Giant virus diversity and host interactions through global metagenomics.

Our current knowledge about nucleocytoplasmic large DNA viruses (NCLDVs) is largely derived from viral isolates that are co-cultivated with protists and algae. Here we reconstructed 2,074 NCLDV genomes from sampling sites across the globe by building on the rapidly increasing amount of publicly available metagenome data. This led to an 11-fold increase in phylogenetic diversity and a parallel 10-fold expansion in functional diversity. Analysis of 58,023 major capsid proteins from large and giant viruses using metagenomic data revealed the global distribution patterns and cosmopolitan nature of these viruses. The discovered viral genomes encoded a wide range of proteins with putative roles in photosynthesis and diverse substrate transport processes, indicating that host reprogramming is probably a common strategy in the NCLDVs. Furthermore, inferences of horizontal gene transfer connected viral lineages to diverse eukaryotic hosts. We anticipate that the global diversity of NCLDVs that we describe here will establish giant viruses-which are associated with most major eukaryotic lineages-as important players in ecosystems across Earth's biomes.

A genome catalogue of mercury-methylating bacteria and archaea from sediments of a boreal river facing human disturbances.

Methyl mercury, a toxic compound, is produced by anaerobic microbes and magnifies in aquatic food webs, affecting the health of animals and humans. The exploration of mercury methylators based on genomes is still limited, especially in the context of river ecosystems. To address this knowledge gap, we developed a genome catalogue of potential mercury-methylating microorganisms. This was based on the presence of hgcAB from the sediments of a river affected by two run-of-river hydroelectric dams, logging activities and a wildfire. Through the use of genome-resolved metagenomics, we discovered a unique and diverse group of mercury methylators. These were dominated by members of the metabolically versatile Bacteroidota and were particularly rich in microbes that ferment butyrate. By comparing the diversity and abundance of mercury methylators between sites subjected to different disturbances, we found that ongoing disturbances, such as the input of organic matter related to logging activities, were particularly conducive to the establishment of a mercury-methylating niche. Finally, to gain a deeper understanding of the environmental factors that shape the diversity of mercury methylators, we compared the mercury-methylating genome catalogue with the broader microbial community. The results suggest that mercury methylators respond to environmental conditions in a manner similar to the overall microbial community. Therefore, it is crucial to interpret the diversity and abundance of mercury methylators within their specific ecological context.

Serum levels of hydroxylated metabolites of arachidonic acid cross-sectionally and longitudinally predict knee pain progression: an observational cohort study.

OBJECTIVE: To examine associations between serum oxylipins, which regulate tissue repair and pain signalling, and knee pain/radiographic osteoarthritis (OA) at baseline and knee pain at 3 year follow-up. METHOD: Baseline, and 3 year follow-up, knee pain phenotypes were assessed from 154 participants in the Knee Pain in the Community (KPIC) cohort study. Serum and radiographic Kellgren and Lawrence (KL) and Nottingham line drawing atlas OA scores were collected at baseline. Oxylipin levels were quantified using liquid chromatography coupled with mass spectrometry. Associations were measured by linear regression and receiver operating characteristics (ROC). RESULTS: Serum levels of 8,9-epoxyeicosatrienoic acid (EET) (ß(95% confidence intervals (CI)) = 1.809 (-0.71 to 2.91)), 14,15-dihydroxyeicosatrienoic acid (DHET) (ß(95%CI) = 0.827 (0.34-1.31)), and 12-hydroxyeicosatetraenoic acid (HETE) (ß(95%CI) = 4.090 (1.92-6.26)) and anandamide (ß(95%CI) = 3.060 (1.35-4.77)) were cross-sectionally associated with current self-reported knee pain scores (numerical rating scale (NRS) item 3, average pain). Serum levels of 9- (ß(95%CI) = 0.467 (0.18-0.75)) and 15-HETE (ß(95%CI) = 0.759 (0.29-1.22)), 14-hydroxydocosahexaenoic acid (ß(95%CI) = 0.483(0.24-0.73)), and the ratio of 8,9-EET:DHET (ß(95%CI) = 0.510(0.19-0.82)) were cross-sectionally associated with KL scores. Baseline serum concentrations of 8,9-EET (ß(95%CI) = 2.166 (0.89-3.44)), 5,6-DHET (ß(95%CI) = 152.179 (69.39-234.97)), and 5-HETE (ß(95%CI) = 1.724 (0.677-2.77) showed positive longitudinal associations with follow-up knee pain scores (NRS item 3, average pain). Combined serum 8,9-EET and 5-HETE concentration showed the strongest longitudinal association (ß(95%CI) = 1.156 (0.54-1.77) with pain scores at 3 years, and ROC curves distinguished between participants with no pain and high pain scores at follow-up (area under curve (95%CI) = 0.71 (0.61-0.82)). CONCLUSIONS: Serum levels of a combination of hydroxylated metabolites of arachidonic acid may have prognostic utility for knee pain, providing a potential novel approach to identify people who are more likely to have debilitating pain in the future.

