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The inaugural Doug Altman scholarship will be offered to an LMIC (lower-to-middle-income country) applicant or a student.
Research prioritization in paediatric orthopaedics and the impact on funding
In 2017, the British Society for Children’s Orthopaedic Surgery engaged the profession and all relevant stakeholders in two formal research prioritization processes. In this editorial, we describe the impact of this prioritization on funding, and how research in children’s orthopaedics, which was until very recently a largely unfunded and under-investigated area, is now flourishing. Establishing research priorities was a crucial step in this process.Cite this article: Bone Joint J 2024;106-B(5):422–424.
Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL
Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
Reverse total shoulder replacement versus anatomical total shoulder replacement for osteoarthritis: population based cohort study using data from the National Joint Registry and Hospital Episode Statistics for England.
OBJECTIVES: To answer a national research priority by comparing the risk-benefit and costs associated with reverse total shoulder replacement (RTSR) and anatomical total shoulder replacement (TSR) in patients having elective primary shoulder replacement for osteoarthritis. DESIGN: Population based cohort study using data from the National Joint Registry and Hospital Episode Statistics for England. SETTING: Public hospitals and publicly funded procedures at private hospitals in England, 2012-20. PARTICIPANTS: Adults aged 60 years or older who underwent RTSR or TSR for osteoarthritis with intact rotator cuff tendons. Patients were identified from the National Joint Registry and linked to NHS Hospital Episode Statistics and civil registration mortality data. Propensity score matching and inverse probability of treatment weighting were used to balance the study groups. MAIN OUTCOME MEASURES: The main outcome measure was revision surgery. Secondary outcome measures included serious adverse events within 90 days, reoperations within 12 months, prolonged hospital stay (more than three nights), change in Oxford Shoulder Score (preoperative to six month postoperative), and lifetime costs to the healthcare service. RESULTS: The propensity score matched population comprised 7124 RTSR or TSR procedures (126 were revised), and the inverse probability of treatment weighted population comprised 12 968 procedures (294 were revised) with a maximum follow-up of 8.75 years. RTSR had a reduced hazard ratio of revision in the first three years (hazard ratio local minimum 0.33, 95% confidence interval 0.18 to 0.59) with no clinically important difference in revision-free restricted mean survival time, and a reduced relative risk of reoperations at 12 months (odds ratio 0.45, 95% confidence interval 0.25 to 0.83) with an absolute risk difference of -0.51% (95% confidence interval -0.89 to -0.13). Serious adverse events and prolonged hospital stay risks, change in Oxford Shoulder Score, and modelled mean lifetime costs were similar. Outcomes remained consistent after weighting. CONCLUSIONS: This study's findings provide reassurance that RTSR is an acceptable alternative to TSR for patients aged 60 years or older with osteoarthritis and intact rotator cuff tendons. Despite a significant difference in the risk profiles of revision surgery over time, no statistically significant and clinically important differences between RTSR and TSR were found in terms of long term revision surgery, serious adverse events, reoperations, prolonged hospital stay, or lifetime healthcare costs.
Microporous titanium and hydroxyapatite improve fixation of the tibial wall in unicompartmental knee replacement.
PURPOSE: Cementless Oxford unicompartmental knee replacement (OUKR) is associated with less pain than cemented OUKR 5 years postoperatively. This may be due to improved fixation at the tibial wall, which transmits tension and reduces stress in the bone below the tibial component. This study compares tibial wall fixation with three different types of fixation: cemented, cementless with hydroxyapatite (HA) and cementless with a microporous titanium coat and HA (HA + MPC). METHODS: Three consecutive cohorts were identified (n = 221 cemented in 2005-2007, n = 118 HA in 2014-2015, n = 125 HA + MPC in 2016-2017). Analysis was performed on anterior-posterior radiographs aligned on the tibial component taken 1-2 years postoperatively. Aligned radiographs are needed to see narrow radiolucencies adjacent to the wall. Alignment was assessed with rotation ratio (RR = wall width/internal wall height). Perfect RR is 0.3, and a maximum threshold of 0.5 was used. Quality of fixation to the wall was assessed with fixation ratio (FR = bone wall contact height/total wall height). Notable radiographic features at the tibial wall were also recorded. RESULTS: A total of 33 knees with cement, 37 knees with cementless with HA and 57 knees cementless with HA + MPC had adequately aligned radiographs. Fixation was significantly better with HA compared with cement (55% vs. 25%, p = 0.0016). The microporous coat further improved fixation (81% vs. 55%, p 80% was achieved in 3% of the cemented implants, 32% of HA and 68% of HA + MPC. In cementless cohorts, features suggestive of a layer of bone that had delaminated from the wall were seen in 8 (22%) HA and 3 (5%) HA + MPC knees. CONCLUSION: Radiographic tibial wall fixation in OUKR is poor with cement. It improves with an HA coating and improves further with an intermediary MPC. Improved tibial wall fixation may explain the lower levels of pain observed with cementless rather than cemented fixation described in the literature, but further clinical correlation is needed. LEVEL OF EVIDENCE: Level III, retrospective cohort study.
