Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.

INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.

Self-Supervised Machine Learning to Characterise Step Counts from Wrist-Worn Accelerometers in the UK Biobank.

PURPOSE: Step count is an intuitive measure of physical activity frequently quantified in health-related studies; however, accurate step counting is difficult in the free-living environment, with error routinely above 20% in wrist-worn devices against camera-annotated ground truth. This study aims to describe the development and validation of step count derived from a wrist-worn accelerometer and assess its association with cardiovascular and all-cause mortality in a large prospective cohort. METHODS: We developed and externally validated a self-supervised machine learning step detection model, trained on an open-source and step-annotated free-living dataset. 39 individuals will free-living ground-truth annotated step counts were used for model development. An open-source dataset with 30 individuals was used for external validation. Epidemiological analysis was performed using 75,263 UK Biobank participants without prevalent cardiovascular disease (CVD) or cancer. Cox regression was used to test the association of daily step count with fatal CVD and all-cause mortality after adjustment for potential confounders. RESULTS: The algorithm substantially outperformed reference models (free-living mean absolute percent error of 12.5%, versus 65-231%). Our data indicate an inverse dose-response association, where taking 6,430-8,277 daily steps was associated with 37% [25-48%] and 28% [20-35%] lower risk of fatal CVD and all-cause mortality up to seven years later, compared to those taking fewer steps each day. CONCLUSIONS: We have developed an open and transparent method that markedly improves the measurement of steps in large-scale wrist-worn accelerometer datasets. The application of this method demonstrated expected associations with CVD and all-cause mortality, indicating excellent face validity. This reinforces public health messaging for increasing physical activity and can help lay the groundwork for the inclusion of target step counts in future public health guidelines.

A transcriptomics-based RNAi screen for regulators of meiosis and early stages of oocyte development in Drosophila melanogaster.

A properly regulated series of developmental and meiotic events must occur to ensure the successful production of gametes. In Drosophila melanogaster ovaries, these early developmental and meiotic events include the production of the 16-cell cyst, meiotic entry, synaptonemal complex (SC) formation, recombination, and oocyte specification. In order to identify additional genes involved in early oocyte development and meiosis, we reanalyzed 3 published single-cell RNA-seq datasets from Drosophila ovaries, using vasa (germline) together with c(3)G, cona, and corolla (SC) as markers. Our analysis generated a list of 2,743 co-expressed genes. Many known SC-related and early oocyte development genes fell within the top 500 genes on this list, as ranked by the abundance and specificity of each gene's expression across individual analyses. We tested 526 available RNAi lines containing shRNA constructs in germline-compatible vectors representing 331 of the top 500 genes. We assessed targeted ovaries for SC formation and maintenance, oocyte specification, cyst development, and double-strand break dynamics. Six uncharacterized genes exhibited early developmental defects. SC and developmental defects were observed for additional genes not well characterized in the early ovary. Interestingly, in some lines with developmental delays, meiotic events could still be completed once oocyte specificity occurred indicating plasticity in meiotic timing. These data indicate that a transcriptomics approach can be used to identify genes involved in functions in a specific cell type in the Drosophila ovary.

Sea lamprey enlightens the origin of the coupling of retinoic acid signaling to vertebrate hindbrain segmentation.

Retinoic acid (RA) is involved in antero-posterior patterning of the chordate body axis and, in jawed vertebrates, has been shown to play a major role at multiple levels of the gene regulatory network (GRN) regulating hindbrain segmentation. Knowing when and how RA became coupled to the core hindbrain GRN is important for understanding how ancient signaling pathways and patterning genes can evolve and generate diversity. Hence, we investigated the link between RA signaling and hindbrain segmentation in the sea lamprey Petromyzon marinus, an important jawless vertebrate model providing clues to decipher ancestral vertebrate features. Combining genomics, gene expression, and functional analyses of major components involved in RA synthesis (Aldh1as) and degradation (Cyp26s), we demonstrate that RA signaling is coupled to hindbrain segmentation in lamprey. Thus, the link between RA signaling and hindbrain segmentation is a pan vertebrate feature of the hindbrain and likely evolved at the base of vertebrates.

Sequencing by avidity enables high accuracy with low reagent consumption.

We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer.

Device-Measured Physical Activity in 3506 Individuals with Knee or Hip Arthroplasty.

