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Beyond correlations: the necessity and the challenges of causal AI

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

High-Dose vs. Standard-Dose Influenza Vaccine in Heart Failure: A Prespecified Analysis of the DANFLU-2 Trial

<jats:p> <jats:bold>Background:</jats:bold> Influenza contributes substantially to disease burden in individuals with heart failure (HF) and is an established trigger of cardiovascular (CV) and HF events. Standard-dose inactivated influenza vaccine (SD-IIV) is recommended for HF, though immune responses may be attenuated. High-dose IIV (HD-IIV) was developed to enhance immunogenicity, but its effectiveness compared with SD-IIV against hospitalization for influenza and CV disease by HF status remains uncertain. </jats:p> <jats:p> <jats:bold>Methods:</jats:bold> This was a prespecified analysis of a pragmatic, prospective, individually randomized, open-label trial with registry-based endpoint-evaluation conducted in Denmark across the 2022/2023 to 2024/2025 influenza seasons. Citizens ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Outcomes included hospitalization for influenza-related illness, laboratory-confirmed influenza (LCI), any CV disease, cardio-respiratory disease, and HF, assessed by HF status. Effect of HD-IIV vs. SD-IIV in reducing risk of outcomes assessed was expressed as risk ratios (RR). </jats:p> <jats:p> <jats:bold>Results:</jats:bold> The trial randomized 332,438 participants (48.6% female, mean age 73.7±5.8 years), including 10,410 with HF at baseline (27.4% female, mean age 76.0±6.3 years). Overall, HD-IIV was associated with a statistically significant lower incidence of hospitalization for influenza-related illness, LCI, cardio-respiratory disease, CV disease, and HF compared with SD-IIV. In participants with HF, effect estimates were similar: RR for influenza-related hospitalization was 0.48 (95%CI, 0.20-1.06; p <jats:sub>interaction</jats:sub> =0.64), for LCI hospitalization 0.55 (95%CI, 0.29-1.02; p <jats:sub>interaction</jats:sub> =0.59), for cardio-respiratory hospitalization 0.89 (95%CI, 0.77-1.02; p <jats:sub>interaction</jats:sub> =0.34), for CV hospitalization 0.86 (95%CI, 0.72-1.02; p <jats:sub>interaction</jats:sub> =0.34), and for HF hospitalization 0.82 (95%CI, 0.61-1.11; p <jats:sub>interaction</jats:sub> =0.83). Findings were consistent across HF subgroups by disease duration, recency of hospitalization, most recent N-terminal pro-B-type natriuretic peptide, and presence of device therapy. </jats:p> <jats:p> <jats:bold>Conclusions:</jats:bold> In this prespecified exploratory analysis of the largest individually randomized influenza vaccine trial ever conducted, HD-IIV was associated with lower rates of influenza and CV hospitalizations compared with SD-IIV, with effect estimates similar across HF status at baseline and HF subgroups. </jats:p>

Paediatric case of invasive group A streptococcal necrotising myositis: diagnostic challenges and lessons learned.

Necrotising myositis is a rare but devastating consequence of invasive group A streptococcal infection. Early presentation could be non-specific, and clinicians might have a low index of clinical suspicion due to the rarity of cases. Prompt recognition and early aggressive surgical management are the cornerstones of treatment to reduce morbidity and mortality. We report the case of a child aged 5 years with necrotising myositis and highlight the successes and potential pitfalls in the treatment of this life-threatening condition.

Knee arthroplasty versus knee joint distraction for osteoarthritis: a phase III randomised controlled trial

Use of a shared decision-making intervention to support treatment decision-making for patients following an anterior cruciate ligament rupture: a mixed methods feasibility study