Polyethylene bearing wear is comparable for cemented and cementless Oxford unicompartmental knee replacements: Ten-year results of a randomized controlled trial.
PURPOSE: There is concern that using cementless components may increase polyethylene wear of the Oxford unicompartmental knee replacement (OUKR). Therefore, this study aimed to measure bearing wear at 10 years in patients from a randomized trial comparing Phase 3 cemented and cementless OUKRs and to investigate factors that may affect wear. It was hypothesized that there would be no difference in wear rate between cemented and cementless OUKRs. METHODS: Bearing thickness was determined using radiostereometric analysis at postoperative, 3-month, 6-month, 1-year, 2-year, 5-year and 10-year timepoints. As creep occurs early, wear rate was calculated using linear regression between 6 months and 10 years for 39 knees (20 cemented, 19 cementless). Associations between wear and implant, surgical and patient factors were analysed. RESULTS: The linear wear rate of the Phase 3 OUKR was 0.06 mm/year with no significant difference (p = 0.18) between cemented (0.054 mm/year) and cementless (0.063 mm/year) implants. Age, Oxford Knee Score, component size and bearing thickness had no correlation with wear. A body mass index ≥ 30 was associated with a significantly lower wear rate (p = 0.007) as was having ≥80% femoral component contact area on the bearing (p = 0.003). Bearings positioned ≥1.5 mm from the tibial wall had a significantly higher wear rate (p = 0.002). CONCLUSIONS: At 10 years, the Phase 3 OUKR linear wear rate is low and not associated with the fixation method. To minimize the risk of wear-related bearing fracture in the very long-term surgeons should consider using 4 mm bearings in very young active patients and ensure that components are appropriately positioned, which is facilitated by the current instrumentation. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
hadge: a comprehensive pipeline for donor deconvolution in single-cell studies.
Single-cell multiplexing techniques (cell hashing and genetic multiplexing) combine multiple samples, optimizing sample processing and reducing costs. Cell hashing conjugates antibody-tags or chemical-oligonucleotides to cell membranes, while genetic multiplexing allows to mix genetically diverse samples and relies on aggregation of RNA reads at known genomic coordinates. We develop hadge (hashing deconvolution combined with genotype information), a Nextflow pipeline that combines 12 methods to perform both hashing- and genotype-based deconvolution. We propose a joint deconvolution strategy combining best-performing methods and demonstrate how this approach leads to the recovery of previously discarded cells in a nuclei hashing of fresh-frozen brain tissue.
Bone erosions and joint damage caused by chikungunya virus: a systematic review.
