Nuffield Orthopaedic Centre

To evaluate the validity of the 3-item visual analog scale (3VAS) and 4-item VAS (4VAS) and determine the minimal clinically important difference (MCID) and minimal detectable change (MDC) for each measure using data from 3 phase III randomized clinical trials of guselkumab in psoriatic arthritis (PsA). Pooled data (1405 participants) from the DISCOVER-1, DISCOVER-2, and COSMOS studies were used. 3VAS/4VAS MCID and MDC were estimated using established formulas. Receiver-operating characteristic curve analysis was used to identify 3VAS/4VAS thresholds for low, moderate, and high disease activity. Criterion validity was assessed by correlating 3VAS/4VAS with other PsA measures. Mixed models evaluated the association between changes from baseline in 3VAS/4VAS at week 8 of guselkumab treatment with the total PsA-modified Sharp-van der Heijde (SvdH) score through week 100. 3VAS/4VAS showed moderate-to-strong correlation with all outcome measures assessed, with coefficients ranging from 0.56/0.62 for Health Assessment Questionnaire-Disability Index to 0.92/0.94 for patient global assessment. MCID was 0.9 for both 3VAS (range 0.7-1.3 depending on method used) and 4VAS (0.6-1.3); MDC was 3.1 and 3.0, respectively. 3VAS cutoffs for low, moderate, and high disease activity were 2.1, 3.3, and 4.8, respectively, and 2.1, 3.4, and 5.0 for 4VAS. Change in 4VAS at week 8 of guselkumab treatment significantly associated with change in SvdH score through week 100 (P = 0.04). These analyses support the validity of 3VAS/4VAS as multidimensional measures of PsA disease activity. 4VAS may be preferred owing to its greater face validity and separate measurements of the 2 cardinal aspects of PsA (joint/skin disease) and pain.

Blood transfusion is one of the most common interventions in hospitals. Blood tests that support this widespread practice are considered routine, such as 'group and save' (also known as 'type and screen'), yet there has been very limited evaluation of the needs for these tests and the associated costs. The aim of this systematic review is to synthesise international evidence on the costs of group and save and crossmatch tests and their component processes. Seventy-two studies published between 2012 and 2023 were identified and data were extracted. Most cost estimates were derived from local institutional sources with few using national reference data, and reporting methods varied widely. Median unit costs for group and save tests were £19.8 (interquartile range [IQR] £11.8-£52.5) overall, £13.8 in the United Kingdom and £57.4 in the United States. Crossmatch costs were £9.6 (IQR £5.9-£37.3). Understanding costs for group and save testing will inform hospital teams making decisions about sample requirements for procedures with a low likelihood of transfusion. It also provides benchmarking to assess the impact of implementing electronic systems to improve safety and efficiency of transfusion practice.

Musculoskeletal (MSK) injuries pose a significant health burden across sub-Saharan Africa (SSA). Despite this, regional research output is limited, constrained by insufficient infrastructure, limited funding, and underdeveloped research capacity. This bibliometric analysis examined research outputs and collaboration patterns in MSK injury research across three SSA countries, representing a spectrum of income levels: low, lower-middle, and upper-middle income. MSK injury research articles from Malawi (MLW), South Africa (SA), and Tanzania (TZN), published between January 2014 and April 2024, were identified using Web of Science and Scopus databases, and cross-referenced with ResearchGate. Data were analyzed descriptively in Excel, and institutional coauthorship and collaboration networks were mapped using VOSviewer. A total of 329 articles were published across MLW (n = 98), SA (n = 141), and TZN (n = 90) between January 2014 and April 2024. We report a steady increase in the number of publications from 2014, with a research focus on fracture management, outcomes, and lower limb injuries. Most of the research was published in partnership with high-income countries (HICs) (SA: 51%, MLW: 98%, TZN: 87%), with high-income country (HIC) institutions dominating first and last authorship in MLW (68% and 61%) and TZN (59% and 69%) publications. Most studies were descriptive and based on secondary records. Institutional networks showed strong regional collaboration in SA, international focus in MLW, and limited connectivity in TZN. MSK injury research is increasing across MLW, SA, and TZN, but remains largely HIC-led and descriptive, particularly in lower-income countries. Strengthening local leadership, regional collaboration, and research capacity is essential for more sustainable and context-specific evidence generation.

