Queen Elizabeth Hospital

Medial knee osteoarthritis is increasingly diagnosed in younger adults who are often unsuitable for joint replacement. High tibial osteotomy corrects varus malalignment but is invasive. Gait retraining is a low-cost, non-surgical option to reduce medial tibiofemoral loading, but its effects in varus deformity are unclear. We quantified the immediate biomechanical effects of short-term gait modifications on internal tibiofemoral loading. Twenty-nine patients (30 knees) with medial knee osteoarthritis scheduled for high tibial osteotomy performed three modified gaits: toe out, wide base, and medial thrust. Motion capture and musculoskeletal modelling estimated internal tibiofemoral joint forces in this pre- high tibial osteotomy, varus-aligned cohort. Toe out increased medial loading in early stance but reduced it in late stance. Wide base increased medial and lateral forces early, then reduced medial loading later with compensatory lateral increases. Medial thrust was difficult: only 20/30 knees achieved the target reduction in maximum knee adduction angle, and successful trials still increased early-stance loading. Overall effects were modest, phase-specific, and inconsistent. Generic gait modifications produced small, phase-dependent changes in internal tibiofemoral loading, with early-stance increases, late-stance reductions, and occasional compensatory lateral loading. Longer-term, individualised retraining incorporating symptoms is needed to determine net clinical benefit.

Idiopathic sudden sensorineural hearing loss (ISSNHL) is an otologic emergency for which hyperbaric oxygen therapy (HBOT) is a potential treatment. This study aimed to evaluate the effectiveness of HBOT in treating ISSNHL, with a focus on the timing of treatment and its impact on hearing outcomes, while also considering other factors such as demographic characteristics, clinical parameters, and treatment methods. This retrospective cohort study analysed 70 ISSNHL patients (April 2019 to August 2024) who received steroid treatment (oral, intratympanic or both). Patients were divided into early HBOT (< 12 days), late HBOT (13-22 days), salvage HBOT (> 22 days), and no HBOT groups. Hearing improvement, measured by pure-tone audiometry (PTA), defined the treatment outcome. Significant PTA improvements were observed in most groups (median changes: early HBOT 33.8 dB [n = 15], late HBOT 6.9 dB [n = 16], salvage HBOT 0.0 dB [n = 5], no HBOT 11.9 dB [n = 34]), with early HBOT showing greater gains than late HBOT (P < 0.001), salvage HBOT (P = 0.001), and no HBOT (P = 0.002). Receiver operating characteristic (ROC) analysis indicated that treatment within 10.5 days predicted marked improvement (AUC = 0.883, P < 0.001), and linear regression showed that each day's delay reduced PTA improvement by 0.832 dB (P < 0.001). HBOT is effective in restoring hearing in patients suffering from ISSNHL and early treatment is associated with better outcome.