BACKGROUND: Chikungunya fever is an emerging global infection transmitted by Aedes mosquitoes that manifests as an acute febrile illness with joint pain and can lead to chronic arthritis. The mechanism underlying chronic joint damage remains unclear; however, chronic chikungunya arthritis shares similarities with rheumatoid arthritis. Disease-modifying antirheumatic drugs have revolutionized rheumatoid arthritis treatment by preventing joint damage. However, the role of these therapies in chronic chikungunya arthritis has not been determined. We conducted a systematic review to evaluate the burden of joint structural damage in chronic chikungunya arthritis to help to define the role of disease-modifying therapy in this disease. METHODS: This systematic review included retrospective and prospective studies, trials, and case reports evaluating joint damage caused by chikungunya virus. Various databases were searched without any date or language restrictions. Study selection was conducted independently by two researchers, and data were extracted from the articles selected. RESULTS: A total of 108 studies were initially evaluated, with 8 meeting the inclusion criteria. Longitudinal studies have reported persistent joint pain from chikungunya infection and the progression of radiographic joint damage up to 13 years post-infection. Joint imaging revealed synovial inflammation, bone erosion, and cartilage destruction in patients with chronic chikungunya arthritis. CONCLUSIONS: Few studies have addressed chikungunya-induced joint damage, limiting our understanding of chronic chikungunya arthritis. Nevertheless, chronic chikungunya arthritis has similarities to rheumatoid arthritis. The success of early disease-modifying antirheumatic drug therapy in rheumatoid arthritis underscores the need for comprehensive research on its role in chikungunya arthritis.
The burden of schizophrenia in the Middle East and North Africa region, 1990-2019.
Schizophrenia ranks as the third-most common cause of disability among mental disorders globally. This study presents findings on the prevalence, incidence and years lived with disability (YLDs) as a result of schizophrenia in the Middle East and North Africa (MENA), stratified by age, sex and sociodemographic index (SDI). We collected publicly accessible data from the Global Burden of Disease (GBD) study 2019. This study reports the burden of schizophrenia, from 1990 to 2019, for the 21 countries that comprise MENA. In 2019, MENA exhibited an age-standardised point prevalence of 248.2, an incidence rate of 14.7 and an YLD rate of 158.7 per 100,000, which have not changed substantially between 1990 and 2019. In 2019, the age-standardised YLD rate was highest in Qatar and lowest in Afghanistan. No MENA countries demonstrated noteworthy changes in the burden of schizophrenia from 1990 to 2019. Furthermore, in 2019, the highest number of prevalent cases and the point prevalence were observed among those aged 35-39, with a higher prevalence among males in almost all age categories. Additionally, in 2019, the age-standardised YLD rates in MENA were below the worldwide average. Finally, there was a positive correlation between the burden of schizophrenia and the SDI from 1990 to 2019. The disease burden of schizophrenia has remained relatively stable over the past thirty years. Nevertheless, as the regional life-expectancy continues to increase, the burden of schizophrenia is also expected to rise. Therefore, early planning for the increase in the burden of the disease is urgently needed in the region.
Global prevalence of psychiatric in- and out-patient treatment following hospital-presenting self-harm: a systematic review and meta-analysis.
BACKGROUND: Hospital-treated self-harm is common, costly, and strongly associated with suicide. Whilst effective psychosocial interventions exist, little is known about what key factors might modify the clinical decision to refer an individual to psychiatric in- and/or out-patient treatment following an episode of hospital-treated self-harm. METHODS: We searched five electronic databases (CENTRAL, CDSR, MEDLINE, Embase, and PsycINFO) until 3 January 2023 for studies reporting data on either the proportion of patients and/or events that receive a referral and/or discharge to psychiatric in- and/or outpatient treatment after an episode of hospital-treated self-harm. Pooled weighted prevalence estimates were calculated using the random effects model with the Freedman-Tukey double arcsine adjustment in R, version 4.0.5. We also investigated whether several study-level and macro-level factors explained variability for these outcomes using random-effects meta-regression. The protocol of this review was pre-registered with PROSPERO (CRD42021261531). FINDINGS: 189 publications, representing 131 unique studies, which reported data on 243,953 individual participants who had engaged in a total of 174,359 episodes of self-harm were included. Samples were drawn from 44 different countries. According to World Bank classifications, most (83.7%) samples were from high income countries. Across the age range, one-quarter of persons were referred for inpatient psychiatric care and, of these, around one-fifth received treatment. Just over one-third were referred to outpatient psychiatric care, whilst around half of those referred received at least one treatment session across the age range. Event rate estimates were generally of a lower magnitude. Subgroup analyses found that older adults (mean sample age: ≥60 years) may be less likely than young people (mean sample age: ≤25 years) and adults (mean sample age: >25 years to <60 years) to be referred for outpatient psychiatric care following self-harm. More recent studies were associated with a small increase in the proportion of presentations (events) that were referred to, and received, psychiatric outpatient treatment. No macro-level factor explained between-study heterogeneity. INTERPRETATION: There is considerable scope for improvement in the allocation and provision of both in- and out-patient psychiatric care following hospital-presenting self-harm, particularly considering that the period after discharge from general hospitals represents the peak risk period for repeat self-harm and suicide. Given the marked between-study heterogeneity, the basis for allocation of aftercare treatment is therefore not yet known and should be further studied. FUNDING: There was no specific funding for this review.