Objectives To understand feasibility, acceptability and indicators of effectiveness of a shared decision-making (SDM) intervention with patients following an anterior cruciate ligament (ACL) rupture. Design Non-randomised feasibility study with embedded qualitative interviews. Setting Orthopaedic and physiotherapy service at an acute National Health Service (NHS) Teaching Hospital in the Midlands, UK, between 29 January and 5 June 2024. Participants Patients diagnosed with an ACL rupture following MRI. Intervention Delivery of a SDM intervention which comprised of two components: (1) patient information leaflet and (2) option grid. Outcome measures The primary outcome was to determine feasibility for a definitive trial using four outcomes: (1) recruitment rate, (2) fidelity of intervention delivery, (3) acceptability and (4) follow-up questionnaire completion. The secondary outcome was to explore indicators of the intervention’s effectiveness using quantitative data from patient reported outcome measures (acceptability questionnaire and satisfaction with decision scale) and qualitative data from patient and clinician interviews. Results 21 patients were approached to take part in the study, 20 were recruited with a mean age of 32.2 (SD 9.7), 40% were female. The recruitment rate was 95.2%, fidelity of intervention 100%, acceptability 94% and follow-up questionnaire completion 100%. The mean overall satisfaction with decision scale score was 24.85/30 (SD 3.82). There were no adverse events. Data from qualitative interviews with patients (n=5) and physiotherapists (n=5) suggested the SDM was acceptable and appeared effective in: (1) supporting decision-making about treatment, (2) conversations between patients and clinicians, (3) improving patient knowledge, (4) providing patients with access to health language and (5) supporting patients to ask questions deemed important to them. Conclusion The novel SDM intervention is acceptable to both patients and physiotherapists. Indicators of effectiveness explored through quantitative and qualitative data suggest the intervention to be beneficial to decision-making processes for patients and clinicians deciding on treatment following an ACL rupture. All four feasibility outcomes were achieved, indicating a full trial is feasible to run in the NHS. Trial registration number ISRCTN17801081.

The clinical effectiveness of clarithromycin versus endoscopic sinus surgery for adults with chronic rhinosinusitis with and without nasal polyps (MACRO): a pragmatic, multicentre, three-arm, randomised, placebo-controlled phase 4 trial

Background: A paucity of evidence regarding use of endoscopic sinus surgery and antibiotics in managing chronic rhinosinusitis has contributed to a five-times variation in endoscopic sinus surgery rates, as well as variation in the use of antibiotics. The main aim of the present trial was to compare the clinical effectiveness of endoscopic sinus surgery or 3 months of clarithromycin treatment alongside intranasal medication in adults with chronic rhinosinusitis with or without nasal polyps. Methods: In this pragmatic, three-arm, randomised, placebo-controlled phase 4 trial, participants were recruited from 20 secondary and tertiary care sites in the UK. Adults (aged ≥18 years) with chronic rhinosinusitis remaining symptomatic following appropriate medical therapy (intranasal corticosteroids, saline nasal irrigations, and a short course of antibiotics) were randomly assigned (1:1:1) to receive endoscopic sinus surgery (within 6 weeks of randomisation if waiting lists allowed) plus intranasal medication, clarithromycin (250 mg twice a day for 2 weeks then 250 mg once a day for 10 weeks) plus intranasal medication, or placebo plus intranasal medication. Intranasal medication comprised intranasal corticosteroids and saline irrigations. Participants were allocated with an automated, web-based secure randomisation system in permuted blocks of varying size (block sizes of three and six), stratified by the presence of polyps and trial site. Participants and site teams were masked to the clarithromycin and placebo allocations, including for outcome assessment. The primary outcome measure was the total score on the 22-item Sino-Nasal Outcome Test (SNOT-22) quality-of-life questionnaire at 6 months after randomisation, with analysis by intention to treat (ITT; available-case basis). Adverse reactions were assessed in the safety population (clarithromycin and placebo), and serious adverse events in the ITT population (all groups). The trial was registered on the ISRCTN registry, ISRCTN36962030, and EudraCT, 2018-001100-11, and is complete, with optional long-term follow-up ongoing. Findings: Between Nov 1, 2018, and Oct 13, 2023, 514 participants (181 [35%] female and 333 [65%] male), with chronic rhinosinusitis with nasal polyps (n=410) or chronic rhinosinusitis without nasal polyps (n=104), were recruited and randomly assigned to receive endoscopic sinus surgery (n=171), clarithromycin (n=172), or placebo (n=171), all with intranasal medication. SNOT-22 scores at 6 months after randomisation were significantly lower (at the 98·33% confidence level after Bonferroni adjustment) in the endoscopic sinus surgery group than in the clarithromycin group (adjusted mean difference –18·13 [98·33% CI –24·26 to –11·99], p<0·0001) and placebo group (–20·44 [–26·42 to –14·46], p<0·0001). 6-month SNOT-22 scores did not differ significantly between participants randomly assigned to clarithromycin versus placebo (–3·11 [–8·56 to 2·33], p=0·17). Ten serious adverse events occurred in nine participants (two events in two [1%] of 172 participants allocated to clarithromycin, three events in three [2%] of 171 allocated to placebo, and five events in four [2%] of 171 allocated to endoscopic sinus surgery), none of which were fatal. Interpretation: The MACRO trial shows that endoscopic sinus surgery has clinical effectiveness in patients with chronic rhinosinusitis, providing significantly improved disease-specific quality of life at 6 months. Conversely, the trial findings do not support routine long-term use of low-dose clarithromycin. Endoscopic sinus surgery should be recommended if intranasal medication alone is unable to achieve symptom control. Funding: National Institute for Health and Care Research Programme Grants for Applied Research.