Faecal microbiota transplantation (FMT) is the standard-of-care for recurrent or refractory Clostridioides difficile infection (CDI) [1]. Numerous variables impact the effectiveness of FMT, including donor, recipient, processing and administration factors. With the expanding use of FMT, it is important to determine the optimal treatment regimen to improve outcomes for patients with CDI and beyond. Paaske et al. carried out an eloquent multi-centre quality-improvement process, aimed at increasing CDI cure rates for patients undergoing FMT [2]. They implemented a number of interventions to enhance the effectiveness of FMT, showing that dose and donor matter. In this real-world study, eight-week cure rates of CDI-associated diarrhoea (CDAD) were increased across seven centres from 50% (95% confidence interval [CI] 45%–56%) to 59% (55%–63%), after the exclusion of three low-performing donors. Two donors had previous cure rates of less than 35%, and the third was observed to have a sudden decrease in effectiveness. Whilst the concept of an FMT super-donor has gained traction in inflammatory bowel disease, its relevance in CDI remains unclear, owing to consistently high cure rates [3]. The current data highlight the need for improved FMT regimens, with real-world efficacy lower than that reported in clinical trials [2, 4]. However, donor factors are not clearly elucidated in this study; rather donor performance is measured on prior outcomes. Donor factors previously associated with reduced efficacy include antibiotics within 3–12 months of donation, and donations with a Bristol Stool Form Scale of ≤ 3 [5]. Donor sex, BMI, smoking status, H. pylori status, birth-mode and donation-weight have not been found to influence the effectiveness of FMT in CDI. Selection of a super-donor has been trialled in one small pilot study in CDI, in which a single donor was selected from nine healthy candidates based on balanced Bacteroidetes/Firmicutes ratio, high stool butyrate concentration, and high alpha-diversity and phylogenetic-diversity [6]. CDI cure at week 10 was achieved in 10/10 patients with recurrent CDI, demonstrating that donor selection is feasible and may offer increased efficacy. Paaske et al. further increased their CDAD cure rates from 59% (55%–63%) to 72% (65%–77%) by implementing an optimised dosing regimen of two-dose capsule FMT [2]. Repeated FMT has been shown to increase clinical effect at week eight compared to single-dose FMT (91% vs. 84%), although it remains unclear which patients would benefit most from repeated doses [4]. In a separate cohort, Paaske and colleagues implemented a three-dose capsule regimen in high-risk patients, including those with fulminant CDI, patients expected to receive antibiotics in the week following FMT, and those aged 65 years or older with severe or antibiotic-refractory CDI [2]. This change did not result in increased overall efficacy (70% [60%–78%] vs. 67% [57%–76%]). FMT is highly effective in the treatment of CDI, but real-world cure rates lag behind those of well-designed clinical trials. Ongoing development of optimal donor, recipient and administration protocols is needed. Repeated dosing increases the efficacy of FMT in CDI, and emerging evidence supports donor selection in this population. To advance the field, we must now define microbial factors associated with efficacy. Perhaps the future is a rationally designed microbial therapeutic, with a defined and reproducible mechanism of action. D. Bogatic: conceptualization, writing – original draft, writing – review and editing. S. P. Costello: conceptualization, writing – original draft, writing – review and editing. R. V. Bryant: conceptualization, writing – original draft, writing – review and editing. The authors have nothing to report. D. Bogatic has received research support from The Gutsy Group and BiomeBank. S.P. Costello is a shareholder of BiomeBank. R.V. Bryant has received grant/research support/speaker honoraria/advisory board fees from AbbVie, Ferring, Janssen, Shire, Takeda, GlaxoSmithKline, Bristol Myers Squibb, and Emerge Health; and is a shareholder in BiomeBank. This article is linked to Paaske et al paper. To view this article, visit https://doi.org/10.1111/apt.70395. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Knee osteoarthritis (OA) is disabling, with few effective treatments. Anti-inflammatory treatments may be effective for patients with an inflammatory phenotype. To evaluate the efficacy of the interleukin-1β blocker diacerein, compared with placebo, on knee pain in people with knee OA who have substantial knee pain and inflammation (effusion-synovitis on magnetic resonance imaging). This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in 4 Australian centers. Participants with clinical knee OA, substantial knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from June 2019 to September 2022. Final follow-up occurred on February 6, 2023. Data analysis began on July 7, 2023. Participants were randomized (1:1) to diacerein, 50 mg, once daily or identical placebo for the first 2 weeks, which increased to 50 mg, twice daily until 24 weeks if adverse effects were tolerable. The primary outcome was change in knee pain as assessed by the visual analogue scale (range, 0-100 mm; minimal clinically important improvement, 15) over 24 weeks. Of 262 participants randomized (mean [SD] age, 54.9 [6.1] years; 147 [56.1%] female and 115 [43.9%] male), 231 (88.2%) completed the trial. Compared with placebo, diacerein did not improve knee pain over 24 weeks (-19.9 mm [diacerein] vs -18.6 mm [placebo]; between-group mean difference, -1.3 mm; 95% CI, -9.8 to 7.3). The most common adverse events were gastrointestinal symptoms, which occurred in 55 participants (41.7%) in the diacerein group and 33 (25.4%) in the placebo group, most commonly diarrhea (51 [38.6%] in the diacerein group vs 29 [22.3%] in the placebo group). Change in urine color was observed among 13 participants (9.8%) who received diacerein. This randomized clinical trial found that, in patients with symptomatic knee OA and effusion-synovitis, diacerein (50 mg, twice daily) over 24 weeks resulted in no greater improvement in knee pain compared with placebo. These findings do not support diacerein for treating knee pain in this population. Australian New Zealand Clinical Trials Registry: ACTRN12618001656224.

Recent years have seen an emergence of collaborative primary care models in the English National Health Service and other international health systems. Primary Care Networks (PCNs) were introduced in England in July 2019, marking the first time collaboration between general practices was incentivised through a nationwide policy. While participation was not mandatory, nearly all general practices joined a PCN, largely due to strong financial incentives. Our study aim was to estimate the impact of PCNs on emergency hospitalisations using an interrupted time series design. Quarterly data between October 2016 and March 2023 from the North West London Whole Systems Integrated Care dataset was used to construct two primary outcomes: all-cause and ambulatory care sensitive conditions (ACSC) emergency hospitalisations, as well as Accident and Emergency attendances, considered as a secondary outcome. Furthermore, we analysed whether the impact of PCNs varied based on practice characteristics. A reduction in all-cause and ACSC hospitalisations was observed following the PCNs' introduction, until the start of the COVID-19 pandemic. The analysis also revealed a smaller reduction in ACSC hospitalisations among practices with more deprived patient populations and larger populations of patients with long-term conditions. While PCNs' implementation appears to have led to a reduction in emergency hospitalisations in North West London, this effect was only observed in the very short term as it stopped with the COVID-19 pandemic. Future studies should examine the effect across England and evaluate their continued impact.