Validation of a questionnaire for Central nervous system Aspects of joint Pain: the CAP questionnaire.

BACKGROUND AND AIMS: Neuropathic-like pain, fatigue, cognitive difficulty, catastrophising, anxiety, sleep disturbance, depression, and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterise this across painful musculoskeletal conditions. METHODS: CAP was derived from the 8 item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had osteoarthritis, back pain or fibromyalgia. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee osteoarthritis. RESULTS: Data were from 3579 participants (58% female, median age; 71 years), including subgroups with osteoarthritis (n = 1158), back pain (n = 1292) or fibromyalgia (n = 177). Across the 3 subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high (ICC= 0.89 (95% CI: 0.84-0.92)) and CAP scores fit to 1 and 2 factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50-0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. CONCLUSIONS: Central Aspects of Pain is reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state.

How Social Connectedness Helps Patients Stay Home After Hospital at Home Enrollment: A Mixed Methods Study.

BACKGROUND: While enrolled in Hospital at Home (HaH) programs, patients rely on their social network to provide supportive behaviors that are routinely provided by hospital staff in the inpatient setting. OBJECTIVE: This study investigated how social connectedness is associated with patient outcomes in a HaH program. DESIGN: The explanatory iterative sequential mixed methods design included an electronic health record review to collect quantitative measures to describe the severity of patient illness and healthcare utilization and then qualitative interviews to explain quantitative findings. PARTICIPANTS: The quantitative phase included 100 patients (18 years or older) admitted to the hospital who were subsequently enrolled in the HaH program. In the qualitative phase, 33 of the 100 patients participated in semi-structured interviews. ANALYSIS: Qualitative data was analyzed using the Sort & Sift, Think & Shift method. Integrated analysis included merged data displays of healthcare utilization data and patient descriptions of their care and genogram-type illustrations to enable variable-oriented analysis of structural support. We then examined patient narratives by two variables: life course and care elevation, to understand differences in the trajectories of six subsets of patients as identified by the quantitative data. KEY RESULTS: Three factors prompted patients to enroll in HaH: low attention from hospital staff during hospital stay; loneliness and isolation during hospital stay; and family encouragement to enroll. After discharge, social support within the home structure facilitated recovery during HaH. Conversely, HaH patients with limited support within the home were more likely to be readmitted. CONCLUSIONS: Structural social connectedness facilitates patient recovery in HaH. Before enrolling patients in HaH, clinicians should take an in-depth social history, including questions about social/familial roles, household responsibilities, and technology acceptance. Clinicians should engage formal and informal caregivers in these conversations early and communicate a clear picture of what caregivers should do to support the patient through recovery.

Medio-dorsal thalamic dysconnectivity in chronic knee pain: A possible mechanism for negative affect and pain comorbidity.

The reciprocal interaction between pain and negative affect is acknowledged but pain-related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed-based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect-related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain-free controls. In conclusion, we demonstrate mediodorsal thalamo-cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect.

Feasibility of conducting a cohort randomised controlled trial assessing the effectiveness of a nurse-led package of care for knee pain.