PURPOSE: Hip and knee arthroplasty aims to reduce joint pain and increase functional mobility in patients with osteoarthritis; however, the degree to which arthroplasty is associated with higher physical activity is unclear. The current study sought to assess the association of hip and knee arthroplasty with objectively measured physical activity. METHODS: This cross-sectional study analyzed wrist-worn accelerometer data collected in 2013-2016 from UK Biobank participants (aged 43-78 yr). Multivariable linear regression was performed to assess step count, cadence, overall acceleration, and activity behaviors between nonarthritic controls, end-stage arthritic, and postoperative cohorts, controlling for demographic and behavioral confounders. From a cohort of 94,707 participants with valid accelerometer wear time and complete self-reported data, electronic health records were used to identify 3506 participants having undergone primary or revision hip or knee arthroplasty and 68,389 nonarthritic controls. RESULTS: End-stage hip or knee arthritis was associated with taking 1129 fewer steps per day (95% confidence interval (CI), 811-1447; P < 0.001) and having 5.8 fewer minutes per day (95% CI, 3.0-8.7; P < 0.001) of moderate-to-vigorous activity compared with nonarthritic controls. Unilateral primary hip and knee arthroplasties were associated with 877 (95% CI, 284-1471; P = 0.004) and 893 (95% CI, 232-1554; P = 0.008) more steps than end-stage osteoarthritic participants, respectively. Postoperative unilateral hip arthroplasty participants demonstrated levels of moderate-to-vigorous physical activity and daily step count equivalent to nonarthritic controls. No difference in physical activity was observed between any cohorts in terms of overall acceleration, or time spent in daily light activity, sedentary behavior, or sleep. CONCLUSIONS: Hip and knee arthroplasties are associated with higher levels of physical activity compared with participants with end-stage arthritis. Unilateral hip arthroplasty patients, in particular, demonstrate equivalence to nonarthritic peers at more than 1 yr after surgery.

Cost-effectiveness analysis of a pragmatic randomized trial evaluating surgical reconstruction versus rehabilitation in patients with long-standing anterior cruciate ligament injury.

Aims: The aim of this study was to estimate the incremental use of resources, costs, and quality of life outcomes associated with surgical reconstruction compared to rehabilitation for long-standing anterior cruciate ligament (ACL) injury in the NHS, and to estimate its cost-effectiveness. Methods: A total of 316 patients were recruited and randomly assigned to either surgical reconstruction or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment). Healthcare resource use and health-related quality of life data (EuroQol five-dimension five-level health questionnaire) were collected in the trial at six, 12, and 18 months using self-reported questionnaires and medical records. Using intention-to-treat analysis, differences in costs, and quality-adjusted life years (QALYs) between treatment arms were estimated adjusting for baseline differences and following multiple imputation of missing data. The incremental cost-effectiveness ratio (ICER) was estimated as the difference in costs divided by the difference in QALYs between reconstruction and rehabilitation. Results: At 18 months, patients in the surgical reconstruction arm reported higher QALYs (0.052 (95% confidence interval (CI) -0.012 to 0.117); p = 0.177) and higher NHS costs (£1,017 (95% CI 557 to 1,476); p < 0.001) compared to rehabilitation. This resulted in an ICER of £19,346 per QALY with the probability of surgical reconstruction being cost-effective of 51% and 72% at a willingness-to-pay threshold of £20,000 and £30,000 per QALY, respectively. Conclusion: Surgical reconstruction as a management strategy for patients with long-standing ACL injury is more effective, but more expensive, at 18 months compared to rehabilitation management. In the UK setting, surgical reconstruction is cost-effective.

Does changes in unicompartmental knee arthroplasty practice pattern influence reasons for revision?