Sonelokimab, an IL-17A- and IL-17F- inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial

Sonelokimab, an IL-17A- and IL-17F- inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial

MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines.

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

The effect of minimum volume recommendations on surgeon activity for first revision total knee replacement: an analysis of 2009-2019 United Kingdom National Joint Registry data.

AIMS: The aim of this study was to investigate changes in first time revision knee replacement (RevKR) volumes following the publication of a report identifying low surgeon volumes in England. As a secondary aim we sought to investigate the rate of accrual of volumes for early career surgeons. METHODS: This population-based cohort study used data from the United Kingdom National Joint Registry. Patients undergoing first time RevKR between 1st January 2009 and 31 December 2019. Annual revision volumes for each surgeon were calculated and trends in surgeon volumes plotted as medians and bootstrapped 95% confidence intervals. Data before and after the report was compared. The rate of accrual of experience for new surgeons inclusive of both first-time revisions and re-revisions was calculated and adjusted for unit volume. RESULTS: A total of 21,067 patients were included. Over the whole study period, 123/1433 (8.58%) of surgeons achieved a mean annual volume of 15 or more revisions. Temporal trends in surgeon revision volumes observed an increase for non-acute indications. New surgeons in lower volume units have 42% lower chance of reaching 15 operations per year compared to those in the highest volume units (HR 0.52; 95% CI 0.33 to 0.83). CONCLUSIONS: We observed an increase in surgeon volumes following the report in first time non acute RevKRs. New RevKR surgeons were more likely to achieve and maintain revision volume targets in higher volume centres, this supports the drive for dual consultant operating and prospective revision knee consultants being appointed to highest volume units.

Risk of Myocarditis or Pericarditis with High-Dose versus Standard-Dose Influenza Vaccine: A Prespecified Analysis of the Randomized DANFLU-2 Trial

European Paediatric Orthopaedic Society consensus study to identify research priorities in paediatric orthopaedic surgery.

BACKGROUND: Paediatric orthopaedic surgery is rarely supported by high-quality evidence, with treatment decisions generally informed by experience or case series. The European Paediatric Orthopaedic Society recognises the need to establish research priorities in the field. This study builds on previous UK research priorities to discover the most important unanswered clinical effectiveness research questions in elective and trauma care and basic science, amongst Paediatric Orthopaedic surgeons across Europe. METHODS: A modified Delphi technique, including an initial scoping survey and a two-round Delphi process conducted amongst paediatric orthopaedic surgeons in Europe. RESULTS: An average of 113 surgeon responses were received in each round, scoring questions from 1 (low priority) to 5 (high priority). The mean score for importance was 3.59 in elective questions, 3.13 in trauma and 3.54 in basic science. The top questions in each group were identified. The top five research priorities for elective care related to the care of - Perthes Disease, Slipped Upper Femoral Epiphysis and Developmental Dysplasia of the Hip. Those in trauma related to the treatment of fractures around the elbow, forearm and femur Basic science priorities related to pharmaceuticals in the management of paediatric orthopaedic conditions and the pathology of Perthes' Disease and Developmental Dysplasia of the Hip. CONCLUSIONS: The results will help guide clinicians, researchers and funding bodies to focus research towards important topics and improve the evidence for practice in paediatric orthopaedic surgery. We hope that this study will encourage the development of collaborative international studies to improve care in paediatric orthopaedics. LEVEL OF EVIDENCE: Level V - decision analysis.

Longitudinal trajectories of polypharmacy in older people, and their association with the risk of mortality: a joint latent class model analysis of real-world data from the UK and the Netherlands.