Bloodstream infections in older persons are associated with greater morbidity and mortality. Older individuals often present with atypical symptoms, such as lethargy, poor oral intake, or falls, rather than classical signs like fever or localized symptoms. This study aims to evaluate the clinical characteristics of older persons admitted with bacteraemia and identify predictors of in-hospital mortality. A retrospective observational cohort study was conducted at a tertiary hospital. Patients admitted to the geriatric ward with bacteraemia over a 1.5-year study period were included in the study. Demographic, clinical, and laboratory data were collected and analyzed to identify independent predictors for in-hospital mortality. A total of 185 older patients were included in this study. Presentations were frequently non-specific, with 33.5% of the patients not fulfilling Systemic Inflammatory Response Syndrome (SIRS) criteria on admission. Advanced age (≥ 76 years old), hypalbuminaemia (< 20 g/L), elevated lactate (> 2 mmol/L), delirium, and absence of SIRS criteria were independently associated with increased in-hospital mortality of the older patients with bacteraemia. Due to immunosenescence and age-related physiological changes, older persons often present atypically and may have normal vital signs or laboratory values despite severe infection. Clinicians should maintain a high index of suspicion for sepsis in older patients, even in the absence of classical symptoms, to enable timely diagnosis and management.

Abstract NRAS mutations drive 20–30% of melanomas and are associated with poor response to immunotherapies. RAS(ON) inhibitors such as daraxonrasib (RMC-6236) have shown promising activity in NRAS-mutant melanoma, yet mutation-specific sensitivity, resistance mechanisms, and rational combination strategies remain largely unresolved. Here, we performed saturation mutagenesis across NRAS mutation hotspots to systematically evaluate mutation-resolved oncogenic fitness and drug responsiveness to six direct RAS inhibitors (sotorasib, adagrasib, ADT-007, BI-2865, RMC-6236, and RMC-7977) using isogenic melanoma spheroids, xenografts, and pooled drug-sensitivity profiling. RMC-6236 and RMC-7977 displayed the broadest activity, sensitizing ∼80% of recurrent NRAS mutations across the P-loop and Switch II regions. Several clinically observed mutations, including Q61P, G13D/V/R, and G60E, showed reduced susceptibility to RAS(ON) inhibition. Structural modelling and thermostability analysis indicated impaired inhibitor engagement or reduced tricomplex stability as potential mechanisms of resistance. RAS(ON) blockade also induced STAT3 activation, particularly in oncogenic Q61 mutants. Co-targeting STAT3 with napabucasin or siRNA enhanced apoptosis, suppressed MYC, and improved tumour control in vitro and in vivo. Together, this study provides the first comprehensive mutation-resolved sensitivity atlas for NRAS-mutant melanoma, highlights structural mechanisms underlying resistance to RAS(ON) inhibitors, and identifies STAT3 inhibition as a rational combination strategy. These findings offer preclinical evidence supporting mutation-guided patient stratification and combination-therapy development for NRAS-mutated melanoma. Statement of Translational Significance NRAS-mutated melanoma lacks effective targeted treatments, and clinical responses to immunotherapy remain suboptimal. This study presents the first comprehensive drug sensitivity map across 95 NRAS mutations in melanoma, identifying the pan-RAS(ON) inhibitors RMC-6236 and RMC-7977 as broadly effective agents. Multiple mutants with reduced susceptibility are identified, providing mutation-specific guidance for patient selection and clinical trial stratification. Mechanistic analyses reveal that STAT3 activation functions as a key survival pathway under RAS(ON) blockade, and its inhibition markedly enhances the efficacy of pan-RAS(ON) inhibitors. These findings support mutation-guided utilization of RAS(ON) inhibition and highlight STAT3 co-targeting as a rational strategy to strengthen and prolong therapeutic responses in NRAS-mutant melanoma. Highlights - Generation of mutation-resolved functional and drug-sensitivity atlas for 95 NRAS missense variants covering &gt;99% of all NRAS recurrent mutation - RMC-6236 and RMC-7977 shows broad and potent activity across major NRAS hotspot mutations - Defines NRAS mutations with reduced susceptibility to provide actionable information for clinical trial stratification - RAS(ON) inhibition and napabucasin shows synergistic anti-tumor activity in NRAS-mutated melanoma