Aims: The aim of this study was to describe the pattern of revision indications for unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA) and any change to this pattern for UKA patients over the last 20 years, and to investigate potential associations to changes in surgical practice over time. Methods: All primary knee arthroplasty surgeries performed due to primary osteoarthritis and their revisions reported to the Danish Knee Arthroplasty Register from 1997 to 2017 were included. Complex surgeries were excluded. The data was linked to the National Patient Register and the Civil Registration System for comorbidity, mortality, and emigration status. TKAs were propensity score matched 4:1 to UKAs. Revision risks were compared using competing risk Cox proportional hazard regression with a shared γ frailty component. Results: Aseptic loosening (loosening) was the most common revision indication for both UKA (26.7%) and TKA (29.5%). Pain and disease progression accounted for 54.6% of the remaining UKA revisions. Infections and instability accounted for 56.1% of the remaining TKA revision. The incidence of revision due to loosening or pain decreased over the last decade, being the second and third least common indications in 2017. There was a decrease associated with fixation method for pain (hazard ratio (HR) 0.40; 95% confidence interval (CI) 0.17 to 0.94) and loosening (HR 0.29; 95% CI 0.10 to 0.81) for cementless compared to cemented, and units UKA usage for pain (HR 0.67, 95% CI 0.50 to 0.91), and loosening (HR 0.51; 95% CI 0.37 to 0.70) for high usage. Conclusion: The overall revision patterns for UKA and TKA for the last 20 years are comparable to previous published patterns. We found large changes to UKA revision patterns in the last decade, and with the current surgical practice, revision due to pain or loosening are significantly less likely.

Epidemiology of revision hip replacement surgery in the UK over the past 15 years-an analysis from the National Joint Registry.

OBJECTIVES: To investigate trends in the incidence rate and main indication for revision hip replacement (rHR) over the past 15 years in the UK. DESIGN: Repeated national cross-sectional study from 2006 to 2020. SETTING/PARTICIPANTS: rHR procedures were identified from the National Joint Registry for England, Wales, Northern Ireland, the Isle of Man and the States of Guernsey. Population statistics were obtained from the Office for National Statistics. MAIN OUTCOME MEASURES: Crude incidence rates of rHR. RESULTS: The incidence rate of rHR doubled from 11 per 100 000 adults in 2006 (95% CI 10.7 to 11.3) to a peak of 22 per 100 000 adults (95% CI 22 to 23) in 2012, before falling to 17 per 100 000 adults in 2019 (95% CI 16 to 17) (24.5% decrease from peak). The incidence rate of rHR reduced by 39% in 2020 compared with 2019 (during the COVID-19 pandemic). The most frequent indications for rHR between 2006 and 2019 were loosening/lysis (27.8%), unexplained pain (15.1%) and dislocation/instability (14.7%). There were incremental increases in the annual number and incidence rates of rHR for fracture, infection, dislocation/instability and a decrease in rHR for aseptic loosening/lysis. CONCLUSIONS: The incidence rate of rHR doubled from 2006 to 2012, likely due to high early failure rates of metal-on-metal hip replacements. The incidence of rHR then decreased by approximately 25% from 2012 to 2019, followed by a large decrease during the COVID-19 pandemic. The decrease in the number of rHR performed for aseptic loosening/lysis may reflect improved wear and implant longevity. Increased healthcare resource will be required to care for the increasing numbers of patients undergoing rHR for fracture and infection.

Identification and Localization of Cell Types in the Mouse Olfactory Bulb Using Slide-SeqV2.

Spatial transcriptomics maps RNA molecules to the location in a tissue where they are expressed. Here we document the use of Slide-SeqV2 to visualize gene expression in the mouse olfactory bulb (OB). This approach relies on spatially identified beads to locate and quantify individual transcripts. The expression profiles associated with the beads are used to identify and localize individual cell types in an unbiased manner. We demonstrate the various cell types and subtypes with distinct spatial locations in the olfactory bulb that are identified using Slide-SeqV2.

Less pain reported 5 years after cementless compared to cemented unicompartmental knee replacement: an analysis of pain, neuropathy, and co-morbidity scores.

