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Phox2a Defines a Developmental Origin of the Anterolateral System in Mice and Humans.
Anterolateral system neurons relay pain, itch, and temperature information from the spinal cord to pain-related brain regions, but the differentiation of these neurons and their specific contribution to pain perception remain poorly defined. Here, we show that most mouse spinal neurons that embryonically express the autonomic-system-associated Paired-like homeobox 2A (Phox2a) transcription factor innervate nociceptive brain targets, including the parabrachial nucleus and the thalamus. We define the Phox2a anterolateral system neuron birth order, migration, and differentiation and uncover an essential role for Phox2a in the development of relay of nociceptive signals from the spinal cord to the brain. Finally, we also demonstrate that the molecular identity of Phox2a neurons is conserved in the human fetal spinal cord, arguing that the developmental expression of Phox2a is a prominent feature of anterolateral system neurons.
A tridimensional atlas of the developing human head.
The evolution and development of the head have long captivated researchers due to the crucial role of the head as the gateway for sensory stimuli and the intricate structural complexity of the head. Although significant progress has been made in understanding head development in various vertebrate species, our knowledge of early human head ontogeny remains limited. Here, we used advanced whole-mount immunostaining and 3D imaging techniques to generate a comprehensive 3D cellular atlas of human head embryogenesis. We present detailed developmental series of diverse head tissues and cell types, including muscles, vasculature, cartilage, peripheral nerves, and exocrine glands. These datasets, accessible through a dedicated web interface, provide insights into human embryogenesis. We offer perspectives on the branching morphogenesis of human exocrine glands and unknown features of the development of neurovascular and skeletomuscular structures. These insights into human embryology have important implications for understanding craniofacial defects and neurological disorders and advancing diagnostic and therapeutic strategies.
Association of intra-articular injection and knee arthroscopy prior to primary knee replacement with the timing and outcomes of surgery: Retrospective cohort study using data from the Clinical Practice Research Datalink GOLD database.
BACKGROUND: Patients with symptomatic knee osteoarthritis may undergo non-surgical interventions such as intra-articular steroid injections and knee arthroscopy. This study aimed to investigate their association with the timing and outcomes of subsequent primary knee replacement. METHODS AND FINDINGS: Observational retrospective analysis of linked Clinical Practice Research Datalink, Hospital Episode Statistics, Patient Reported Outcome Measures (CPRD GOLD-HES-PROMS) data of 38,494 patients undergoing primary knee replacements in England. Prior use of intra-articular steroid injections and knee arthroscopy were identified. Hazard ratios (HRs) with 95% CIs were estimated for primary outcomes of revision and reoperation using Cox regression. Secondary outcomes included time from first diagnosis of ipsilateral knee osteoarthritis to knee replacement, 6-month post-operative Oxford Knee Scores (OKS), mortality (90-days and 3-months), and post-operative surgical site infection (SSI) (3-months) using linear and logistic regression. Prior steroid injections were associated with an increased risk of revision (HR = 1.25 95%CI (1.06 to 1.49)), re-operation (HR = 1.18 95%CI (1.05 to 1.32)), and SSI (HR = 3.10 95%CI (1.14 to 8.46). Timing from diagnosis of knee osteoarthritis to knee replacement was 6 months longer in patients receiving steroid injections. Knee arthroscopy was associated with an increased risk of revision (HR = 3.14 95%CI (2.64 to 3.73)), re-operation (HR = 3.25 95%CI (2.89 to 3.66)), lower post-operative OKS -1.63 95%CI (-2.31 to -0.95). Both interventions were associated with a lower risk of mortality. CONCLUSIONS: Steroid injection and knee arthroscopy prior to primary knee replacement are each associated with worse outcomes. The observed association of lower mortality risk is suggestive of confounding by indication. The observed associations in this study could be used to inform shared decision making with patients on the treatment pathway for knee osteoarthritis.
Medium-term results of arthroscopic hip surgery compared with physiotherapy and activity modification for the treatment of femoroacetabular impingement syndrome: a multi-centre randomised controlled trial.
OBJECTIVE: To report a 3-year follow-up from the FemoroAcetabular Impingement Trial, comparing arthroscopic surgery with physiotherapy in the management of femoroacetabular impingement (FAI) syndrome for the dual primary outcomes of radiographic hip osteoarthritis (OA) and patient-reported outcome measures of activities of daily living. METHODS: Two-group parallel, assessor-blinded, pragmatic randomised controlled trial across seven sites. 222 participants aged 18-60 years with FAI syndrome confirmed clinically and radiologically were randomised (1:1) to receive arthroscopic hip surgery (n=112) or physiotherapy (n=110). Dual primary outcome measure was minimum joint space width (mJSW) on anteroposterior radiograph at 38 months post-randomisation and Hip Outcome Score ADL (HOS ADL) (higher score indicates superior outcomes). Secondary outcome measures were Scoring Hip Osteoarthritis with MRI (SHOMRI) (lower score indicates less pathology). RESULTS: mJSW, HOS ADL and MRI data were available for 45%, 77% and 62% of participants at 38 months, respectively. No significant difference in mJSW was seen between groups at 38 months. HOS ADL was higher in the arthroscopy group (mean (SD) 84.2 (17.4)) compared with the physiotherapy group (74.2 (21.9)), difference 8.9 (95% CI 7.0, 10.8)). SHOMRI score total at 38 months was lower in the arthroscopy group (mean (SD) 9.22 (11.43)) compared with the physiotherapy group (22.76 (15.26)), differences (95% CIs) -15.94 (-18.69, -13.19). CONCLUSIONS: No difference was seen between groups on radiographic measures of OA progression. Patients with FAI syndrome treated surgically may experience superior pain and function outcomes, and less MRI-measured cartilage damage compared with physiotherapy. TRIAL REGISTRATION NUMBER: NCT01893034.
