Multiplexed spatial profiling of Hodgkin Reed-Sternberg cell neighborhoods in classic Hodgkin lymphoma.

PURPOSE: Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown. EXPERIMENTAL DESIGN: We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors. RESULTS: We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity. CONCLUSIONS: Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.

Frailty and socioeconomic position: A systematic review of observational studies.

BACKGROUND: Frailty, an age-related state of reduced physiological reserve, is often associated with lower socio-economic position (SEP). This systematic review synthesised observational studies assessing (i) the association between SEP and frailty prevalence; (ii) how changes in frailty status over time vary by SEP; and (iii) whether the association between frailty and clinical outcomes is modified by SEP. METHODS: We searched three electronic databases from 2001 to 2023. We included observational studies measuring early-, mid-, and late-life indicators of SEP (education, income, wealth, housing, occupation, and area-based measures of multiple deprivation) and frailty (assessed using any validated measure). Screening and extraction were performed in duplicate. Findings were synthesised using narrative synthesis. RESULTS: We included 383 studies reporting findings from 265 independent samples/cohorts across 64 countries. Lower SEP was associated with higher frailty prevalence across all indicators (childhood deprivation 7/8 studies, education 227/248, occupation 28/32, housing 8/9, income 98/108, wealth 39/44 and area-based deprivation 32/34). Lower SEP was also associated with higher frailty incidence (27/30), with greater odds of transitioning towards a more severe frailty state (35/43), lower odds of frailty reversion (7/11), and (in some studies) with more rapid accumulation of deficits (7/15). The relationship between frailty and mortality was not modified by SEP. INTERPRETATION: Preventative measures across multiple levels of individual and structural inequality are likely to be required to reduce the rising levels of frailty. Resourcing of interventions and services to support people living with frailty should be proportionate to needs in the population to avoid widening existing health inequalities.

Evaluating the STarTBack stratified treatment approach for low back pain: exploring study-level factors potentially explaining differences in results of studies - a literature review.

OBJECTIVE: To explore if there are differences in the design and/or conduct of studies that have tested the STarTBack treatment approach for the management of low back pain (LBP), potentially explaining differences in study results. DESIGN: A literature review. DATA SOURCES: MEDLINE, CINAHL and EMBASE were searched from inception to 26 July 2023. ELIGIBILITY CRITERIA: We included studies that included (1) participants with LBP and/or leg pain, (2) randomised controlled trials, controlled clinical trials and interrupted time series designs, (3) used the STarTBack Tool to stratify participants into subgroups and (4) studies provided matched treatments according to participants STarTBack score. DATA EXTRACTION AND SYNTHESIS: Two review authors independently reviewed the search results and extracted data into the data extraction form. Due to the exploratory nature of this study, results are presented descriptively. RESULTS: 11 studies conducted across 5 countries were included. There were substantial differences in the proportion of participants allocated to the different risk groups; low-risk group (range: 19%-58%), medium risk group (range: 31%-52%) and high-risk group (range: 6%-38%). There were large differences between studies in the implementation of the STarTBack approach. The original STarTBack trial (Hill et al, 2011) had a more explanatory design while in many subsequent studies, the design was more pragmatic/real world. Only the two original studies provided clear evidence that the implementation of the STarTBack tool led to a higher proportion of participants receiving matched treatment. In the other studies, there was no evidence of a difference, or it was unclear. In two studies, a researcher made the decision about which matched treatment participants received based on the STartTback Tool, while in nine studies, this was done by a clinician. Most studies recommended the same matched treatment for each risk group as per the original study except for a small number of studies. Only three studies reported whether the clinician delivering matched treatment followed the recommended treatment as per the tool. There was substantial variability in the training clinicians received. CONCLUSIONS: Reporting of important study-level factors (eg, differences in study design, whether clinicians were trained and how the tool was used in each study) in how the STarTBack approach was implemented was unclear. There is some suggestion that key factors may include the individual who implemented the STarTBack tool, whether the recommendations of the tool were followed, the amount of training the clinician delivering the matched treatment received, and whether clinicians actually delivered the matched treatment.