Abstract Aims Free tissue transfer is a common plastic surgical procedure with a wide array of applications. There is limited consensus on how free flap ischaemia time impacts flap survival. This systematic review aims to evaluate the association between free flap ischaemia time and acute flap failure rate. Methods A systematic review and meta-analysis in compliance with PRISMA statement standards was conducted following registration on the PROSPERO Register (CRD420251052841). A search strategy was developed and the search conducted in September 2024. Studies eligible for inclusion reported length of ischaemia time for free flap surgery and acute flap failure rate. 78 articles were eligible for inclusion and were published between 1997 and 2024. Study populations ranged from 7 to 3926 patients, with a pooled total of 26 374 free flaps in 23 615 patients. The meta-analysis showed overall risk of flap failure was 3.5% (95% c.i. 3%–4.1%). Meta-regression using ischaemia time as a continuous variable showed an increasing risk of acute flap failure from 3% (2.3%–3.9%) at 30 min ischaemia time to 7.5% (4.4%–12.5%) at 240 min. The variables study type, flap type, indication and risk of bias did not account for between study heterogeneity which was substantial. Conclusions This study has systematically assessed existing literature to show a significant association between prolonged ischaemia time and acute free flap loss. This association can guide microsurgical training as carrying out microsurgery in a time efficient manner has a positive impact on free flap survival.

Summary Background Rifampicin-resistant tuberculosis (RR-TB) is a major threat to public health in Viet Nam, with nearly 10,000 incident cases estimated annually. It is uncertain whether these cases are driven by transmission of resistant strains or de novo resistance acquisition during treatment. Methods We undertook dense, city-wide sampling of adults newly diagnosed with pulmonary RR-TB in Ho Chi Minh City, Viet Nam’s largest city, between March 2020 and April 2024. Participants provided sputum for culture and whole-genome sequencing (WGS), and demographic and clinical data were collected at enrolment. Phylogenetic analyses were combined with clinical histories to infer transmitted versus acquired rifampicin resistance. Estimates were corrected for sampling coverage using simulation-extrapolation (SIMEX). Temporal emergence of rifampicin resistance was reconstructed by lineage using Bayesian phylogenetic dating, and the geographic and demographic structure of transmission networks was assessed using geocoded residential data and commute time-based analyses. Findings Among 2,319 RR-TB cases diagnosed during the study period, 1,491 (64%) isolates were successfully sequenced. After accounting for sampling and phylogenetic uncertainty, we estimated that between 72% and 87% of all RR-TB arose through transmission of already-resistant strains with the remainder due to de novo acquired resistance. Bayesian dating analyses revealed that resistance emergence events occurred repeatedly from the 1980s to the present, with early events seeding long-lived, city-wide transmission networks. Transmission networks were geographically dispersed across the city, with limited household clustering, and only weakly structured by host demographics, consistent with diffuse, city-wide transmission rather than localised or assortative spread. Interpretation RR-TB in Ho Chi Minh City is driven predominantly by ongoing transmission, but a substantial minority of cases arise from newly acquired resistance. Alongside promoting early diagnosis and treatment to interrupt transmission, the main drivers of acquired resistance need to be identified to control RR-TB. Funding The Rhodes Trust, Wellcome. Research in context Evidence before this study We searched PubMed from database inception up to November 2025 for studies describing the transmission and acquisition of multidrug /rifampicin-resistant tuberculosis (MDR/RR-TB), using terms including “tuberculosis”, “rifampicin resistance”, “multidrug resistance”, “genomic epidemiology”, “whole-genome sequencing”, “transmission” and “acquired resistance”. We additionally added terms “Ho Chi Minh City” and “Viet Nam” to identify results specific our study setting. Previous studies from high burden settings typically reported that MDR/RR-TB isolates clustered with high proportions, suggesting transmission is the major contributor to MDR/RR-TB burden. However, estimates varied widely across settings, study designs and analytic approaches. Many studies relied on SNP-based clustering thresholds and did not account for incomplete sampling. Few studies integrated treatment history and homoplasy-aware phylogenetic inference or accounted for uncertainty in their estimates of the population-level contribution of de novo rifampicin resistance acquisition. No studies from Viet Nam addressed this question and the extent to which transmitted and acquired resistance contribute to the burden of MDR/RR-TB remains unknown. Added value of this study We combined dense, city-wide sampling of RR-TB in a high-burden metropolitan setting with whole-genome sequencing, historic genomic context and phylogenetic analyses to quantify the contributions of transmission and de novo acquisition to MDR/RR-TB burden. By integrating phylogenetic placement of resistance mutations with individual treatment history, we provide robust population-level estimates of transmission and independent resistance emergence while explicitly accounting for phylogenetic and sampling uncertainty. Acknowledging the potential effect of sampling coverage on these estimates, we further provide estimates extrapolated to complete coverage using a simulation-extrapolation framework. We show that the majority of RR-TB in Ho Chi Minh City is attributable to transmission, but that a substantial minority of cases reflect de novo acquisition of rifampicin resistance. Our findings demonstrate that de novo resistance acquisition continues to occur notwithstanding improvements in programmatic TB control, treatment success rates, and diagnostic capacity. Implications of all of the available evidence Our findings emphasise that MDR/RR-TB in Ho Chi Minh City is overwhelmingly driven by transmission and that controlling it requires a transmission-focused response. Intensified efforts to interrupt transmission through earlier case detection and rapid treatment initiation should be programmatic priorities. Concurrently, further investigation into the precise drivers of acquired drug resistance, which represents a potentially preventable fraction of the RR-TB burden, remains warranted