OBJECTIVE: To evaluate the feasibility of conducting a cohort randomised-controlled trial (RCT) of a nurse-led package of care for knee pain and determine treatment sequence for use in a future trial. METHODS: Open label, three-arm, single-centre, mixed-methods, feasibility cohort RCT. Adults aged ≥40 years with moderate-to-severe knee pain for ≥3 months were eligible. Participants were randomised into groups A (non-pharmacological treatment first), B (pharmacological treatment first), or group C (usual care). The intervention was delivered over 26-weeks. Outcomes were dropout rate, recruitment rate, intervention fidelity, ability to collect outcome data and treatment acceptability. RESULTS: Seventeen participants were randomised and enrolled into each of groups A and B (5.2% recruitment rate), and 174 randomised to group C. Participant characteristics at randomisation were comparable across the three arms. COVID-19 paused the study from March-November-2020. Participants enrolled in groups A and B before March-2020 were withdrawn at restart. Of the 20 participants enrolled after restart, 18 completed the study (10% dropout). The nurse reported delivering most aspects of the intervention with high fidelity. Participants viewed the package of care as structured, supportive and holistic, they learnt about self-managing knee pain, and could engage with and follow the non-pharmacological treatment. Most found the non-pharmacological treatment more useful than the pharmacological treatment, preferring to receive it before or alongside analgesia. Many self-reported questionnaires were not fully completed. CONCLUSIONS: The nurse-led package of care for knee pain was acceptable with low dropout, although the cohort RCT design may not be feasible for a definitive trial. TRIAL REGISTRATION: clinicaltrials.gov; NCT03670706.

An in vitro platform for study of the human gut microbiome under an oxygen gradient.

The complex, dynamic environment of the human lower gastrointestinal tract is colonized by hundreds of bacterial species that impact health and performance. Ex vivo study of the functional interactions between microbial community members in conditions representative of those in the gut is an ongoing challenge. We have developed an in vitro 40-plex platform that provides an oxygen gradient to support simultaneous maintenance of microaerobic and anaerobic microbes from the gut microbiome that can aid in rapid characterization of microbial interactions and direct comparison of individual microbiome samples. In this report, we demonstrate that the platform more closely maintained the microbial diversity and composition of human donor fecal microbiome samples than strict anaerobic conditions. The oxygen gradient established in the platform allowed the stratification and subsequent sampling of diverse microbial subpopulations that colonize microaerobic and anaerobic micro-environments. With the ability to run forty samples in parallel, the platform has the potential to be used as a rapid screening tool to understand how the gut microbiome responds to environmental perturbations such as toxic compound exposure, dietary changes, or pharmaceutical treatments.

Clinical Outcomes of a Newly Instituted Hospital at Home Program During the COVID19 Pandemic.

Context: The COVID19 pandemic stressed U.S. health systems beyond their capacity and created worsening clinical outcomes. Hospital a Home (HaH) programs were utilized infrequently prior to pandemic. The Acute Care at Home Waiver was introduced in 2020 to facilitate the creation of HaH programs with a goal of promoting treatment in the home setting. A potential alternative approach to creating rapid inpatient level health system capacity is providing hospital-level care at home to substitute for inpatient hospitalization. The overall impact on clinical outcomes of a HaH program in patients with COVID19 is not well understood. Objective: To compare clinical outcomes of a HaH program versus usual hospital care for patients admitted for COVID19. Study Design: Matched case-control retrospective chart review. Setting or Dataset: Academic medical center. Population studied: Patients admitted with COVID19 and subsequently enrolled into the HaH program from February 1, 2021 to January 31, 2022. Patients aged <18 were excluded from consideration for enrollment. A case-control sample was matched on age, gender, and severity of illness. A total of 200 patients (100 HaH and 100 control) were included for analysis. Outcome Measures: Primary outcome: 30-day readmissions, Secondary outcomes: Inpatient length of stay (iLOS) defined as length of stay in the physical hospital, total length of stay (tLOS) (sum of iLOS and HaH program days), time to readmission, and 30-day emergency department visits. Results: Analysis included 200 patents. The mean age was 50.4. The sample was 55% female. 48.5% were black, 43.5% were white, and 8% were other races. Compared with usual care patients, HaH patients had no difference in 30-day readmissions (11% vs. 14%, p=0.648), mean days to readmission (9.0 vs. 11.8, p=0.201), or return ED visits (17% vs. 20%, p=0.701). Inpatient LOS (5.7 vs. 9.4 days, p=0.005) was shorter in the HaH group. Total LOS (13.0 vs. 9.4 days, p<0. 001) was longer in the HaH group. Conclusions: The HaH program was associated with no difference in readmissions, time to readmission, or return ED visits compared to usual hospital care. HaH programs were associated with shorter inpatient length of stays, but longer total length of stays. In surge times, HaH programs could potentially reduce iLOS and increase bed capacity. Future studies should look to evaluate the economic impact of HaH programs and investigate the drivers of the increased tLOS.

