Significant pain variability in persons with, or at high risk of, knee osteoarthritis: preliminary investigation based on secondary analysis of cohort data

BACKGROUND: While knee osteoarthritis (OA) is characterised as a slowly progressive disease, acute flares, episodes of severe pain, and substantial fluctuations in pain intensity appear to be part of the natural history for some patients. We sought to estimate what proportion of symptomatic community-dwelling adults might be affected, and to identify patient and problem characteristics associated with higher risk of such variability in pain. METHODS: We analysed data collected at baseline, 18, 36, 54, and 72 month follow-up of a prospective cohort of symptomatic adults aged over 50 years with current/recent knee pain. At each time point we estimated the proportion of participants reporting 'significant pain variability' (defined as worst pain intensity in the past 6 months ≥5/10 and ≥2 points higher than average pain intensity during the same 6-month period). The associations between significant pain variability and demographic, socioeconomic, lifestyle, clinical, radiographic, and healthcare utilisation factors measured at baseline were estimated by adjusted odds ratios and 95% confidence intervals (aOR; 95%CI) from multivariable discrete-time survival analysis. RESULTS: Seven hundred and nineteen participants were included in the final analysis. At each time point, 23-32% of participants were classed as reporting significant pain variability. Associated factors included: younger age (aOR (per year): 0.96; 95% CI 0.94, 0.97), higher BMI (per kg/m(2):1.03; 1.01, 1.06), higher WOMAC Pain score (per unit: 1.06; 1.03, 1.10), longer time since onset (e.g. 1-5 years vs < 1 year: 1.79; 1.16, 2.75) and morning stiffness (≤30 min vs none: 1.43; 1.10, 1.85). The models accounting for multiple periods of significant symptom variability found similar associations. CONCLUSIONS: Our findings are consistent with studies showing that, for some patients OA symptoms are significantly variable over time. Future prospective studies on the nature and frequency of flare ups are needed to help determine triggers and their underlying pathophysiology in order to suggest new avenues for effective episode management of OA to complement long-term behaviour change

Exercise for lower limb osteoarthritis : systematic review incorporating trial sequential analysis and network meta-analysis

Objective: To determine whether there is sufficient evidence to conclude that exercise interventions are more effective than no exercise control and to compare the effectiveness of different exercise interventions in relieving pain and improving function in patients with lower limb osteoarthritis. Data sources: Nine electronic databases searched from inception to March 2012. Study selection: Randomised controlled trials comparing exercise interventions with each other or with no exercise control for adults with knee or hip osteoarthritis. Data extraction: Two reviewers evaluated eligibility and methodological quality. Main outcomes extracted were pain intensity and limitation of function. Trial sequential analysis was used to investigate reliability and conclusiveness of available evidence for exercise interventions. Bayesian network meta-analysis was used to combine both direct (within trial) and indirect (between trial) evidence on treatment effectiveness. Results: 60 trials (44 knee, two hip, 14 mixed) covering 12 exercise interventions and with 8218 patients met inclusion criteria. Sequential analysis showed that as of 2002 sufficient evidence had been accrued to show significant benefit of exercise interventions over no exercise control. For pain relief, strengthening, flexibility plus strengthening, flexibility plus strengthening plus aerobic, aquatic strengthening, and aquatic strengthening plus flexibility, exercises were significantly more effective than no exercise control. A combined intervention of strengthening, flexibility, and aerobic exercise was also significantly more effective than no exercise control for improving limitation in function (standardised mean difference −0.63, 95% credible interval −1.16 to −0.10). Conclusions: As of 2002 sufficient evidence had accumulated to show significant benefit of exercise over no exercise in patients with osteoarthritis, and further trials are unlikely to overturn this result. An approach combining exercises to increase strength, flexibility, and aerobic capacity is likely to be most effective in the management of lower limb osteoarthritis. The evidence is largely from trials in patients with knee osteoarthritis