Reprogrammed lipid metabolism with massive upregulation of tumor cell-autonomous synthesis of saturated fatty acids is a hallmark of prostate cancer (PCa) and is driven in part by aberrations in androgen receptor (AR) signaling. While lipid alterations are well described in primary PCa, the extent to which the circulating lipidome reflects tumor-associated metabolic changes in metastatic disease, and its role in therapy response, remains to be determined. This study aims to assess whether plasma lipid profiling captures tumor metabolic rewiring, and whether this reflects response to AR-targeting therapy, in metastatic castration-resistant PCa (mCRPC). Quantitative plasma lipidomics was performed on plasma samples collected from patients with mCRPC (n = 50) and cancer-free subjects (C-FS, n = 14). Samples from patients with mCRPC were collected longitudinally at the time of progression on androgen deprivation therapy prior to initiation of first-line enzalutamide (Enza), after the start of treatment with Enza, before progression on Enza. Compared to C-FS, patients with mCRPC showed distinct lipidomic signatures, characterized by increased levels of monounsaturated lipids and altered composition of the phospholipid and sphingolipid pool, mimicking the aberrations known to occur in primary PCa tissue. Enza treatment markedly reduced total lipid levels, decreased major phospholipid classes and ceramides, while increasing sphingomyelins. Notably, quantitative differences in specific sphingolipid species occurring after Enza treatment correlated with survival outcomes. Plasma lipidomics reflects key metabolic features of PCa and is profoundly impacted by AR inhibition, with prognostic relevance in patients with mCRPC. These findings support its potential as a non-invasive tool for monitoring disease activity and treatment response, and lay the groundwork for lipid-based biomarkers in mCRPC, while indicating that the lipidomic alterations observed may help inform ongoing and forthcoming research on metabolic targeting.

Abstract A definitive correlate of protection (CoP) for SARS-CoV-2 has yet to be formally established. Previously, using data from a series of non-human primate vaccine challenge studies, we reported that neutralising antibodies (NAbs) are the strongest candidate for clinical protection against COVID-19 and that spike binding antibody is the strongest candidate CoP for viral burden post-challenge. In this study, we further characterised the protective binding antibody profile by analysing spike antibody-dependent complement deposition, FcγR binding, isotype and antibody glycosylation. Using the machine learning platform SIMON, we demonstrate that antibody-dependent complement deposition (ADCD) and FcγR binding are strong candidate co-correlates for each of the post-challenge outcomes; viral load and lung pathology. We found that spike antibody sialylation closely followed by FcγR2A, was the spike antibody feature with the strongest negative correlation with histopathology score. Spike antibody ADCD, FcγR binding, isotype and glycosylation significantly differed by immunisation regimen and sex, which demonstrates the heterogeneity of immune mechanisms induced by different immunisation platforms. We conclude that spike binding antibody, with the protective functional characteristics described herein, is a candidate CoP that captures both protection from severe clinical disease and protection against a high viral burden. These findings should be taken into consideration for future SARS-CoV-2 vaccine development.

Cubital tunnel syndrome is the second most prevalent upper limb compression neuropathy. Limitations in non-operative and surgical treatment warrant an adjunctive preventative approach targeting modifiable risk factors. However, risk factors are poorly characterized given methodologic shortcomings in previous studies. In this case-control study in the UK Biobank (1971 cases, 398,639 controls), multivariable logistic regression with extensive covariate correction was conducted to assess the association between cubital tunnel syndrome and sex, age, ethnicity, socioeconomic deprivation, smoking status, alcohol intake, height, body mass index, plasma lipids, HbA1c, diabetes, hypertension, carpal tunnel syndrome, osteoarthritis, rheumatoid arthritis, hypothyroidism and gastroesophageal reflux disease. Cubital tunnel syndrome was significantly associated with several modifiable risk factors: smoking status (odds ratio 2.08, 95% CI: 1.83-2.37), diabetes with microvascular complications (OR 1.80, 95% CI: 1.40-2.30), hypertension (OR 1.37, 95% CI: 1.24-1.52) and raised body mass index (OR 1.13, 95% CI: 1.08-1.19). Male sex (OR 1.77, 95% CI: 1.54-2.04) and age (OR 0.981, 95% CI: 0.975-0.986) were non-modifiable risk factors. Several comorbidities were associated with cubital tunnel syndrome: carpal tunnel syndrome (OR 11.7, 95% CI: 10.6-12.9), osteoarthritis (OR 2.12, 95% CI: 1.92-2.34), rheumatoid arthritis (OR 1.72, 95% CI: 1.42-2.07), and gastroesophageal reflux disease (OR 1.66, 95% CI: 1.50-1.83). Cubital tunnel syndrome had a weak association with socioeconomic deprivation and no association with ethnicity, height, alcohol intake, plasma lipids, HbA1c and hypothyroidism. Cubital tunnel syndrome is robustly associated with several modifiable risk factors that may be targeted in primary and secondary prevention. III.