Chronic pain in people living with dementia: challenges to recognising and managing pain, and personalising intervention by phenotype.

Pain is common in people with dementia, and pain can exacerbate the behavioural and psychological symptoms of dementia. Effective pain management is challenging, not least in people with dementia. Impairments of cognition, communication and abstract thought can make communicating pain unreliable or impossible. It is unclear which biopsychosocial interventions for pain management are effective in people with dementia, and which interventions for behavioural and psychological symptoms of dementia are effective in people with pain. The result is that drugs, physical therapies and psychological therapies might be either underused or overused. People with dementia and pain could be helped by assessment processes that characterise an individual's pain experience and dementia behaviours in a mechanistic manner, phenotyping. Chronic pain management has moved from a 'one size fits all' approach, towards personalised medicine, where interventions recommended for an individual depend upon the key mechanisms underlying their pain, and the relative values they place on benefits and adverse effects. Mechanistic phenotyping through careful personalised evaluation would define the mechanisms driving pain and dementia behaviours in an individual, enabling the formulation of a personalised intervention strategy. Central pain processing mechanisms are particularly likely to be important in people with pain and dementia, and interventions to accommodate and address these may be particularly helpful, not only to relieve pain but also the symptoms of dementia.

The bidirectional relationship between chronic joint pain and frailty: data from the Investigating Musculoskeletal Health and Wellbeing cohort.

BACKGROUND: Pain and frailty are associated, but this relationship is insufficiently understood. We aimed to test whether there is a unidirectional or bidirectional relationship between joint pain and frailty. METHODS: Data were from Investigating Musculoskeletal Health and Wellbeing, a UK-based cohort. Average joint pain severity over the previous month was assessed using an 11-point numerical rating scale (NRS). Frailty was classified as present/absent using the FRAIL questionnaire. Multivariable regression assessed the association between joint pain and frailty, adjusted for age, sex, and BMI class. Two-wave cross-lagged path modelling permitted simultaneous exploration of plausible causal pathways between pain intensity and frailty at baseline and 1-year. Transitions were assessed using t-tests. RESULTS: One thousand one hundred seventy-nine participants were studied, 53% female, with a median age of 73 (range 60 to 95) years. FRAIL classified 176 (15%) participants as frail at baseline. Mean (SD) baseline pain score was 5.2 (2.5). Pain NRS ≥ 4 was observed in 172 (99%) of frail participants. Pain severity was associated with frailty at baseline (aOR 1.72 (95%CI 1.56 to 1.92)). In cross-lagged path analysis, higher baseline pain predicted 1-year frailty [ß = 0.25, (95%CI 0.14 to 0.36), p < 0.001] and baseline frailty predicted higher 1-year pain [ß = 0.06, (95%CI 0.003 to 0.11), p = 0.040]. Participants transitioning to frailty over one year had higher mean pain scores (6.4 (95%CI 5.8 to 7.1)) at baseline than those who remained non-frail (4.7 (95%CI 4.5 to 4.8)), p < 0.001. CONCLUSIONS: The bidirectional relationship between pain and frailty could lead to a vicious cycle in which each accelerates the other's progression. This justifies attempts to prevent frailty by addressing pain and to include pain measures as an outcome in frailty studies.

Chronic Low Back Pain with and without Concomitant Osteoarthritis: A Retrospective, Longitudinal Cohort Study of Patients in England.