OBJECTIVE: Polypharmacy is the use of multiple drugs. Many definitions have been established for polypharmacy, often cross-sectionally, despite it naturally changing over time. In this study, we aimed to identify clusters of older people with distinct polypharmacy trajectories over time and associated mortality risks. We then characterised the identified clusters and assessed their generalisability in two external databases. METHODS: Data were extracted from three primary care databases: the UK Clinical Practice Research Datalink (CPRD) GOLD, CPRD Aurum and the Dutch Integrated Primary Care Information (IPCI). People aged ≥65 on 1 January 2015 were included. Polypharmacy, defined as the cumulative number of prescribed ingredients, was calculated at baseline and at the end of each subsequent follow-up year (2015-19). We applied joint latent class modelling, which divides the population into clusters with different trajectories and associated mortality risks. The model was trained in GOLD and validated in Aurum and IPCI. RESULTS: Four clusters were identified and characterised based on polypharmacy baseline and rate of progression: low-steady, intermediate-slow/increasing, intermediate-fast/increasing and high-decreasing. The high-decreasing cluster had the highest average baseline polypharmacy (intercept = 23.4) and prevalence of non-cancer chronic comorbidities, whilst the intermediate-fast/increasing had the steepest polypharmacy rate of progression per year (slope = 6.4), highest baseline and cumulative incidence of cancer, and worst survival outcome. Good validation was found in Aurum and IPCI. CONCLUSION: High baseline levels and increasing levels of polypharmacy were associated with an increased mortality risk in older people. The clusters identified in this study were externally validated in two European databases, confirming their robustness and generalisability.

A Randomised Controlled Trial of Clarithromycin and Endoscopic Sinus Surgery for Adults with Chronic Rhinosinusitis with and without nasal polyps

Higher surgeon volume reduces early failure in first time revision of non-infected total knee arthroplasty: An analysis using data from the United Kingdom National Joint Registry.

PURPOSE: Revision total knee replacement (RevKR) is an increasingly common procedure. It is hypothesised that higher surgical volume is linked to lower levels of adverse outcomes. The aim was to estimate the association of surgical volume on patient outcomes following first single-stage RevKR for non-infected indications. METHODS: This population-based cohort study used data from the United Kingdom National Joint Registry, Hospital Episode Statistics and National Patient Reported Outcome Measures. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. The primary outcome measure was re-revision within 2 years; chosen to reflect the quality of the surgical provision. Fixed effect multivariable regression models were used to examine the association between surgeon and surgical unit annual caseload and the risk of adverse outcomes. RESULTS: A total of 8695 patients underwent first time single stage revision for aseptic loosening, instability, or malalignment across 389 surgical units and 1204 surgeons. Following adjustment for age, gender, ASA grade, year of surgery and operation funder, higher surgeon volume was associated with a lower risk of re-revision at 2 years. The risk of re-revision decreased amongst surgeons performing ≥9 annual revisions (OR 0.77, 95% CI 0.62-0.95, p-value = 0.02) compared to those performing <9 annual revisions. CONCLUSIONS: Annual surgeon case volume of ≥9 first single-stage RevKR for non-infected indications is independently associated with reductions in early re-revision. This evidence supports the setting of minimum volume targets to improve outcomes for patients. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.

Threaded rods versus arthrodesis nail as a static spacer for two-stage revision total knee arthroplasty.

INTRODUCTION: A spacer is required to maintain limb length and alignment and to provide a stable limb for mobilisation in two-stage revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI). Static spacers are indicated in cases of massive bone loss, compromised soft tissues, and ligamentous and/or extensor mechanism insufficiency. The aim of this study was to compare the use of Ilizarov rods to arthrodesis nails for static spacer constructs in first-stage rTKA for PJI. METHODS: This was a retrospective cohort study of 40 patients who underwent two-stage rTKA for PJI between 2019 and 2022. Static spacers were used in all cases, constructed from Ilizarov rods 20 patients and nails in 20 patients. Data collected included number of previous revisions, patient age at first revision, comorbidities and identified organisms. Groups were compared based on outcome measures including complications, reoperations, length of stay and re-revision rates. RESULTS: The use of Ilizarov rods showed higher rates of intraoperative complications (5% vs. 0%), readmissions (55% vs. 5%), and interstage re-operations (50% vs. 10%). Spacer-related complications occurred in 10 of 20 cases (50%) in the Ilizarov rod group, all due to spacer fractures, compared to none in the nail group (0%) (p 

Use of dual-energy X-ray absorptiometry to evaluate variation in bone shape and alignment associated with radiographic knee osteoarthritis: findings from a study of 19,053 individuals in UK Biobank

Recommended methodologies for clinical investigations of high-risk medical devices – Conclusions from the European Union CORE–MD Project

High-dose versus standard-dose inactivated influenza vaccine and cardiovascular risk: the DANFLU-2 trial