 headers; CONT-Low Dose) or high dose (>40 headers; CONT-High Dose) groups. Performance on pro-saccade (reflexive visual response), anti-saccade (executive inhibition), and memory-guided saccade (MGS, spatial working memory) computer-based laboratory tasks were assessed. Primary saccade measures included latency/reaction time, inhibition error rate (anti-saccade only), and spatial accuracy (MGS only). NON-CONT ( n  = 20 ) , CONT-Low Dose ( n  = 17), and CONT-High Dose ( n  = 7) groups significantly differed on pre-season versus post-season latency on tasks with executive functioning demands (anti-saccade and MGS, p  ≤ 0.001). Specifically, NON-CONT and CONT-Low Dose demonstrated shorter (i.e., faster) anti-saccade (1.84% and 2.68%, respectively) and MGS (5.74% and 2.76%, respectively) latencies from pre-season to post-season, whereas CONT-High Dose showed 1.40% average longer anti-saccade, and 0.74% shorter MGS, latencies. NON-CONT and CONT-Low Dose demonstrated reduced (i.e., improved) inhibition error rate on the anti-saccade task at post-season versus pre-season, whereas CONT-High Dose demonstrated relative stability ( p  = 0.021). The results of this study suggest differential exposure to subconcussive head impacts in collegiate female athletes is associated with differential change in reaction time and inhibitory control performances on executive saccadic oculomotor testing., Competing Interests: No competing financial interests exist., (© Virginia T. Gallagher et al., 2020; Published by Mary Ann Liebert, Inc.)

The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Austin CC et al.)

Background: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age., Methods: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs., Results: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT., Conclusions: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes., Competing Interests: Declaration of Competing Interest Dr. Brody reports grants and personal fees from Vertex Pharmaceuticals, outside the submitted work. Dr. Carr reports personal fees and other from Vertex Pharmaceuticals, other from Chiesi Pharmaceuticals, personal fees from Actavis Pharmaceuticals, other from Pharmaxis Pharmaceuticals, outside the submitted work. Dr Davies reports personal fees from Chiesi Pharmaceuticals, outside the submitted work. All other authors report no other potential competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: To identify predictors of the specific (difference between treatment and placebo) and overall (change from baseline in treatment arm) treatment effects of topical NSAIDs in OA., Methods: Randomized controlled trials (RCTs) of topical NSAIDs in OA were identified through systematic literature searching and inquiry to pharmaceutical companies. The raw, de-identified data were analysed in one-stage individual patient data meta-analysis (IPD-MA). Negative values for treatment effects (0-100 scale) indicate pain reduction., Results: Of 63 eligible RCTs, 15 provided IPD (n = 1951 on topical NSAID), including 11 placebo-controlled RCTs (n = 1587 on topical NSAIDs, 1553 on placebo). Seven potential predictors of response were examined. Topical NSAIDs were superior to placebo [-6 (95% CI -9, -4)], with a small, but statistically significant greater effect in women than men [difference -4 (95% CI -8, -1)]. The overall treatment effect was 4-fold larger than the specific effect [-25 (95% CI -31, -19)] and increased with greater baseline pain severity (P < 0.001). No differences in efficacy were observed for age, BMI, features of inflammation, duration of complaints or radiographic OA severity., Conclusion: Topical NSAIDs are effective for OA pain relief. Greater overall pain relief in individuals with more baseline pain might be due to contextual and non-specific effects, including regression to the mean. Additional factors that have been linked either mechanistically or through empirical evidence to outcomes should be selected for inclusion across future RCTs in order to facilitate the identification of response predictors through IPD-MA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: In an ageing population, pain, frailty and disability frequently coexist across a wide range of musculoskeletal diagnoses, but their associations remain incompletely understood. The Investigating Musculoskeletal Health and Wellbeing (IMH&W) study aims to measure and characterise the development and progression of pain, frailty and disability, and to identify discrete subgroups and their associations. The survey will form a longitudinal context for nested research, permitting targeted recruitment of participants for qualitative, observational and interventional studies; helping to understand recruitment bias in clinical studies; and providing a source cohort for cohort randomised controlled trials., Methods: IMH&W will comprise a prospective cohort of 10,000 adults recruited through primary and secondary care, and through non-clinical settings. Data collection will be at baseline, and then through annual follow-ups for 4 years. Questionnaires will address demographic characteristics, pain severity (0-10 Numerical Rating Scale), pain distribution (reported on a body Manikin), pain quality (McGill Pain Questionnaire), central aspects of pain (CAP-Knee), frailty and disability (based on Fried criteria and the FRAIL questionnaire), and fracture risk. Baseline characteristics, progression and associations of frailty, pain and disability will be determined. Discrete subgroups and trajectories will be sought by latent class analysis. Recruitment bias will be explored by comparing participants in nested studies with the eligible IMH&W population., Discussion: IMH&W will elucidate associations and progression of pain, frailty and disability. It will enable identification of people at risk of poor musculoskeletal health and wellbeing outcomes who might be suitable for specific interventions, and facilitate generalisation and comparison of research outcomes between target populations. The study will benefit from a large sample size and will recruit from diverse regions across the UK. Purposive recruitment will enrich the cohort with people with MSK problems with high representation of elderly and unwell people., Trial Registration: Clinicaltrials.gov NCT03696134. Date of Registration: 04 October 2018.