Objective: Despite the high prevalence of chronic low back pain (CLBP) and osteoarthritis (OA), few estimates of the economic cost of these conditions in England have been published. The aim of the present analysis was to characterise the economic burden of moderate-to-severe pain associated with CLBP + OA and CLBP alone compared with general population-matched controls without CLBP or OA. The primary objective was to describe the total healthcare resource use (HCRU) and direct healthcare costs associated with the target patient populations. Secondary objectives were to describe treatment patterns and surgical procedures. Methods: This was a retrospective, observational cohort study of patients receiving healthcare indicative of moderate-to-severe chronic pain associated with CLBP, with or without OA. We used linked longitudinal data from the Clinical Practice Research Datalink GOLD and Hospital Episode Statistics (HES). Patients (cases) were matched 1 : 1 with controls on age, sex, comorbidity burden, GP practice, and HES data availability. Results: The CLBP-alone cohort comprised 13 554 cases with CLBP and 13 554 matched controls; the CLBP + OA cohort comprised 7803 cases with both OA and CLBP and 7803 matched controls. Across all follow-up periods, patients with CLBP alone and those with CLBP + OA had significantly more GP consultations, outpatient attendances, emergency department visits, and inpatient stays than controls (all p < 0.0001). By 36 months after indexing, the mean (SD) per-patient total direct healthcare cost in the CLBP-alone cohort was £5081 (£5905) for cases and £1809 (£4451) for controls (p < 0.0001); in the CLBP + OA cohort, the mean (SD) per-patient total direct healthcare cost was £8819 (£7143) for cases and £2428 (£4280) for controls (p < 0.0001). Conclusion: Moderate-to-severe chronic pain associated with CLBP-with or without OA-has a substantial impact on patients and healthcare providers, leading to higher HCRU and costs versus controls among people with CLBP alone or together with OA.

What is missing from how we measure and understand the experience of poverty and deprivation in population health analyses?

BACKGROUND: Explaining why some populations are healthier than others is a core task of epidemiology. Socioeconomic position (SEP), encompassing a broad range of exposures relating to economic circumstances, social class and deprivation, is an important explanation, but lacks a comprehensive framework for understanding the range of relevant exposures it encompasses. METHODS: We reviewed existing literature on experiential accounts of poverty through database searching and the identification of relevant material by experts. We mapped relevant concepts into a complex systems diagram. We developed this diagram through a process of consultation with academic experts and experts with direct experience of poverty. Finally, we categorized concepts on the basis of whether they have previously been measured, their importance to the causal flow of the diagram, and their importance to those consulted, creating a list of priorities for future measurement. RESULTS: There are a great many aspects of SEP which are not frequently measured or used in epidemiological research and, for some of these, work is needed to better conceptualize and develop measures. Potentially important missing aspects include stigma, social class processes, access to education, sense of lost potential, neighbourhoods, fairness and justice, emotional labour, masking poverty, being (in)visible, costs, and experiences of power. CONCLUSIONS: Analyses seeking to understand the extent to which SEP exposures explain differences in the health of populations are likely to benefit from a comprehensive understanding of the range and inter-relationships between different aspects of SEP. More research to better conceptualize and measure these aspects is now needed.

The STAR care pathway for patients with chronic pain after total knee replacement: four-year follow-up of a randomised controlled trial.

BACKGROUND: The Support and Treatment After Replacement (STAR) care pathway is a clinically important and cost-effective intervention found to improve pain outcomes over one year for people with chronic pain three months after total knee replacement (TKR). We followed up STAR trial participants to evaluate the longer-term clinical- and cost-effectiveness of this care pathway. METHODS: Participants who remained enrolled on the trial at one year were contacted by post at a median of four years after randomisation and invited to complete a questionnaire comprising the same outcomes collected during the trial. We captured pain (co-primary outcome using the Brief Pain Inventory (BPI) pain severity and interference scales; scored 0-10, best to worst), function, neuropathic characteristics, emotional aspects of pain, health-related quality of life, and satisfaction. Electronic hospital informatics data on hospital resource use for the period of one to four years post-randomisation were collected from participating hospital sites. The economic evaluation took an National Health Service (NHS) secondary care perspective, with a four-year time horizon. RESULTS: Overall, 226/337 (67%) of participants returned completed follow-up questionnaires, yielding adjusted between-group differences in BPI means of -0.42 (95% confidence interval, CI (-1.07, 0.23); p = 0.20) for pain severity and - 0.64 (95% CI -1.41, 0.12); p = 0.10) for pain interference. Analysis using a multiple imputed data set (n = 337) showed an incremental net monetary benefit in favour of the STAR care pathway of £3,525 (95% CI -£990 to £8,039) at a £20,000/QALY willingness-to-pay threshold, leading to a probability that the intervention was cost-effective of 0.94. CONCLUSIONS: The magnitude of the longer-term benefits of the STAR care pathway are uncertain due to attrition of trial participants; however, there is a suggestion of some degree of sustained clinical benefit at four years. The care pathway remained cost-effective at four years. TRIAL REGISTRATION: ISRCTN: 92,545,361.