Consultant-led UK paediatric palliative care services: Professional configuration, services, funding

Objectives: To systematically gather information on the professional team members, services provided, funding sources and population served for all consultant-led specialised paediatric palliative care (SPPC) teams in the UK. Methods: Two-part online survey. Results: Survey 1: All 17 medical leads from hospital-based or hospice-based SPPC teams responded to the survey (100% response rate). Only six services met the NICE guidance for minimum SPPC team. All services reported providing symptom management, specialist nursing care, end-of-life planning and care, and supporting discharges and transfers to home or hospice for the child's final days-hours. Most services also provided care coordination (n=14), bereavement support (n=13), clinical psychology (n=10) and social work-welfare support (n=9). Thirteen had one or more posts partially or fully funded by a charity. Survey 2: Nine finance leads provided detailed resource/funding information, finding a range of statutory and charity funding sources. Only one of the National Health Service (NHS)-based services fully funded by the NHS. Conclusions: One-third of services met the minimum criteria of professional team as defined by NICE. Most services relied on charity funding to fund part or all of one professional post and only one NHS-based service received all its funding directly from the NHS

Short‐term recovery trajectories of acute flares in knee pain: a UK‐Netherlands multi‐centre prospective cohort analysis

Objective To identify distinct recovery trajectories of acute flares of knee pain and associated participant characteristics. Methods Data were from the FLARE randomized controlled trial, a multicenter trial in 27 primary care centers in the UK and Netherlands of 3 regimes of oral nonsteroidal antiinflammatory therapy for acute flares of knee pain. Individuals with a history of inflammatory/crystal arthritis, fibromyalgia, and chronic pain syndrome were excluded. Latent class growth analysis was applied to measures of pain intensity repeated over 5 days to identify distinct recovery trajectories. The concurrent courses of interference with activity, stiffness, and swelling for each trajectory group were modelled using generalized estimating equations. Participant age, sex, obesity, and osteoarthritis diagnosis were described for each trajectory group. Results A total of 449 participants were included (median age 55 years, 41% female, 35% obese, and 42% diagnosed with osteoarthritis). A 6‐group cubic model was deemed optimal, with trajectories distinguished by rate of pain reduction and absolute level at final measurement. At the extremes were rapid and near‐complete resolution (n = 41, 9%) and persistent, high pain (n = 25, 6%), but most participants showed a reduction and plateau in pain severity within 3–5 days. Within each pain trajectory group, interference with activity, stiffness, and swelling followed the same course as pain. Baseline characteristics did not differ substantially between trajectory groups. Conclusion Even under a well‐adhered to regime of oral nonsteroidal antiinflammatory medication, recovery following acute flares of knee pain is heterogeneous. Our observations that favorable trajectories are apparent within 3–5 days can help to inform treatment decision‐making in the patient–health care professional consultation

A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

ML, CD, IvL, GP, TM, SD, MS, APF, CT, DL, MAH, KL and SL: project grants from the Swedish Research Council, the Swedish Cancer Society and the Swedish Childhood Cancer Foundation. MHi and JC: Cancer Research UK (C8/A6613). MC, EP and WE: Wellcome Trust (073915). MN and BV: projects MEYS-NPS-LO1413 and GACR P206/12/G151. EMC, MP, MMS, ZF and PG: Norwegian Cancer Society (182735, 732200) and Helse Vest (911884, 911789). RB and SC: NIH (R01 CA95684), the Leukemia and Lymphoma Society and the Waxman Foundation. NW, AH, Ad’H: Cancer Research UK (C21383/A6950) and Engineering and Physical Sciences Research Council Doctoral Training Program. JL and YZ: Cancer Research UK (C240/A15751). MH and BW: SARomics Biostructures ABUY, KF: DDDP SciLife, Sweden. LJ, MHa, RS and A-LG: CBCS, Sweden. VP: SciLife fellowship. AT: Breast Cancer Research Scotland.The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.Publisher PDFPeer reviewe

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination