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Periprosthetic Knee Infection: The Multidisciplinary Oxford Bone Infection Unit Experience
Periprosthetic Joint Infection (PJI) is well recognised as a complication of total joint arthroplasty which carries significant morbidity and mortality. The management of PJI is one of the biggest challenges facing the orthopaedic community and significant efforts have been made over the last decade to address this important domain. There is a growing body of evidence suggesting that the management of patients with PJI can be optimized by using a multi-disciplinary team (MDT) approach. This chapter aims to outline the approach to the diagnosis and management of PJI within a national bone infection unit within an MDT setting.
Are Time Series Foundation Models Ready for Vital Sign Forecasting in Healthcare?
The rise of foundation models, particularly large language models like ChatGPT, has revolutionized natural language processing and demonstrated remarkable generalization across numerous healthcare applications. Building on this success, foundation models for time series forecasting have emerged, offering new opportunities by leveraging pretraining on large-scale datasets. However, existing time series foundation models are pretrained with minimal clinical data, and their potentials for continuously recorded clinical time series, such as vital signs, remain largely under-explored. This motivates our endeavor to integrate time series foundation models with vital sign data to address critical clinical challenges, particularly in predicting patient deterioration. Through an extensive evaluation of various settings and configurations of these models, alongside comparisons with conventional forecasting models, we highlight the significant opportunities for improvement in developing clinically useful time series forecasting models. In a word, the “ChatGPT” moment for time series foundation models, in the typical clinical domain, is yet to come.
TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.
The loss of TBK1, or both TBK1 and the related kinase IKKε, results in uncontrolled cell death-driven inflammation. Here, we show that the pathway leading to cell death depends on the nature of the activating signal. Previous models suggest that in steady state, TBK1/IKKε-deficient cells die slowly and spontaneously predominantly by uncontrolled tumor necrosis factor-RIPK1-driven death. However, upon infection of cells that express the NLRP3 inflammasome, (e.g., macrophages), with pathogens that activate this pathway (e.g., Listeria monocytogenes), TBK1/IKKε-deficient cells die rapidly, prematurely, and exclusively by enhanced NLRP3-driven pyroptosis. Even infection with the RIPK1-activating pathogen, Yersinia pseudotuberculosis, results in enhanced RIPK1-caspase-8 activation and enhanced secondary NLRP3 activation. Mechanistically, TBK1/IKKε control endosomal traffic, and their loss disrupts endosomal homeostasis, thereby signaling cell stress. This results in premature NLRP3 activation even upon sensing "signal 2" alone, without the obligatory "signal 1." Collectively, TBK1/IKKε emerge as a central brake in limiting death-induced inflammation by both RIPK1 and NLRP3 death-inducing pathways.
Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study.
OBJECTIVE: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. DESIGN: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. RESULTS: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06). CONCLUSIONS: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.
Treatment choice for adult patients with moderate-to-severe asthma – The TAILOR study
BackgroundIn patients with uncontrolled asthma treated with medium dose (md) inhaled corticosteroid/long-acting beta2 agonist (ICS/LABA), The Global Initiative for Asthma (GINA) recommends to increase to high dose (hd) ICS/LABA or to start therapy consisting of md ICS/LABA+LAMA (long-acting muscarinic antagonist). Adding LAMA on top of hd ICS/LABA is not recommended for Step 4 asthma patients, yet it is used in the real world. Patient characteristics influencing treatment step-up are unknown.ObjectivesIdentify determinants of step-up option (hd ICS/LABA, md ICS/LABA+LAMA, hd ICS/LABA+LAMA) in patients with moderate to severe asthma.MethodsA retrospective cohort study using three primary care databases (IPCI, HSD, CPRD GOLD) and one prescription database (Aarhus) included asthma patients with step-up after≥3 months use of md ICS/LABA, from January 2010 to April 2020. Characteristics of patients were described and determinants of choice for md ICS/LABA+LAMA or high dose ICS/LABA were investigated.Results492 639 adults with asthma and≥1 year of database history were identified and 25 558 were eligible for analysis. 6126 patients stepped-up to md ICS/LABA+LAMA and 18 947 patients stepped-up to hd ICS/LABA. Determinants for step-up to md ICS/LABA+LAMA were higher age and presence of COPD whereas history of atopy lowered this choice. Other covariates were differentially associated with specific treatment step-up depending on the databases.ConclusionIn uncontrolled asthma patients on md ICS/LABA, treatment step-up with add-on LAMA was more likely than step-up to hd ICS/LABA in older patients, current smokers, with a history of asthma exacerbations and concomitant diagnosis of COPD.
Independent and combined effects of long-term air pollution exposure and genetic predisposition on COVID-19 severity: A population-based cohort study.
The relationships between air pollution, genetic susceptibility, and COVID-19-related outcomes, as well as the potential interplays between air pollution and genetic susceptibility, remain largely unexplored. The Cox proportional hazards model was used to assess associations between long-term exposure to air pollutants and the risk of COVID-19 outcomes (infection, hospitalization, and death) in a COVID-19-naive cohort (n = 458,396). Additionally, associations between air pollutants and the risk of COVID-19 severity (hospitalization and death) were evaluated in a COVID-19 infection cohort (n = 110,216). Furthermore, this study investigated the role of host genetic susceptibility in the relationships between exposure to air pollutants and the development of COVID-19-related outcomes. Long-term exposure to air pollutants was significantly associated with an increased risk of COVID-19-related outcomes in the COVID-19 naive cohort. Similarly, in COVID-19 infection cohort, hazard ratios (HRs) for COVID-19 hospital admission were 1.23 (1.19, 1.27) for PM2.5 and 1.22 (1.17, 1.26) for PM10, whereas HRs for COVID-19 death were 1.28 (1.18, 1.39) for PM2.5 and 1.25 (1.16, 1.36) for PM10. Notably, significant interactions were found between PM2.5/PM10 and genetic susceptibility in COVID-19 death. In COVID-19 infection cohort, participants with both high genetic risk and high air pollutants exposure had 1.86- to 1.97-fold and 1.91- to 2.14-fold higher risk of COVID-19 hospitalization and death compared to those with both low genetic risk and low air pollutants exposure. Exposure to air pollution is significantly associated with an increased burden of severe COVID-19, and air pollution-gene interactions may play a crucial role in the development of COVID-19-related outcomes.
Tight Control and Radiological Progression: The Radiographic Outcomes of the TICOPA Study
J Rheumatol 2025; doi:10.3899/jrheum.2024-1035In the Abstract, Results, regarding the definition of radiographic progression, the text should be "an increase in total erosion score of ≥ 2 at week 48." Similarly, in the Results section on page 3, paragraph 1, the text should be "On evaluation of radiographic progression (defined as an increase in total erosion score of ≥ 2) at week 48, 17/169 patients (10.1%) were found to have radiographic progression, representing 14.1% (12/85) of the StdC arm vs 6% (5/84) of the TC arm." The authors would like to clarify that radiographic progression is defined as an increase in the total erosion score of ≥ 2. We apologize for any lack of clarity. This clarification does not affect the conclusions of the study.This correction applies only to the February 15 2025 First Release. The correct text appears in the print and online issues.
A randomised controlled trial of blood pressure self-monitoring in the management of hypertensive pregnancy. OPTIMUM-BP: A feasibility trial.
OBJECTIVE: To assess the feasibility of a blood pressure self-monitoring intervention for managing pregnancy hypertension. STUDY DESIGN: OPTIMUM-BP was an unmasked randomised controlled trial comparing a self-monitoring of blood pressure (SMBP) intervention versus usual care for the management of pregnancy hypertension. Women with chronic (CH) or gestational hypertension (GH) from 4 UK centres were randomised (2:1) intervention to control. Self-monitoring involved daily home blood pressure (BP) measurements, with recording via study diary or telemonitoring. Clinicians were invited to use the home readings in clinical and antihypertensive titration decisions. MAIN OUTCOMES: The primary outcomes were recruitment, retention, adherence and persistence with the intervention. RESULTS: Women from four UK centres were randomised: 158/222 (71%) of those approached agreed, comprising: 86 women with chronic hypertension (55 SMBP, 31 control) and 72 with gestational hypertension (49 SMBP, 23 control) of whom outcome data were available from 154 (97%) and were included in the analysis. The median (IQR) number of days with home BP readings per week were 5.5 (3.1-6.5) for those with chronic hypertension and 6.1 (4.5-6.7) with gestational hypertension. Participants persisted with the intervention for 80% or more of their time from enrolment until delivery in 86% (43/50) and 76% (38/49) of those with chronic and gestational hypertension respectively. Recorded clinic and study BPs were similar for both groups. CONCLUSIONS: This is the first randomised investigation of BP self-monitoring for the management of pregnancy hypertension and indicates that a large RCT would be feasible.
Self-monitoring of blood pressure following a stroke or transient ischaemic attack (TASMIN5S): a randomised controlled trial.
BACKGROUND: Blood pressure (BP) control following stroke is important but currently sub-optimal. This trial aimed to determine whether self-monitoring of hypertension with telemonitoring and a treatment escalation protocol, results in lower BP than usual care in people with previous stroke or transient ischaemic attack (TIA). METHODS: Unblinded randomised controlled trial, comparing a BP telemonitoring-based intervention with control (usual care) for hypertension management in 12 primary care practices in England. People with previous stroke or TIA with clinic systolic BP 130-180 mmHg, taking ≤ 3 antihypertensive medications and on stable treatment for at least four weeks were randomised 1:1 using secure online system to intervention or control. The BP:Together intervention comprised self-monitoring of blood pressure with a digital behavioural intervention which supported telemonitoring of self-monitored BP with feedback to clinicians and patients regarding medication titration. The planned primary outcome was difference in clinic measured systolic BP 12 months from randomisation but was not available following early study termination due to withdrawal of funding during the COVID-19 pandemic. Instead, in addition to pre-randomised data, routinely recorded BP was extracted from electronic patient records both pre- and post-randomisation and presented descriptively only. An intention to treat approach was taken. RESULTS: From 650 postal invitations, 129 (20%) responded, of whom 95 people had been screened for eligibility prior to the pandemic (November 2019-March 2020) and 55 (58%) were randomised. Pre-randomisation routinely recorded mean BP was 145/78 mmHg in the control (n = 26) and 145/79 mmHg in the self-monitoring (n = 21) groups. Post-randomisation mean BP was 134/73 mmHg in the control (n = 19) and 130/75 mmHg in the self-monitoring (n = 25) groups. Participants randomised to self-monitoring used the intervention for ≥ 7 months in 25/27 (93%) of cases. CONCLUSIONS: Recruitment of people with stroke/TIA to a trial comparing a BP self-monitoring and digital behavioural intervention to usual care was feasible prior to the COVID-19 pandemic and the vast majority of those randomised to intervention used it while the trial was running. Routinely recorded blood pressure control improved in both groups. Digital interventions including self-monitoring are feasible for people with stroke/TIA and should be definitively evaluated in future trials. TRIAL REGISTRATION: ISRCTN57946500 06/09/2019 Prospective.
Effect of antihypertensive deprescribing on hospitalisation and mortality: long-term follow-up of the OPTiMISE randomised controlled trial.
BACKGROUND: Deprescribing of antihypertensive medications is recommended for some older patients with low blood pressure and frailty. The OPTiMISE trial showed that this deprescribing can be achieved with no differences in blood pressure control at 3 months compared with usual care. We aimed to examine effects of deprescribing on longer-term hospitalisation and mortality. METHODS: This randomised controlled trial enrolled participants from 69 general practices across central and southern England. Participants aged 80 years or older, with systolic blood pressure less than 150 mm Hg and who were receiving two or more antihypertensive medications, were randomly assigned (1:1) to antihypertensive medication reduction (removal of one antihypertensive) or usual care. General practitioners and participants were aware of the treatment allocation following randomisation but individuals responsible for analysing the data were masked to the treatment allocation throughout the study. Participants were followed up via their primary and secondary care electronic health records at least 3 years after randomisation. The primary outcome was time to all-cause hospitalisation or mortality. Intention-to-treat analyses were done using Cox regression modelling. A per-protocol analysis of the primary outcome was also done, excluding participants from the intervention group who did not reduce treatment or who had medication reinstated during the initial trial 12-week follow-up period. This study is registered with the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT2016-004236-38) and the ISRCTN Registry (ISRCTN97503221). FINDINGS: Between March 20, 2017, and Sept 30, 2018, a total of 569 participants were randomly assigned. Of these, 564 (99%; intervention=280; control=284) were followed up for a median of 4·0 years (IQR 3·7-4·3). Participants had a mean age of 84·8 years (SD 3·4) at baseline and 273 (48%) were women. Medication reduction was sustained in 109 participants at follow-up (51% of the 213 participants alive in the intervention group). Participants in the intervention group had a larger reduction in antihypertensives than the control group (adjusted mean difference -0·35 drugs [95% CI -0·52 to -0·18]). Overall, 202 (72%) participants in the intervention group and 218 (77%) participants in the control group experienced hospitalisation or mortality during follow-up (adjusted hazard ratio [aHR] 0·93 [95% CI 0·76 to 1·12]). There was some evidence that the proportion of participants experiencing the primary outcome in the per-protocol population was lower in the intervention group (aHR 0·80 [0·64 to 1·00]). INTERPRETATION: Half of participants sustained medication reduction with no evidence of an increase in all-cause hospitalisation or mortality. These findings suggest that an antihypertensive deprescribing intervention might be safe for people aged 80 years or older with controlled blood pressure taking two or more antihypertensives. FUNDING: British Heart Foundation and National Institute for Health and Care Research.
Clinical and cost-effectiveness of nurse-delivered sleep restriction therapy for insomnia in primary care (HABIT): a pragmatic, superiority, open-label, randomised controlled trial.
BACKGROUND: Insomnia is prevalent and distressing but access to the first-line treatment, cognitive behavioural therapy (CBT), is extremely limited. We aimed to assess the clinical and cost-effectiveness of sleep restriction therapy, a key component of CBT, which has the potential to be widely implemented. METHODS: We did a pragmatic, superiority, open-label, randomised controlled trial of sleep restriction therapy versus sleep hygiene. Adults with insomnia disorder were recruited from 35 general practices across England and randomly assigned (1:1) using a web-based randomisation programme to either four sessions of nurse-delivered sleep restriction therapy plus a sleep hygiene booklet or a sleep hygiene booklet only. There was no restriction on usual care for either group. Outcomes were assessed at 3 months, 6 months, and 12 months. The primary endpoint was self-reported insomnia severity at 6 months measured with the insomnia severity index (ISI). The primary analysis included participants according to their allocated group and who contributed at least one outcome measurement. Cost-effectiveness was evaluated from the UK National Health Service and personal social services perspective and expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The trial was prospectively registered (ISRCTN42499563). FINDINGS: Between Aug 29, 2018, and March 23, 2020 we randomly assigned 642 participants to sleep restriction therapy (n=321) or sleep hygiene (n=321). Mean age was 55·4 years (range 19-88), with 489 (76·2%) participants being female and 153 (23·8%) being male. 580 (90·3%) participants provided data for at least one outcome measurement. At 6 months, mean ISI score was 10·9 (SD 5·5) for sleep restriction therapy and 13·9 (5·2) for sleep hygiene (adjusted mean difference -3·05, 95% CI -3·83 to -2·28; p<0·0001; Cohen's d -0·74), indicating that participants in the sleep restriction therapy group reported lower insomnia severity than the sleep hygiene group. The incremental cost per QALY gained was £2076, giving a 95·3% probability that treatment was cost-effective at a cost-effectiveness threshold of £20 000. Eight participants in each group had serious adverse events, none of which were judged to be related to intervention. INTERPRETATION: Brief nurse-delivered sleep restriction therapy in primary care reduces insomnia symptoms, is likely to be cost-effective, and has the potential to be widely implemented as a first-line treatment for insomnia disorder. FUNDING: The National Institute for Health and Care Research Health Technology Assessment Programme.
Informed consent in randomised controlled trials: further development and evaluation of the participatory and informed consent (PIC) measure.
BACKGROUND: Informed consent is an accepted ethical and legal prerequisite for trial participation, yet there is no standardised method of assessing patient understanding for informed consent. The participatory and informed consent (PIC) measure was developed for application to recruitment discussions to evaluate recruiter information provision and evidence of patient understanding. Preliminary evaluation of the PIC indicated the need to improve inter-rater and intra-rater reliability ratings and conduct further psychometric evaluation. This paper describes the assessment, revision and evaluation of the PIC within the context of OPTiMISE, a pragmatic primary care-based trial. METHODS: This study used multiple methods across two phases. In phase one, one researcher applied the existing PIC measure to 18 audio-recorded recruitment discussions from the OPTiMISE study and made detailed observational notes about any uncertainties in application. Appointments were sampled to be maximally diverse for patient gender, study centre, recruiter and before and after an intervention to optimise information provision. Application uncertainties were reviewed by the study team, revisions made and a coding manual developed and agreed. In phase two, the coding manual was used to develop tailored guidelines for applying the PIC to appointments within the OPTiMISE trial. Two researchers then assessed 27 further appointments, purposively sampled as above, to evaluate inter-rater and intra-rater reliability, content validity and feasibility. RESULTS: Application of the PIC to 18 audio-recorded OPTiMISE recruitment discussions resulted in harmonisation of the scales rating recruiter information provision and evidence of patient understanding, minor amendments to clarify wording and the development of detailed generic coding guidelines for applying the measure within any trial. Application of the revised measure using these guidelines to 27 further recruitment discussions showed good feasibility (time to complete), content validity (completion rate) and reliability (inter- and intra-rater) of the measure. CONCLUSION: The PIC provides a means to evaluate the content of information provided by recruiters, patient participation in recruitment discussions and, to some extent, evidence of patient understanding. Future work will use the measure to evaluate recruiter information provision and evidence of patient understanding both across and within trials.