The relationship between frailty and social vulnerability: a systematic review.

Both frailty (reduced physiological reserve) and social vulnerability (scarcity of adequate social connections, support, or interaction) become more common as people age and are associated with adverse consequences. Analyses of the relationships between these constructs can be limited by the wide range of measures used to assess them. In this systematic review, we synthesised 130 observational studies assessing the association between frailty and social vulnerability, the bidirectional longitudinal relationships between constructs, and their joint associations with adverse health outcomes. Frailty, across assessment type, was associated with increased loneliness and social isolation, perceived inadequacy of social support, and reduced social participation. Each of these social vulnerability components was also associated with more rapid progression of frailty and lower odds of improvement compared with the absence of that social vulnerability component (eg, more rapid frailty progression in people with social isolation vs those who were not socially isolated). Combinations of frailty and social vulnerability were associated with increased mortality, decline in physical function, and cognitive impairment. Clinical and public health measures targeting frailty or social vulnerability should, therefore, account for both frailty and social vulnerability.

Opioids for Acute Musculoskeletal Pain: A Systematic Review with Meta-Analysis.

OBJECTIVE: To evaluate the efficacy of opioids for people with acute musculoskeletal pain against placebo. STUDY DESIGN: Systematic review and meta-analyses of randomised, placebo-controlled trials of opioid analgesics for acute musculoskeletal pain in any setting. The primary outcomes were pain and disability at the immediate timepoint (< 24 h). DATA SOURCES: Multiple databases were searched from their inception to February 22nd, 2023. DATA SYNTHESIS: Continuous outcomes were converted to a 0-100 scale. Dichotomous outcomes were presented as risk differences. Risk of bias and certainty of evidence was assessed. RESULTS: We located 17 trials (1 intravenous and 16 oral route of administration). For adults, high certainty evidence from 11 comparisons shows that oral opioids provide small benefits relative to placebo in the immediate term for pain (mean difference [MD] - 8.8 95% confidence interval [CI] - 12.0 to - 5.6). For disability, the difference is uncertain (MD - 6.2, 95% CI - 17.8 to 5.4). Opioid groups were at higher risk of adverse events (MD 14.3%, 95% CI 8.3-20.4%, very low certainty). There was moderate certainty evidence of a large effect of IV morphine on sciatica pain (MD -42.5, 95% CI - 49.9 to - 35.1, n = 197, 1 study). In paediatric populations, moderate certainty evidence from 3 trials shows that oral opioids probably do not provide benefit beyond that of placebo for pain (MD 6.1, 95% CI - 1.7 to 12.8) and there was no evidence for disability. There was low certainty evidence that there may be no difference in adverse events (MD 10.4%, 95% CI - 0.6 to 21.4%). DISCUSSION: Intravenous morphine likely offers benefits, but oral opioids may not provide clinically meaningful benefits. PROSPERO REGISTRATION: CRD42021249346.

Defining domains: developing consensus-based definitions for foundational domains in OMERACT core outcome sets.

OBJECTIVE: To develop a set of detailed definitions for foundational domains commonly used in OMERACT (Outcome Measures in Rheumatology) core domain sets. METHODS: We identified candidate domain definitions from prior OMERACT publications and websites and publications of major organizations involved in outcomes research for six domains commonly used in OMERACT Core Domain Sets: pain intensity, pain interference, physical function, fatigue, patient global assessment, and health-related quality of life. We conducted a two-round survey of OMERACT working groups, patient research partners, and then the OMERACT Technical Advisory Group to establish their preferred domain definitions. Results were presented at the OMERACT 2023 Methodology Workshop, where participants discussed their relevant lived experience and identified potential sources of variability giving the needed detail in our domain definitions. RESULTS: One-hundred four people responded to both rounds of the survey, and a preferred definition was established for each of the domains except for patient global assessment for which no agreement was reached. Seventy-five participants at the OMERACT 2023 Methodology Workshop provided lived experience examples, which were used to contextualise domain definition reports for each of the five domains. CONCLUSION: Using a consensus-based approach, we have created a detailed definition for five of the foundational domains in OMERACT core domain sets; patient global assessment requires further research. These definitions, although not mandatory for working groups to use, may facilitate the initial domain-match assessment step of instrument selection, and reduce the time and resources required by future OMERACT groups when developing core outcome sets.