Effect of graphite, graphene oxide, and multi-walled carbon nanotubes on the physicochemical characteristics and biocompatibility of chitosan/hyaluronic acid/hydroxyapatite scaffolds for tissue engineering applications
Bone tissue engineering (BTE) is a promising alternative approach to the repair of damaged bone tissue. This study aims to fabricate and characterize scaffolds composed of chitosan (CS), hyaluronic acid (HA), hydroxyapatite (HAp), and a combination of graphite (Gr), graphene oxide (GO), and multi-walled carbon nanotubes (MWCNT) for BTE applications. The Gr and MWCNT were functionalized by acid oxidation, while the GO was synthesized using the improved Hummers' method. The scaffolds were prepared by lyophilization, and the physical, chemical, and biological properties were evaluated. Scanning electron microscopy (SEM), energy-dispersive x-ray spectroscopy (EDS), Fourier transform infrared (FTIR) spectroscopy, mechanical testing, water contact angle, degradation, and biocompatibility assays were used to characterize the scaffolds. The degradation rate was determined using the liquid displacement method. Pores of different sizes were present on the surface of and throughout the scaffold. According to the FTIR results, the scaffolds contained functional groups that promote cell differentiation and proliferation. These scaffolds have compressive strength, Young's modulus, and toughness similar to cancellous bone, with reasonable porosity and controllable degradation rates. Biocompatibility testing confirmed that the scaffolds support cell proliferation and differentiation.
Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation
Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signalling. The specific role of EL in cardiac atrial fibrillation (AF) is not well understood. We isolated atrial EL organelles from AF goat biopsies and conducted a comprehensive integrated omics analysis to study the EL-specific proteins and pathways. We also performed electron tomography, protein and enzyme assays on these biopsies. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates, including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophagic-vacuole formation, irregularly shaped mitochondria, and glycogen deposition. Our results provide molecular information suggesting EL play a role in AF disease process over extended time frames.
Understanding the effects of microbubble concentration on localization accuracy in super-resolution ultrasound imaging.
Super-Resolution Ultrasound (SRUS) through localising and tracking of Microbubbles (MBs) can achieve sub-wavelength resolution for imaging microvascular structure and flow dynamics in deep tissue in-vivo. The technique assumes that signals from individual MBs can be isolated and localised accurately, but this assumption starts to break down when the MB concentration increases and the signals from neighbouring MBs start to interfere. The aim of this study is to gain understanding of the effect of MB-MB distance on ultrasound images and their localisation. Ultrasound images of two MBs approaching each other were synthesised by simulating both ultrasound field propagation and nonlinear MB dynamics. Besides the distance between MBs, a range of other influencing factors including MB size, ultrasound frequency, transmit pulse sequence, pulse amplitude and localisation methods were studied. The results show that as two MBs approach each other, the interference fringes can lead to significant and oscillating localisation errors, which are affected by both the MB and imaging parameters. When modelling a clinical linear array probe operating at 6MHz, localisation errors between 20 to 30 µm (∼1/10th wavelength) can be generated when MBs are ∼ 500µm (2 wavelengths or ∼ 1.7 times the Point Spread Function (PSF)) away from each other. When modelling a cardiac probe operating at 1.5 MHz, the localisation errors were as high as 200 µm (∼1/5th wavelength) even when the MBs were more than 10 wavelengths apart (2.9 times the PSF). For both frequencies, at smaller separation distances, the two MBs were misinterpreted as one MB located in between the two true positions. Cross-correlation or Gaussian fitting methods were found to generate slightly smaller localisation errors than centroiding. In conclusion, caution should be taken when generating and interpreting SRUS images obtained using high agent concentration with MBs separated by less than 1.7 to 3 times the PSF, as significant localisation errors can be generated due to interference between neighbouring MBs.