Fatigue in early rheumatoid arthritis: data from the Early Rheumatoid Arthritis Network.

OBJECTIVES: Fatigue is a disabling symptom in people with RA. This study aims to describe the prevalence, risk factors and longitudinal course of fatigue in early RA. METHODS: Demographic, clinical, quality of life (QoL), comorbidities and laboratory data were from the Early RA Network (ERAN), a UK multicentre inception cohort of people with RA. Fatigue was measured using the vitality subscale of the 36-item Short Form Health Survey, where higher values represent better QoL. Baseline prevalences of fatigue classifications were age and sex standardized. Linear regression, hierarchical growth curve modelling and group-based trajectory modelling (GBTM) were utilized. RESULTS: At baseline (n = 1236, 67% female, mean age 57 years), the mean vitality was 41 (s.d. 11) and disease duration was 11 months (interquartile range 7-18). Age- and sex-standardized prevalence rates of fatigue and severe fatigue were 44% (95% CI 39, 50) and 19% (95% CI 15, 23), respectively. Fatigue changed little over 3 years and five measurement occasions ß = -0.13 (95% CI -0.23, -0.02). GBTM identified two subgroups, which we named 'Fatigue' (53%) and 'No-fatigue' (47%). Female sex, worse pain, mental health and functional ability were associated with greater fatigue and predicted Fatigue group membership (area under the receiver operating characteristics curve = 0.81). Objective measures of inflammation-swollen joint count and ESR-were not significantly associated with fatigue. CONCLUSIONS: Fatigue is prevalent and persistent in early RA. Diverse characteristics indicative of central mechanisms are associated with persistent fatigue. Management of fatigue might require interventions targeted at central mechanisms in addition to inflammatory disease modification. People who require such interventions might be identified at presentation with early RA.

Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis.

OBJECTIVES: To identify groups of people with RA with different disability trajectories over 10 years, despite comparable levels of inflammation. METHODS: Data for this analysis came from three European prospective cohort studies of people with RA [Norfolk Arthritis Register (NOAR), Early RA Network (ERAN), Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR)]. Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1 January 2000, <24 months baseline symptom duration, and disability (HAQ) and inflammation [two-component DAS28 (DAS28-2C)] recorded at baseline and at one other follow-up. People in each cohort also completed patient-reported outcome measures at each assessment (pain, fatigue, depressive symptoms). Group-based trajectory models were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up. RESULTS: This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). ESPOIR included more women and the participants were younger [mean (standard deviation) age: NOAR: 57.1 (14.6), ESPOIR: 47.6 (12.5), ERAN: 56.8 (13.8); women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories following the hypothesized pattern (comparable DAS28-2Cs but different HAQs) were identified. Higher pain, fatigue and depressive symptoms were associated with increased odds of being in the high HAQ trajectories. CONCLUSION: Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function.

Using heterogeneity in disease to understand the relationship between health and personality.