Objectives: We investigated whether baseline scores for a self-report trait linked to central mechanisms predict 1 year pain outcomes in the Knee Pain in the Community cohort., Method: 1471 participants reported knee pain at baseline and responded to a 1-year follow-up questionnaire, of whom 204 underwent pressure pain detection thresholds (PPTs) and radiographic assessment at baseline. Logistic and linear regression models estimated the relative risks (RRs) and associations (β) between self-report traits, PPTs and pain outcomes. Discriminative performance for each predictor was compared using receiver-operator characteristics (ROC) curves., Results: Baseline Central Mechanisms trait scores predicted pain persistence (Relative Risk, RR = 2.10, P = 0.001) and persistent pain severity (β = 0.47, P < 0.001), even after adjustment for age, sex, BMI, radiographic scores and symptom duration. Baseline joint-line PPTs also associated with pain persistence (RR range = 0.65 to 0.68, P < 0.02), but only in univariate models. Lower baseline medial joint-line PPT was associated with persistent pain severity (β = -0.29, P = 0.013) in a fully adjusted model. The Central Mechanisms trait model showed good discrimination of pain persistence cases from resolved pain cases (Area Under the Curve, AUC = 0.70). The discrimination power of other predictors (PPTs (AUC range = 0.51 to 0.59), radiographic OA (AUC = 0.62), age, sex and BMI (AUC range = 0.51 to 0.64), improved significantly (P < 0.05) when the central mechanisms trait was included in each logistic regression model (AUC range = 0.69 to 0.74)., Conclusion: A simple summary self-report Central Mechanisms trait score may indicate a contribution of central mechanisms to poor knee pain prognosis., Competing Interests: Competing interests Kehinde Akin-Akinyosoye: None declared. Aliya Sarmanova: None declared. Gwen Sascha Fernandes: None declared. Nadia Frowd: None declared. Laura Marshall: None declared. Joanne Stocks: None declared. Ana Valdes: None declared. Daniel McWilliams: None declared. Michael Doherty: None declared. Weiya Zhang: Consultation fees: AstraZeneca (Lesinurad) and Gruenthal (Lesinurad); Speaker fees: Husin (Chinese Society of Rheumatology Annual Congress 2016) and Bioberica (EULAR 2016 symposium) in the past 3 years; Eamonn Ferguson: Royalties: GL assessment for the Paediatric Index of Emotional Distress (PI-ED); Research grants: Co-investigator on the US Defense Medical Research and Development Program (Study to examine psychological processes in suicidal ideation and behaviour), the ESRC (Individual Differences in the Impact of Socio- Economic Events on Health and Well-being), the ESRC (Integrating Prospect theory (Framing Effects) and the Common Sense Model of illness to improve medication compliance in glaucoma patients), Chief Scientists Office – Scotland (A randomised controlled trial to test if a simple anticipated regret manipulation leads to a significant increase in organ donor registrations), DEFRA (Overcoming barriers to uptake of best welfare practice by sheep farmers), Pfizer (Pain phenotypes in rheumatoid arthritis: a patient-centred, stratified approach to optimising disease modifying and analgesic treatments), Arthritis UK Research (Pain Centre) that funds the current work, ESRC PhD studentships on reluctant altruism and Schizophrenia and Empathy; Paid Journal Editorships: Deputy Editor British Journal of Psychology and Associate Editor for Annals of Behavioral Medicine; Honorariums and expenses paid: Speaker at ISBT, Workshops include (i) Right Patient, Right Place, Right Time: When and How to Use the Emergency Department: Health Literacy, Decision-Making and Communication. Unversita Cattolic del Sacro Cuore. Milan, Italy, April 11th-12th, (ii) Taxometrics, Psychometrics and Clinometrics: Stratified Medicine and Assessing Phenotypes. ESRC Advanced Quantitative Methods National Conference, White Rose DTC, Sheffield University, Sheffield, 24th to 25th July 2014, (iii) Personality: Myths, Misconceptions and Misunderstandings – Implications for Current and Future Medical Education, Selection and Training. INReSH London, 10- 11th November, (iv) ABC (America's Blood Centres) 55th Annual Meeting in Washington (24th to 28th March 2017). Motivation and Innovations in Donor Recruitment, Australian Red Cross Transfusion Update Meeting Sydney 2017 (27th to 28th April). (v) What really motivates people to donate and what can we do with what we find out? Australian Red Cross Transfusion Sydney 2017 (26th April). (vi) What really motivates people to donate and what can we do with what we find out. Address to Sydney Office Staff, Australian Red Cross Transfusion Melburne 2017 (1st May). (vii) What really motivates people to donate and what can we do with what we find out. Address to Melbourne Office Staff; External Examiner: External Examiner at Edinburgh University and Goldsmith's and currently at Lancaster University; Presidential roles (unpaid): co-founding president of the British Society for the Psychology of Individual Differences (BSPID). David Walsh: Employment: University of Nottingham as Professor of Rheumatology, Director of Arthritis Research UK Pain Centre and Musculoskeletal Theme lead in the NIHR Nottingham Biomedical Research Centre, with honorary consultant appointments with Sherwood Forest Hospitals NHS Foundation Trust and Nottingham University Hospitals NHS Trust. Paid employments include the management of patients with arthritis pain, and developing and delivering on a programme of research aiming to better understand the mechanisms of arthritis pain in order to improve its treatment; Research grants: Nottingham Hospital Charity N of 1 trial for topical ibuprofen gel and capsaicin cream, NIHR Clinical Research Facility of £2.4 across 5 research themes in Nottingham, NIHR Biomedical Research Centre (musculoskeletal theme) of £23.6 m total award to Nottingham, ERAN Database support, Arthritis Research Campaign Centre Initiative grant Centre of Excellence in Mechanisms of Pain in Arthritis, NIHR Programme: Chronic pain after total knee replacement: better post-operative prevention and management NIHR HTA Sub-Cutaneous Injection of Adalimumab Trial compared with Control (SCIATiC), NIHR HTA Facet Feasibility (FF). Chief Investigator Prof Martin Underwood, University of Warwick, Assessing surgical outcomes for osteoarthritis of the knee following short-term psychological therapy: A single blind feasibility randomised controlled trial; Funds for staff or department: Consultancy for Pfizer Ltd 2017 undertaken through Nottingham University Consultancy Ltd, providing approximately £3,000 to facilitate staff development within the Arthritis Research UK Pain Centre; Non-financial interests: Trustee of the Early Rheumatoid Arthritis Network, UK Registered Charity., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Eye movement (EM) measures can serve as biomarkers to evaluate pharmacological effects on brain systems involved in cognition. In recent onset schizophrenia, antipsychotic treatment can improve attentional control on the antisaccade task and exacerbate working memory impairment on the memory guided saccade task; effects in treatment-resistant schizophrenia (TRS) are less clear. This study evaluated the effects of high versus low dose lurasidone on EM performance in TRS., Methods: TRS patients completed EM testing: 1) at baseline, on existing medication regimen (n = 42), 2) after 6 weeks of low dose (80 mg) lurasidone (n = 38), 3) after 12 weeks following randomization to low (80 mg) or high dose (240 mg) lurasidone (n = 27), and 4) after 24 weeks of treatment (n = 23). EM testing included prosaccade, antisaccade, and memory guided saccade tasks., Results: Six weeks of lurasidone resulted in increased prosaccade saccade latency and reduced antisaccade errors, with no change in memory guided saccade accuracy. After randomization, prosaccade and antisaccade latencies increased in only the high dose group, with no change in antisaccade errors in both groups. Memory guided saccade error increased in the high dose group and remained stable in the low dose group., Conclusion: Among TRS, stabilization on low dose lurasidone was associated with improved executive control of attention reflected by reduced antisaccade errors. High dose lurasidone resulted in prolonged speed of reflexive and executive shifts of attention and reduced spatial working memory relative to low dose. These findings indicate that EM measures are helpful biomarkers of dose-dependent antipsychotic treatment effects on executive cognitive abilities in TRS., Competing Interests: Declaration of competing interest Herbert Meltzer receives, or has received, other grant support from ACADIA, Allergan, Dainippon Sumitomo, Sunovion, Eli Lilly, Janssen, Lundbeck, Neurocrine, and Reviva. He also receives support from the Weisman Family Foundation. None of the other authors have potential conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Exercise is an effective treatment for osteoarthritis. However, the effect may vary from one patient (or study) to another., Objective: To evaluate the efficacy of exercise and its potential determinants for pain, function, performance, and quality of life (QoL) in knee and hip osteoarthritis (OA)., Methods: We searched 9 electronic databases (AMED, CENTRAL, CINAHL, EMBASE, MEDLINE Ovid, PEDro, PubMed, SPORTDiscus and Google Scholar) for reports of randomised controlled trials (RCTs) comparing exercise-only interventions with usual care. The search was performed from inception up to December 2017 with no language restriction. The effect size (ES), with its 95% confidence interval (CI), was calculated on the basis of between-group standardised mean differences. The primary endpoint was at or nearest to 8 weeks. Other outcome time points were grouped into intervals, from<1 month to≥18 months, for time-dependent effects analysis. Potential determinants were explored by subgroup analyses. Level of significance was set at P≤0.10., Results: Data from 77 RCTs (6472 participants) confirmed statistically significant exercise benefits for pain (ES 0.56, 95% CI 0.44-0.68), function (0.50, 0.38-0.63), performance (0.46, 0.35-0.57), and QoL (0.21, 0.11-0.31) at or nearest to 8 weeks. Across all outcomes, the effects appeared to peak around 2 months and then gradually decreased and became no better than usual care after 9 months. Better pain relief was reported by trials investigating participants who were younger (mean age<60 years), had knee OA, and were not awaiting joint replacement surgery., Conclusions: Exercise significantly reduces pain and improves function, performance and QoL in people with knee and hip OA as compared with usual care at 8 weeks. The effects are maximal around 2 months and thereafter slowly diminish, being no better than usual care at 9 to 18 months. Participants with younger age, knee OA and not awaiting joint replacement may benefit more from exercise therapy. These potential determinants, identified by study-level analyses, may have implied ecological bias and need to be confirmed with individual patient data., (Crown Copyright © 2019. Published by Elsevier Masson SAS. All rights reserved.)

Background: Guidelines recommend exercise as a core treatment for osteoarthritis (OA). However, it is unclear which type of exercise is most effective, leading to inconsistency between different recommendations., Objectives: The aim of this systematic review and network meta-analysis was to investigate the relative efficacy of different exercises (aerobic, mind-body, strengthening, flexibility/skill, or mixed) for improving pain, function, performance and quality of life (QoL) for knee and hip OA at, or nearest to, 8 weeks., Methods: We searched nine electronic databases up until December 2017 for randomised controlled trials that compared exercise with usual care or with another exercise type. Bayesian network meta-analysis was used to estimate the relative effect size (ES) and corresponding 95% credibility interval (CrI) (PROSPERO registration: CRD42016033865)., Findings: We identified and analysed 103 trials (9134 participants). Aerobic exercise was most beneficial for pain (ES 1.11; 95% CrI 0.69, 1.54) and performance (1.05; 0.63, 1.48). Mind-body exercise, which had pain benefit equivalent to that of aerobic exercise (1.11; 0.63, 1.59), was the best for function (0.81; 0.27, 1.36). Strengthening and flexibility/skill exercises improved multiple outcomes at a moderate level. Mixed exercise was the least effective for all outcomes and had significantly less pain relief than aerobic and mind-body exercises. The trend was significant for pain (p = 0.01), but not for function (p = 0.07), performance (p = 0.06) or QoL (p = 0.65)., Conclusion: The effect of exercise varies according to the type of exercise and target outcome. Aerobic or mind-body exercise may be the best for pain and function improvements. Strengthening and flexibility/skill exercises may be used for multiple outcomes. Mixed exercise is the least effective and the reason for this merits further investigation.

Anxiety and depression are associated with increased pain responses in chronic pain states. The extent to which anxiety drives chronic pain, or vice versa, remains an important question that has implications for analgesic treatment strategies. Here, the effect of existing anxiety on future osteoarthritis (OA) pain was investigated, and potential mechanisms were studied in an animal model. Pressure pain detection thresholds, anxiety, and depression were assessed in people with (n = 130) or without (n = 100) painful knee OA. Separately, knee pain and anxiety scores were also measured twice over 12 months in 4730 individuals recruited from the general population. A preclinical investigation of a model of OA pain in normo-anxiety Sprague-Dawley (SD) and high-anxiety Wistar Kyoto (WKY) rats assessed underlying neurobiological mechanisms. Higher anxiety, independently from depression, was associated with significantly lower pressure pain detection thresholds at sites local to (P < 0.01) and distant from (P < 0.05) the painful knee in patients with OA. Separately, high anxiety scores predicted increased risk of knee pain onset in 3274 originally pain-free people over the 1-year period (odds ratio = 1.71; 95% confidence interval = 1.25-2.34, P < 0.00083). Similarly, WKY rats developed significantly lower ipsilateral and contralateral hind paw withdrawal thresholds in the monosodium iodoacetate model of OA pain, compared with SD rats (P = 0.0005). Linear regressions revealed that baseline anxiety-like behaviour was predictive of lowered paw withdrawal thresholds in WKY rats, mirroring the human data. This augmented pain phenotype was significantly associated with increased glial fibrillary acidic protein immunofluorescence in pain-associated brain regions, identifying supraspinal astrocyte activation as a significant mechanism underlying anxiety-augmented pain behaviour.

We report on the ongoing project "PREDICT-ADFTD: Multimodal Imaging Prediction of AD/FTD and Differential Diagnosis" describing completed and future work supported by this grant. This project is a multi-site, multi-study collaboration effort with research spanning seven sites across the US and Canada. The overall goal of the project is to study neurodegeneration within Alzheimer's Disease, Frontotemporal Dementia, and related neurodegenerative disorders, using a variety of brain imaging and computational techniques to develop methods for the early and accurate prediction of disease and its course. The overarching goal of the project is to develop the earliest and most accurate biomarker that can differentiate clinical diagnoses to inform clinical trials and patient care. In its third year, this project has already completed several projects to achieve this goal, focusing on (1) structural MRI (2) machine learning and (3) FDG-PET and multimodal imaging. Studies utilizing structural MRI have identified key features of underlying pathology by studying hippocampal deformation that is unique to clinical diagnosis and also post-mortem confirmed neuropathology. Several machine learning experiments have shown high classification accuracy in the prediction of disease based on Convolutional Neural Networks utilizing MRI images as input. In addition, we have also achieved high accuracy in predicting conversion to DAT up to five years in the future. Further, we evaluated multimodal models that combine structural and FDG-PET imaging, in order to compare the predictive power of multimodal to unimodal models. Studies utilizing FDG-PET have shown significant predictive ability in the prediction and progression of disease., Competing Interests: CONFLICTS OF INTEREST IRM receives financial compensation as a member of the scientific advisory committee for Prevail Therapeutics. KK serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly, and receives funding from NIH and Alzheimer’s Drug Discovery Foundation. The other authors declare that they have no conflicts of interest.

Objective: To compare the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) with topical capsaicin for pain relief in osteoarthritis (OA)., Design: A systematic literature search was conducted for randomised controlled trials (RCTs) examining any topical NSAID or capsaicin in OA. Pain relief at or nearest to 4 weeks was pooled using a random-effects network meta-analysis (NMA) in a Frequentist and Bayesian setting. Analysis was conducted for all trials and for trials using drugs listed as licensed for OA in the British National Formulary (BNF)., Results: The trial network comprised 28 RCTs (7372 participants), of which 17 RCTs (3174 participants) were included in the as licensed analyses. No RCTs directly compared topical NSAIDs with capsaicin. Placebo was the only common comparator for topical NSAIDs and capsaicin. Frequentist and Bayesian effect size (ES) estimates were in agreement. Topical NSAIDs were statistically superior to placebo overall (ES 0.30, 95% confidence interval [CI] 0.19 to 0.41) and as licensed (ES 0.32, 95% CI 0.24 to 0.39). However, capsaicin was only statistically superior to placebo when used at licensed doses (ES 0.41, 95% CI 0.17 to 0.64). No significant differences were observed in pain relief between topical NSAIDs and capsaicin (overall: ES 0.04, 95% CI -0.26 to 0.33; as licensed: ES-0.09, 95% CI -0.34 to 0.16)., Conclusions: Current evidence indicates that topical NSAIDs and capsaicin in licensed doses may be equally effective for pain relief in OA. Whether the equivalence varies between individuals remains unknown., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Disturbed sleep is strongly correlated with chronic pain. The aim of this study was to examine the association between sleep disturbance and incident joint pain focusing on neuropathic-like pain symptoms., Methods: A total of 423 individuals who had undergone total joint replacement (TJR) for osteoarthritis were assessed at the mean time of 3.6 years post-surgery and again at 5.9 years post-TJR, using the Medical Outcomes Survey sleep subscale, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and painDETECT questionnaire instruments. Cox hazard ratios (HRs) and 95% confidence intervals (CIs) were computed adjusting for age, body mass index, sex, and use of hypnotic and analgesic medication., Results: The presence of neuropathic pain symptoms predicted incidence of disturbed sleep after adjustment for covariates and pain severity (adjusted HR [aHR] 2.01, 95% CI: 1.00-4.10; p <0.05). There was no association between joint pain and incidence of disturbed sleep when individuals with neuropathic pain symptoms at the baseline visit were excluded (aHR 1.11, 95% CI: 0.47-2.67). Disturbed sleep at baseline predicted incident neuropathic joint pain symptoms (aHR 2.75, 95% CI: 1.21-6.26; p <0.016) but had no effect on incidence of joint pain when all types of pain were considered together (aHR 0.63, 95% CI: 0.30-1.39)., Conclusion: These data suggest a causal bidirectional link between sleep disturbance and joint pain with neuropathic features but not with other types of joint pain., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This study aimed to identify self-report correlates of central pain augmentation in individuals with knee pain. A subset of participants (n = 420) in the Knee Pain and related health In the Community (KPIC) baseline survey undertook pressure pain detection threshold (PPT) assessments. Items measuring specific traits related to central pain mechanisms were selected from the survey based on expert consensus, face validity, item association with underlying constructs measured by originating host questionnaires, adequate targeting, and PPT correlations. Pain distribution was reported on a body manikin. A "central pain mechanisms" factor was sought by factor analysis. Associations of items, the derived factor, and originating questionnaires with PPTs were compared. Eight self-report items measuring traits of anxiety, depression, catastrophizing, neuropathic-like pain, fatigue, sleep disturbance, pain distribution, and cognitive impact were identified as likely indices of central pain mechanisms. Pressure pain detection thresholds were associated with items representing each trait and with their originating scales. Pain distribution classified as "pain below the waist additional to knee pain" was more strongly associated with low PPT than were alternative classifications of pain distribution. A single factor, interpreted as "central pain mechanisms," was identified across the 8 selected items and explained variation in PPT (R = 0.17) better than did any originating scale (R = 0.10-0.13). In conclusion, including representative items within a composite self-report tool might help identify people with centrally augmented knee pain.

Introduction: The beneficial effect of dietary omega-3 supplementation in younger adults or older people with acute or chronic disease is established. Knowledge is now needed about the effect in medically stable older people. The objective of this study is to examine and assess the evidence for a role of dietary omega-3 polyunsaturated fatty acid (PUFA) supplementation in older adults on (1) muscle mass and muscle strength, (2) inflammatory biomarkers and (3) physical activity., Methods and Analysis: A systematic review and data synthesis will be conducted of randomised controlled trials in older people not recruited for any given disease diagnosis. Placebo-controlled studies reporting interventions involving dietary supplementation of omega-3 PUFAs, eicosapentaenoic acid and docosahexaenoic acid will be included. Outcomes must include changes from baseline to last available follow-up for one or more of the following: muscle mass, inflammatory biomarkers, physical activity, walking speed, weight change, hand grip strength or muscle strength. Once the search strategy has been carried out, two independent researchers will assess relevant papers for eligibility. Articles up until 31 December 2017 in any language will be included. We will provide a narrative synthesis of the findings from the included studies. Studies will be grouped for meta-analysis according to the outcome(s) provided. Where studies have used the same type of intervention, with the same outcome measure, we will pool the results using a random effects meta-analysis, with standardised mean differences for continuous outcomes and risk ratios for binary outcomes, and calculate 95% CI and two-sided p values for each outcome., Ethics and Dissemination: No research ethics approval is required for this systematic review as no confidential patient data will be used. The results of this systematic review will be disseminated through publication in an open-access peer-reviewed journal and through conference presentations., Prospero Registration Number: CRD42017080240., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Accelerators in rubber gloves constitute an important group of contact allergens, particularly in healthcare workers., Objectives: To assess the efficacy of accelerator-free medical gloves in the secondary prevention of allergic contact dermatitis caused by rubber accelerators in healthcare workers., Methods: Nine healthcare workers with hand eczema were advised to use accelerator-free rubber gloves after a diagnosis of allergic contact dermatitis caused by rubber accelerators., Results: Switching from conventional medical single-use gloves containing accelerators to accelerator-free medical gloves led to improvement in all cases, and more than two-thirds of the patients were completely free of symptoms., Conclusion: The use of accelerator-free medical gloves can be an effective alternative in healthcare workers who are allergic to rubber accelerators., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV 0.5 ), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV 0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV 0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Aims: Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A 1 -PI; 60 mg kg -1  week -1 ) therapy completed to date, demonstrated for the first time that A 1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response., Methods: A disease progression model was constructed, utilizing observed A 1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A 1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A 1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A 1 -PI exposure to lung density decline rate at varying exposure levels., Results: A dose of 60 mg kg -1  week -1 achieved trough serum levels >11 μmol l -1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A 1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l -1  year -1 occurred more often in patients receiving A 1 -PI: 63 vs. 12%., Conclusion: Weight-based A 1 -PI dosing reliably raises serum levels above the 11 μmol l -1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A 1 -PI therapy in AATD. The model suggested higher doses of A 1 -PI would yield greater clinical effects., (© 2017 CSL Behring. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The incidence, progression and related risk factors for recent-onset knee pain (KP) remain uncertain. This study aims to examine the natural history of KP including incidence and progression and to identify possible phenotypes and their associated risk factors., Methods: A prospective community-based cohort of men and women aged 40 years or over within the East Midlands region (UK) will be recruited via a postal questionnaire from their general practices. The questionnaire will enquire about: presence and onset of KP; pain severity (0–10 numerical rating scale (NRS)); pain catastrophizing and neuropathic-like pain (NP) using the painDETECT questionnaires (definite NP scores ≥19–38); risk factors for KP and/ or osteoarthritis (OA) (age, body mass index, constitutional knee alignment, nodal OA, index: ring finger length (2D4D) ratio); quality of life (SF12); and mental health (Hospital Anxiety and Depression Scale). Clinical assessments will be undertaken in a sample of 400 participants comprising three groups: early KP (≤3 year’s duration), established KP (>3 years) and no KP. Assessments will include knee radiographs (standing semi-flexed and 30(0) skyline views); knee ultrasound (synovial effusion, hypertrophy, and Doppler activity); quantitative sensory testing; muscle strength (quadriceps, hip abductor, and hand-grip); balance; gait analysis (GAITrite); and biomarker sampling. A repeat questionnaire will be sent to responders at years 1 and 3. The baseline early KP group will undergo repeat assessments at year 1 (apart from radiographs) and year 3 (with radiographs). Any incident KP individuals identified at year 1 or 3 questionnaires will have clinical and radiographic assessments at the respective time points., Discussion: Baseline data will be used to examine risk factors for early onset KP and to identify KP phenotypes. Subsequent prospective data, at least to Year 3, will allow examination of the natural history of KP and risk factors for incidence and progression., Trial Registration: The study was registered on the clinicaltrials.gov portal: NCT02098070) on the 14th of March 2014.