Practical guide to implementing patient-reported outcome measures in gender-affirming care: evaluating acceptability, appropriateness and feasibility.
OBJECTIVE: Assess acceptability, appropriateness and feasibility of the Practical Guide to Implementing patient-reported outcome measures (PROMs) in Gender-Affirming Care (PG-PROM-GAC) from a sample of patients and healthcare professionals. DESIGN: Cross-sectional study conducted August-October 2023. SETTING: Participants were recruited from a National Health Service (NHS) gender clinic. PARTICIPANTS: Patient participants seeking care and healthcare professionals working at an NHS gender clinic were eligible for participation. The PG-PROM-GAC was sent to participants via email for review. OUTCOME MEASURES: Three validated tools to measure acceptability, appropriateness and feasibility were administered: the acceptability of intervention measure (AIM), intervention appropriateness measure (IAM) and feasibility of intervention measure (FIM). The percentage of participants indicating agreement or disagreement with items on the AIM, IAM and FIM was calculated. RESULTS: A total of 132 transgender and gender diverse (TGD) patients (mean age, SD: 33, 14) and 13 gender-affirming healthcare professionals (mean age, SD: 43, 11) completed the AIM, IAM and FIM, representing a range of gender identities. The cumulative percentage of patients indicating agree or strongly agree on the AIM, IAM and FIM for the patient-relevant strategies in the PG-PROM-GAC was over 50% for each item. The cumulative percentage of patients indicating disagree or strongly disagree on the AIM, IAM and FIM for the PG-PROM-GAC was less than 20% for each item. The cumulative percentage of healthcare professionals indicating agree or strongly agree on the AIM, IAM and FIM for the healthcare professional-relevant strategies in the PG-PROM-GAC was over 38% for each item. The cumulative percentage of healthcare professionals indicating disagree or strongly disagree on the AIM, IAM and FIM for the PG-PROM-GAC was less than 15% for each item. CONCLUSIONS: Gender-affirming healthcare professionals and TGD patients find the PG-PROM-GAC acceptable, appropriate and feasible. The PG-PROM-GAC is ready-to-use for clinicians, policy-makers and researchers committed to service improvement for gender-affirming care.
Nanopore sequencing of influenza A and B in Oxfordshire and the United Kingdom, 2022-23.
OBJECTIVES: We evaluated Nanopore sequencing for influenza surveillance. METHODS: Influenza A and B PCR-positive samples from hospital patients in Oxfordshire, UK, and a UK-wide population survey from winter 2022-23 underwent Nanopore sequencing following targeted rt-PCR amplification. RESULTS: From 941 infections, successful sequencing was achieved in 292/388(75%) available Oxfordshire samples: 231(79%) A/H3N2, 53(18%) A/H1N1, and 8(3%) B/Victoria and in 53/113(47%) UK-wide samples. Sequencing was more successful at lower Ct values. Most same-sample replicate sequences had identical haemagglutinin segments (124/141;88%); 36/39(92%) Illumina vs. Nanopore comparisons were identical, and 3(8%) differed by 1 variant. Comparison of Oxfordshire and UK-wide sequences showed frequent inter-regional transmission. Infections were closely-related to 2022-23 vaccine strains. Only one sample had a neuraminidase inhibitor resistance mutation. 849/941(90%) Oxfordshire infections were community-acquired. 63/88(72%) potentially healthcare-associated cases shared a hospital ward with ≥1 known infectious case. 33 epidemiologically-plausible transmission links had sequencing data for both source and recipient: 8 were within ≤5 SNPs, of these, 5(63%) involved potential sources that were also hospital-acquired. CONCLUSIONS: Nanopore influenza sequencing was reproducible and antiviral resistance rare. Inter-regional transmission was common; most infections were genomically similar. Hospital-acquired infections are likely an important source of nosocomial transmission and should be prioritised for infection prevention and control.