PURPOSE: To compare patient-reported pain scores and assess the influence of neuropathy and co-morbidity, on knee pain following cemented and cementless medial unicompartmental knee replacement (UKR) 5 years after surgery. METHOD: In this longitudinal study, 262 cemented and 262 cementless Oxford UKR performed for the same indications and with the same techniques were recruited. Patients were reviewed at five years, evaluating patient-reported pain and association with clinical outcomes. Intermittent and Constant Osteoarthritis Pain (ICOAP), PainDETECT (PD), Charnley score, Oxford Knee Score (OKS) and American Knee Society Score (AKSS) were compared. RESULTS: In both cohorts, intermittent pain was more common than constant pain (47% vs 21%). Cementless knees reported significantly less pain than cemented (ICOAP-Total 5/100 vs 11/100, p < 0.0001). A greater proportion of cementless knees experienced no pain at all (ICOAP = 0/100, 61% vs 43%, p < 0.0001) and 75% fewer experienced severe or extreme pain. Pain sub-scores in PD, OKS and AKSS follow this trend. Pain was unlikely to be neuropathic (PD positive: 5.26%), but patients reporting high levels of 'strongest' pain were three times more likely to be neuropathic. Patients with co-morbidities (Charnley C) experienced greater pain than those without (Charnley A+B) across all knee-specific scores, despite scores being knee specific. CONCLUSION: Both cemented and cementless UKR in this study had substantially less pain than that reported in literature following TKR. Cementless UKR had significantly less pain than cemented UKR in all scores. Two-thirds of patients with a cementless UKR had no pain at all at 5 years, and pain experienced was most likely to be mild and intermittent with no patients in severe or extreme pain. Patients with cementless UKR that had higher levels of pain were more likely to have co-morbidity or evidence or neuropathic pain. It is unclear why cementless UKR have less pain than cemented; further study is necessary.

Patient-relevant outcomes following elective, aseptic revision knee arthroplasty: a systematic review.

BACKGROUND: The aim of this systematic review was to summarise the evidence for the clinical effectiveness of revision knee arthroplasty (rKA) compared to non-operative treatment for the management of patients with elective, aseptic causes for a failed knee arthroplasty. METHODS: MEDLINE, Embase, AMED and PsychINFO were searched from inception to 1st December 2020 for studies on patients considering elective, aseptic rKA. Patient-relevant outcomes (PROs) were defined as implant survivorship, joint function, quality of life (QoL), complications and hospital admission impact. RESULTS: No studies compared elective, aseptic rKA to non-operative management. Forty uncontrolled studies reported on PROs following elective, aseptic rKA (434434 rKA). Pooled estimates for implant survivorship were: 95.5% (95% CI 93.2-97.7%) at 1 year [seven studies (5524 rKA)], 90.8% (95% CI 87.6-94.0%) at 5 years [13 studies (5754 rKA)], 87.4% (95% CI 81.7-93.1%) at 10 years [nine studies (2188 rKA)], and 83.2% (95% CI 76.7-89.7%) at 15 years [two studies (452 rKA)]. Twelve studies (2382 rKA) reported joint function and/or QoL: all found large improvements from baseline to follow-up. Mortality rates were low (0.16% to 2% within 1 year) [four studies (353064 rKA)]. Post-operative complications were common (9.1 to 37.2% at 90 days). CONCLUSION: Higher-quality evidence is needed to support patients with decision-making in elective, aseptic rKA. This should include studies comparing operative and non-operative management. Implant survivorship following elective, aseptic rKA was ~ 96% at 1 year, ~ 91% at 5 years and ~ 87% at 10 years. Early complications were common after elective, aseptic rKA and the rates summarised here can be shared with patients during informed consent. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020196922.

The Swi-Snf chromatin remodeling complex mediates gene repression through metabolic control.

In eukaryotes, ATP-dependent chromatin remodelers regulate gene expression in response to nutritional and metabolic stimuli. However, altered transcription of metabolic genes may have significant indirect consequences which are currently poorly understood. In this study, we use genetic and molecular approaches to uncover a role for the remodeler Swi-Snf as a critical regulator of metabolism. We find that snfΔ mutants display a cysteine-deficient phenotype, despite growth in nutrient-rich media. This correlates with widespread perturbations in sulfur metabolic gene transcription, including global redistribution of the sulfur-sensing transcription factor Met4. Our findings show how a chromatin remodeler can have a significant impact on a whole metabolic pathway by directly regulating an important gene subset and demonstrate an emerging role for chromatin remodeling complexes as decisive factors in metabolic control.

Cellular characterisation of advanced osteoarthritis knee synovium.

OBJECTIVES: Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores. METHODS: Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected. RESULTS: The proportion of immune cells in OA synovium varied between patients (8-38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45-PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer. CONCLUSIONS: There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes.

Patient-Relevant Outcomes Following First Revision Total Knee Arthroplasty, by Diagnosis: An Analysis of Implant Survivorship, Mortality, Serious Medical Complications, and Patient-Reported Outcome Measures Utilizing the National Joint Registry Data Set.