The Global Lung Function Initiative (GLI) Network has become the largest resource for reference values for routine lung function testing ever assembled. This article addresses how the GLI Network came about, why it is important, and its current challenges and future directions. It is an extension of an article published in Breathe in 2013 [1], and summarises recent developments and the future of the GLI Network., Key Points: The Global Lung Function Initiative (GLI) Network was established as a result of international collaboration, and altruism between researchers, clinicians and industry partners. The ongoing success of the GLI relies on network members continuing to work together to further improve how lung function is reported and interpreted across all age groups around the world.The GLI Network has produced standardised lung function reference values for spirometry and gas transfer tests.GLI reference equations should be adopted immediately for spirometry and gas transfer by clinicians and physiologists worldwide.The recently established GLI data repository will allow ongoing development and evaluation of reference values, and will offer opportunities for novel research., Educational Aims: To highlight the advances made by the GLI Network during the past 5 years.To highlight the importance of using GLI reference values for routine lung function testing ( e.g.  spirometry and gas transfer tests).To discuss the challenges that remain for developing and improving reference values for lung function tests., Competing Interests: Conflict of interest None declared.

Osteoarthritis (OA), the most common form of arthritis, causes pain and disability, as well as emotional distress. While total joint replacement is one of the most effective treatments available for improving the quality of life in people with severe OA, it is not suitable for all patients and all joints. Current pharmacological analgesics have limited efficacy, and their use is often restricted by adverse events. Medications that might reduce pain by slowing or preventing structural disease remain elusive. Our increasing understanding of the complex mechanisms that underlie OA pain offers a wide range of potential new treatment targets. New drugs for OA pain might come from repurposing those developed for other conditions, as well as novel compounds targeting pain mechanisms specific to the joint. Here we discuss the mechanisms of OA pain and its therapeutic implications. We explore evolving treatment modalities, including combination treatment. We review recent research and patents pointing to future OA therapies. We discuss the potential for biomarkers to facilitate drug development and targeting.

Early nutritional insults may increase risk of adult lung disease. We aimed to quantify the impact of severe acute malnutrition (SAM) on spirometric outcomes 7 years post-treatment and explore predictors of impaired lung function.Spirometry and pulse oximetry were assessed in 237 Malawian children (median age: 9.3 years) who had been treated for SAM and compared with sibling and age/sex-matched community controls. Spirometry results were expressed as z-scores based on Global Lung Function Initiative reference data for the African-American population.Forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were low in all groups (mean FEV 1 z-score: -0.47 for cases, -0.48 for siblings, -0.34 for community controls; mean FVC z-score: -0.32, -0.38, and -0.15 respectively). There were no differences in spirometric or oximetry outcomes between SAM survivors and controls. Leg length was shorter in SAM survivors but inter-group sitting heights were similar. HIV positive status or female sex was associated with poorer FEV 1 , by 0.55 and 0.31 z-scores, respectively.SAM in early childhood was not associated with subsequent reduced lung function compared to local controls. Preservation of sitting height and compromised leg length suggest "thrifty" or "lung-sparing" growth. Female sex and HIV positive status were identified as potentially high-risk groups., (Copyright ©ERS 2017.)

Background: The management of osteoarthritis (OA) is unsatisfactory, as most treatments are not clinically effective over placebo and most drugs have considerable side effects. On average, 75 % of the analgesic effect from OA treatments in clinical trials can be attributed to a placebo response, and this response varies greatly from patient to patient. This individual patient data (IPD) meta-analysis aims to identify placebo responders and the potential determinants of the placebo response in OA., Methods: This study is undertaken in conjunction with the OA Trial Bank, an ongoing international consortium aiming to collect IPD from randomised controlled trials (RCTs) for all treatments of OA. RCTs for each treatment of OA have been systematically searched for, and authors of the relevant trials have been contacted to request the IPD. We will use the IPD of placebo-controlled RCTs held by the OA Trial Bank for this project. The IPD in placebo groups will be used to investigate the placebo response according to the minimum clinically important difference (MCID) threshold (e.g. 20 % pain reduction). Responders to placebo will be compared with non-responders to identify predictors of response. The quality of the trials will be assessed and potential determinants will be examined using multilevel logistic regression analyses., Discussion: This study explores the varying magnitude of the placebo response and the proportion of participants that experience a clinically important placebo effect in OA RCTs. Potential determinants of the placebo response will also be investigated. These determinants may be useful for future studies as it may allow participants to be stratified into groups based on their likely response to placebo. The results of this study may also be useful for pharmaceutical companies, who could improve the design of their studies in order to separate the specific treatment from the non-specific contextual (i.e. placebo) effects., Systematic Review Registration: PROSPERO CRD42016033212.