The aim of this study was to compare the relationship between two health outcomes (pain and self-reported health) and personality while accounting for heterogeneity in arthritic disease. Traditionally health research has treated patients' disease experiences as homogeneous but stratified medicine suggests that doing so might over-generalise findings and miss important effects. We present a longitudinal analysis over 14 years, on a subsample of 443 arthritic respondents from the English Longitudinal Study of Ageing (ELSA). Using linear regressions, we modelled how the Big Five domains of personality (wave 5) moderated the relationship between past (at wave 1) and present health (at wave 7). Then, to model heterogeneity in arthritis experience we included assignment to 4 different sub-groups based on their experience of pain progression. The results showed that modelling heterogeneity led to the identification of specific stratified effects for personality (neuroticism, agreeableness, and extraversion) not observed when these data are treated as homogenous. Higher agreeableness was associated with worse pain for those in a sub-group reporting the greatest pain, and higher extraversion was protective against pain among those whose pain improved. The results highlight the importance of modelling heterogeneity of disease.

Identifying multiple knee pain trajectories and the prediction of opioid and NSAID medication used: A latent class growth approach.

BACKGROUND: Knee pain is a major source of distress and disability, with pain progression highly variable between individuals. Previous studies defining pain trajectories have all used a single measure of pain, and these differ across studies. Different measures reflect diverse pain mechanisms. To ascertain the clinical utility of pain trajectories, we explored associations between opioid and non-steroidal anti-inflammatory drug (NSAID) use. METHODS: We model pain trajectories using two measures-Intermittent and Constant Osteoarthritis Pain (ICOAP) and the painDETECT, in 2141 participants, across 3 waves (the baseline, 1- and 3-year assessments) of the Knee Pain In the Community (KPIC) cohort. RESULTS: Latent class growth analysis identified six trajectories using ICOAP subscales (High-Stable, Low-Stable, Moderate Worsening, Moderate Recovering, Worsening, and Recovering) and four trajectories using painDETECT (High-stable, Low-stable, Moderate Worsening, and Moderate Recovering). There was a high degree of correspondence between people assigned to pain trajectories between ICOAP intermittent and constant subscales, but less so using painDETECT. Opioid use was associated with ICOAP trajectories only (e.g., High-Stable and Worsening intermittent ICOAP trajectories) and in women. CONCLUSION: Different measures of pain produce different patterns of pain progression and these are differentially related to medication use. Opioid use is linked to trajectories of pain based on the impact of pain on behavior and not pain symptoms. Thus, managing pain's behavioral impact is more central to understanding opioid use than managing pain symptoms. These findings support more in-depth questioning about the type of pain and its progression in clinical practice.

The efficacy of systemic glucocorticosteroids for pain in rheumatoid arthritis: a systematic literature review and meta-analysis.

OBJECTIVES: Glucocorticosteroids (GCs) are recommended to suppress inflammation in people with active RA. This systematic review and meta-analysis aimed to quantify the effects of systemic GCs on RA pain. METHODS: A systematic literature review of randomized controlled trials (RCTs) in RA comparing systemic GCs to inactive treatment. Three databases were and spontaneous pain and evoked pain outcomes were extracted. Standardized mean differences (SMDs) and mean differences were meta-analysed. Heterogeneity (I2, tau statistics) and bias (funnel plot, Egger's test) were assessed. Subgroup analyses investigated sources of variation. This study was pre-registered (PROSPERO CRD42019111562). RESULTS: A total of 18 903 titles, 880 abstracts and 226 full texts were assessed. Thirty-three RCTs suitable for the meta-analysis included 3123 participants. Pain scores (spontaneous pain) decreased in participants treated with oral GCs; SMD = -0.65 (15 studies, 95% CI -0.82, -0.49, P <0.001) with significant heterogeneity (I2 = 56%, P =0.0002). Efficacy displayed time-related decreases after GC initiation. Mean difference visual analogue scale pain was -15 mm (95% CI -20, -9) greater improvement in GC than control at ≤3 months, -8 mm (95% CI -12, -3) at >3-6 months and -7 mm (95% CI -13, 0) at >6 months. Similar findings were obtained when evoked pain outcomes were examined. Data from five RCTs suggested improvement also in fatigue during GC treatment. CONCLUSION: Oral GCs are analgesic in RA. The benefit is greatest shortly after initiation and GCs might not achieve clinically important pain relief beyond 3 months. Treatments other than anti-inflammatory GCs should be considered to reduce the long-term burden of pain in RA.

Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials.

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.