BACKGROUND: The purpose of this study was to investigate patient-relevant outcomes following first revision total knee arthroplasties (rTKAs) performed for different indications. METHODS: This population-based cohort study utilized data from the United Kingdom National Joint Registry, Hospital Episode Statistics Admitted Patient Care, National Health Service Patient-Reported Outcome Measures, and the Civil Registrations of Death. Patients undergoing a first rTKA between January 1, 2009, and June 30, 2019, were included in our data set. Patient-relevant outcomes included implant survivorship (up to 11 years postoperatively), mortality and serious medical complications (up to 90 days postoperatively), and patient-reported outcome measures (at 6 months postoperatively). RESULTS: A total of 24,540 first rTKAs were analyzed. The patient population was 54% female and 62% White, with a mean age at the first rTKA of 69 years. At 2 years postoperatively, the cumulative incidence of re-revision surgery ranged from 2.7% (95% confidence interval [CI], 1.9% to 3.4%) following rTKA for progressive arthritis to 16.3% (95% CI, 15.2% to 17.4%) following rTKA for infection. The mortality rate at 90 days was highest following rTKA for fracture (3.6% [95% CI, 2.5% to 5.1%]) and for infection (1.8% [95% CI, 1.5% to 2.2%]) but was <0.5% for other indications. The rate of serious medical complications requiring hospital admission within 90 days was highest for patients treated for fracture (21.8% [95% CI, 17.9% to 26.3%]) or infection (12.5% [95% CI, 11.2% to 13.9%]) and was lowest for those treated for progressive arthritis (4.3% [95% CI, 3.3% to 5.5%]). Patients who underwent rTKA for stiffness or unexplained pain had some of the poorest postoperative joint function (mean Oxford Knee Score, 24 and 25 points, respectively) and had the lowest proportion of responders (48% and 55%, respectively). CONCLUSIONS: This study found large differences in patient-relevant outcomes among different indications for first rTKA. The rate of complications was highest following rTKA for fracture or infection. Although rTKA resulted in large improvements in joint function for most patients, those who underwent surgery for stiffness and unexplained pain had worse outcomes. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Detailed Management of Brachial Plexus Birth Injuries: The Miami Protocol at Nicklaus Children's Hospital.

The management of children with brachial plexus birth injuries is complex and requires a multidisciplinary approach. In the following article, we describe our approach to evaluation and management at Nicklaus Children's Hospital. It is our aim is to elucidate nuances in management.

Development and Validation of a Machine Learning Wrist-worn Step Detection Algorithm with Deployment in the UK Biobank.

Background: Step count is an intuitive measure of physical activity frequently quantified in a range of health-related studies; however, accurate quantification of step count can be difficult in the free-living environment, with step counting error routinely above 20% in both consumer and research-grade wrist-worn devices. This study aims to describe the development and validation of step count derived from a wrist-worn accelerometer and to assess its association with cardiovascular and all-cause mortality in a large prospective cohort study. Methods: We developed and externally validated a hybrid step detection model that involves self-supervised machine learning, trained on a new ground truth annotated, free-living step count dataset (OxWalk, n=39, aged 19-81) and tested against other open-source step counting algorithms. This model was applied to ascertain daily step counts from raw wrist-worn accelerometer data of 75,493 UK Biobank participants without a prior history of cardiovascular disease (CVD) or cancer. Cox regression was used to obtain hazard ratios and 95% confidence intervals for the association of daily step count with fatal CVD and all-cause mortality after adjustment for potential confounders. Findings: The novel step algorithm demonstrated a mean absolute percent error of 12.5% in free-living validation, detecting 98.7% of true steps and substantially outperforming other recent wrist-worn, open-source algorithms. Our data are indicative of an inverse dose-response association, where, for example, taking 6,596 to 8,474 steps per day was associated with a 39% [24-52%] and 27% [16-36%] lower risk of fatal CVD and all-cause mortality, respectively, compared to those taking fewer steps each day. Interpretation: An accurate measure of step count was ascertained using a machine learning pipeline that demonstrates state-of-the-art accuracy in internal and external validation. The expected associations with CVD and all-cause mortality indicate excellent face validity. This algorithm can be used widely for other studies that have utilised wrist-worn accelerometers and an open-source pipeline is provided to facilitate implementation.

A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development.

CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL. SIGNIFICANCE: Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949.