Evolving and evaluating the OMERACT fellows program: insights and implications from OMERACT 2023 fellows.

OBJECTIVE: To describe the evolution of the OMERACT Fellows Program (OM FP) and to evaluate the innovative changes implemented in the 2023 program. METHODS: The OM FP, the first of its kind in global rheumatology, was developed in 2000 to mentor early career researchers in methods and processes for reaching evidence-driven consensus for outcome measures in clinical studies. The OM FP has evolved through continuing iterations of face to face and online feedback. Key new features delivered in 2023 included e-learning modules, virtual introductory pre-meetings, increased networking with Patient Research Partners (PRPs), learning opportunities to give and receive personal feedback, ongoing performance feedback during the meeting from Fellow peers, PRPs, senior OMERACTers (members of the OMERACT community) and Emerging Leader mentors, involvement in pitching promotions, two-minute Lightning Talks in a plenary session and an embedded poster tour. An online survey was distributed after the meeting to evaluate the program. RESULTS: OM FP has included 208 fellows from 16 countries across 4 continents covering 47 different aspects of rheumatology outcomes since its inception. Over 50 % have remained engaged with OMERACT work. In 2023, 18 Fellows attended and 15 (83 %) completed the post-meeting survey. A dedicated OM FP was deemed important by all respondents, and 93 % would attend the meeting in future. The PRP/Fellow Connection Carousel and Lightning Talks were rated exceptional by 93 %. Key components to improve included clarification of expectations, overall workload, the Emerging Leaders Mentoring Program, and the content and duration of daily summary sessions. CONCLUSION: The innovations in the 2023 OM FP were well received by the majority of participants and supports early career rheumatology researchers to develop collaborations, skills and expertise in outcome measurement. Implementation of feedback from Fellows will enhance the program for future meetings, continuing to facilitate learning and succession planning within OMERACT.

Exploring the complexities of pain phenotypes: OMERACT 2023 chronic pain working group workshop.

OBJECTIVE: To educate and discuss pain mechanisms (nociceptive, neuropathic, nociplastic) illuminating its possible impact when measuring different outcomes, which may modify, confound and potentially bias the outcome measures applied across various aspects of Rheumatic Musculoskeletal Diseases (RMDs) clinical trials. METHODS: In the plenary presentations, PM lectured on different pain mechanisms and impact on disease activity assessment. Data from two data sets of RMDs patients, which assessed the prevalence and impact of nociplastic pain were presented and reviewed. Audience breakout group sessions and polling were conducted. RESULTS: Mixed pain etiologies may differentially influence disease activity assessment and therapeutic decision-making. Polling demonstrated a consensus on the need to assess different types of pain as a phenotype, as it constitutes an important contextual factor (a variable that is not an outcome of the trial, but needs to be recognized [and measured] to understand the study results), and to standardize across RMDs. CONCLUSION: There is need for a standardized pain measure that can differentiate underlying pain mechanisms.

An optimization case study for solving a transport robot scheduling problem on quantum-hybrid and quantum-inspired hardware.

We present a comprehensive case study comparing the performance of D-Waves' quantum-classical hybrid framework, Fujitsu's quantum-inspired digital annealer, and Gurobi's state-of-the-art classical solver in solving a transport robot scheduling problem. This problem originates from an industrially relevant real-world scenario. We provide three different models for our problem following different design philosophies. In our benchmark, we focus on the solution quality and end-to-end runtime of different model and solver combinations. We find promising results for the digital annealer and some opportunities for the hybrid quantum annealer in direct comparison with Gurobi. Our study provides insights into the workflow for solving an application-oriented optimization problem with different strategies, and can be useful for evaluating the strengths and weaknesses of different approaches.

General practitioners' decision-making process to prescribe pain medicines for low back pain: a qualitative study.

BACKGROUND: Pain medicines are widely prescribed by general practitioners (GPs) when managing people with low back pain (LBP), but little is known about what drives decisions to prescribe these medicines. OBJECTIVES: The aim of this study was to investigate what influences GPs' decision to prescribe pain medicines for LBP. DESIGN: Qualitative study with in-depth interviews. SETTING: Australian primary care. PARTICIPANTS: We interviewed 25 GPs practising in Australia experienced in managing LBP (mean (SD) age 53.4 (9.1) years, mean (SD) years of experience: 24.6 (9.3), 36% female). GPs were provided three vignettes describing common LBP presentations (acute exacerbation of chronic LBP, subacute sciatica and chronic LBP) and were asked to think aloud how they would manage the cases described in the vignettes. DATA ANALYSIS: We summarised GP's choices of pain medicines for each vignette using content analysis and used framework analysis to investigate factors that affected GP's decision-making. RESULTS: GPs more commonly prescribed opioid analgesics. Anticonvulsants and antidepressants were also commonly prescribed depending on the presentation described in the vignette. GP participants made decisions about what pain medicines to prescribe for LBP largely based on previous experiences, including their own personal experiences of LBP, rather than guidelines. The choice of pain medicine was influenced by a range of clinical factors, more commonly the patient's pathoanatomical diagnosis. While many adhered to principles of judicious use of pain medicines, polypharmacy scenarios were also common. Concerns about drug-seeking behaviour, adverse effects, stigma around opioid analgesics and pressure from regulators also shaped their decision-making process. CONCLUSIONS: We identified several aspects of decision-making that help explain the current profile of pain medicines prescribed for LBP by GPs. Themes identified by our study could inform future implementation strategies to improve the quality use of medicines for LBP.

Adding Brief Pain Science or Ergonomics Messages to Guideline Advice Did Not Increase Feelings of Reassurance in People With Acute Low Back Pain: A Randomized Experiment.

OBJECTIVE: To investigate the effects of adding pain science or ergonomics messages to guideline advice on feelings of reassurance and management intentions among people with acute low back pain (LBP). DESIGN: Three-arm parallel-group randomized experiment. METHODS: We recruited people with acute LBP (pain for ≤6 weeks) to participate in an online experiment. Participants were randomized at a 1:1:1 ratio to one of three groups: guideline advice alone or guideline advice with the addition of brief pain science or ergonomics messages. The intervention was delivered via prerecorded videos in all 3 groups. Coprimary outcomes were reassurance that (1) no serious condition is causing LBP and (2) continuing with daily activities is safe. Secondary outcomes were perceived risk of developing chronic pain, management intentions (bed rest, see a health professional, see a specialist, and imaging), credibility, and relevance of the advice in addressing the participant's concerns. RESULTS: Two thousand two hundred ninety-seven responses (99.3% of 2,313 randomized) were analyzed. Adding brief pain science or ergonomics messages to guideline advice did not change reassurance that LBP was not caused by serious disease. The addition of ergonomics advice provided worse reassurance that it is safe to continue with daily activities compared to guideline advice (mean difference [MD], -0.33; 95% CI: 0.13, 0.53). There was no difference between groups on management intentions. CONCLUSION: Adding pain science or ergonomics messages to guideline advice did not increase reassurance or change management intentions in people with acute LBP. Ergonomics messages may lead to reduced feelings of reassurance. J Orthop Sports Phys Ther 2023;53(12)1-11. Epub 26 September 2023. doi:10.2519/jospt.2023.12090.

Are Physician Assistants Able to Correctly Identify Prescribing Errors? A Cross-Sectional Study.

PURPOSE: (1) To describe how often physician assistant (PA) students correctly identify prescribing errors and (2) examine between-cohort differences on ability to correctly identify prescribing errors. METHODS: This was a cross-sectional study of 2 cohorts of PA students at one institution. Students were presented with 3 hypothetical prescriptions, 2 of which contained a prescribing error. For each prescription, students were asked to (1) identify whether an error occurred and (2) indicate the type of error. A simple Poisson regression model analyzed the data. RESULTS: We received responses from 130 students (72.6% response rate). Approximately 12% (12.3%, n = 16) correctly identified whether all 3 prescriptions were correct. The median number of correctly identified prescriptions was 1 (interquartile range = 1). There was not a statistically significant between-cohort difference identifying the correct number of prescriptions (ß = 0.27, P = .10). CONCLUSION: Physician assistant students' prescribing error identification was similar to previous research in medical and nursing students. Efforts to improve prescribing training are critical to ensure patient safety.

Treatment burden for people experiencing homelessness with a recent non-fatal overdose: a questionnaire study.

BACKGROUND: People experiencing homelessness (PEH) who have problem drug use have complex medical and social needs, with barriers to accessing services and treatments. Their treatment burden (workload of self-management and impact on wellbeing) remains unexplored. AIM: To investigate treatment burden in PEH with a recent non-fatal overdose using a validated questionnaire, the Patient Experience with Treatment and Self-management (PETS). DESIGN AND SETTING: The PETS questionnaire was collected as part of a pilot randomised control trial (RCT) undertaken in Glasgow, Scotland; the main outcome is whether this pilot RCT should progress to a definitive RCT. METHOD: An adapted 52-item, 12-domain PETS questionnaire was used to measure treatment burden. Greater treatment burden was indicated by higher PETS scores. RESULTS: Of 128 participants, 123 completed PETS; mean age was 42.1 (standard deviation [SD] 8.4) years, 71.5% were male, and 99.2% were of White ethnicity. Most (91.2%) had >5 chronic conditions, with an average of 8.5 conditions. Mean PETS scores were highest in domains focusing on the impact of self-management on wellbeing: physical and mental exhaustion (mean 79.5, SD 3.3) and role and social activity limitations (mean 64.0, SD 3.5) Scores were higher than those observed in studies of patients who are not homeless. CONCLUSION: In a socially marginalised patient group at high risk of drug overdose, the PETS showed a very high level of treatment burden and highlights the profound impact of self-management work on wellbeing and daily activities. Treatment burden is an important person-centred outcome to help compare the effectiveness of interventions in PEH and merits inclusion in future trials as an outcome measure.

Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial.

BACKGROUND: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. METHODS: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). FINDINGS: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI -0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). INTERPRETATION: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. FUNDING: National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and SafeWork SA.

Developing a patient decision aid for Achilles tendon rupture management: a mixed-methods study.

OBJECTIVE: To develop and user-test a patient decision aid portraying the benefits and harms of non-surgical management and surgery for Achilles tendon ruptures. DESIGN: Mixed methods. SETTING: A draft decision aid was developed using guidance from a multidisciplinary steering group and existing patient decision aids. Participants were recruited through social media. PARTICIPANTS: People who have previously sustained an Achilles tendon rupture and health professionals who manage these patients. PRIMARY AND SECONDARY OUTCOMES: Semi-structured interviews and questionnaires were used to gather feedback on the decision aid from health professionals and patients who had previously suffered an Achilles tendon rupture. The feedback was used to redraft the decision aid and assess acceptability. An iterative cycle of interviews, redrafting according to feedback and further interviews was used. Interviews were analysed using reflexive thematic analysis. Questionnaire data were analysed descriptively. RESULTS: We interviewed 18 health professionals (13 physiotherapists, 3 orthopaedic surgeons, 1 chiropractor, 1 sports medicine physician) and 15 patients who had suffered an Achilles tendon rupture (median time since rupture was 12 months). Most health professionals and patients rated the aid's acceptability as good-excellent. Interviews showcased agreement among health professionals and patients on most aspects of the decision aid: introduction, treatment options, comparing benefits and harms, questions to ask health professionals and formatting. However, health professionals had differing views on details about Achilles tendon retraction distance, factors that modify the risk of harms, treatment protocols and evidence on benefits and harms. CONCLUSION: Our patient decision aid is an acceptable tool to both patients and health professionals, and our study highlights the views of key stakeholders on important information to consider when developing a patient decision aid for Achilles tendon rupture management. A randomised controlled trial evaluating the impact of this tool on the decision-making of people considering Achilles tendon surgery is warranted.