Mucosal Healing with Vedolizumab in Patients with Chronic Pouchitis: EARNEST, a Randomized, Double-Blind, Placebo-Controlled Trial.
BACKGROUND & AIMS: Vedolizumab is indicated for the treatment of chronic pouchitis in the European Union. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODS: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histologic evaluation was performed at baseline, Week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn's Disease in the pouch, and Pouchitis Disease Activity Index histologic component were evaluated. Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 were compared by MH status at W14. RESULTS: Following treatment, mean (standard deviation) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 versus placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% confidence interval]: W14: -8.4 [-14.3 to -2.6]; W34: -7.0 [-12.0 to -2.0]). More patients receiving vedolizumab versus placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference, 32.4 percentage points [p.p] [9.7, 51.4]; W34: 52.1% vs 12.9%; difference, 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), Simple Endoscopic Score for Crohn's Disease remission (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), and MH (W14: 16.7% vs 2.5%; difference, 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 than those without. CONCLUSIONS: Vedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. (ClinicalTrials.gov number, NCT02790138.).
Enhancing broadly neutralising antibody suppression of HIV by immune modulation and vaccination.
Although HIV infection can be managed with antiretroviral drugs, there is no cure and therapy has to be taken for life. Recent successes in animal models with HIV-specific broadly neutralising antibodies (bNAbs) have led to long-term virological remission and even possible cures in some cases. This has resulted in substantial investment in human studies to explore bNAbs as a curative intervention for HIV infection. Emerging data are encouraging, but suggest that combinations of bNAbs with other immunomodulatory agents may be needed to induce and sustain long-term viral control. As a result, a number of clinical trials are currently underway exploring these combinations. If successful, the impact for the millions of people living with HIV could be substantial. Here, we review the background to the use of bNAbs in the search for an HIV cure and how different adjunctive agents might be used together to enhance their efficacy.
Learning patterns of HIV-1 resistance to broadly neutralizing antibodies with reduced subtype bias using multi-task learning.
The ability to predict HIV-1 resistance to broadly neutralizing antibodies (bnAbs) will increase bnAb therapeutic benefits. Machine learning is a powerful approach for such prediction. One challenge is that some HIV-1 subtypes in currently available training datasets are underrepresented, which likely affects models' generalizability across subtypes. A second challenge is that combinations of bnAbs are required to avoid the inevitable resistance to a single bnAb, and computationally determining optimal combinations of bnAbs is an unsolved problem. Recently, machine learning models trained using resistance outcomes for multiple antibodies at once, a strategy called multi-task learning (MTL), have been shown to improve predictions. We develop a new model and show that, beyond the boost in performance, MTL also helps address the previous two challenges. Specifically, we demonstrate empirically that MTL can mitigate bias from underrepresented subtypes, and that MTL allows the model to learn patterns of co-resistance to combinations of antibodies, thus providing tools to predict antibodies' epitopes and to potentially select optimal bnAb combinations. Our analyses, publicly available at https://github.com/iaime/LBUM, can be adapted to other infectious diseases that are treated with antibody therapy.
Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection.
Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.
Avoiding "a piece of paper on the wall that everyone ignores": A qualitative study on the barriers for implementing open fracture guidelines.
BACKGROUND: Ortho-plastic evidence-based clinical guidelines for open fractures have demonstrated to standardise care and improve outcomes for patients admitted following lower extremity trauma. Despite its benefits, very few countries have introduced such guidance. The aim of this study was to explore the attitudes, barriers and limitations to the development and implementation of guidelines for lower limb open fractures METHODS: Twelve renowned orthopaedic and plastic surgeons, based in countries with no guidelines at present, underwent semi-structured interviews. A qualitative appraisal was conducted using reflexive thematic analysis methodology. Systematic coding led to the development and refinement of themes to address the research question. RESULTS: Individualistic decision-making, reliance on multidisciplinary interpersonal relationships, and the presence of immobile determinants of open fracture care emerged as three themes that define how patients are currently managed in settings with no guidelines in place. Although guidelines can potentially improve care by presenting evidence-based recommendations, introducing audit practices, establishing pathways for multidisciplinary collaboration, and enhancing effective leadership; if barriers to the implementation are not considered, they may end up as a "piece of paper on the wall that everyone ignores" CONCLUSIONS: This study is the first to explore the challenges of introducing ortho-plastic guidelines for open extremity trauma. The themes presented describe the status quo in settings with no such protocols in place, establishing the foundation for future initiatives aiming to provide a practical strategy to aid the development and introduction of clinical guidelines for open lower limb fractures.
Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.
The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.
Recreational Physical Activity and Risk of Incident Knee Osteoarthritis: An International Meta-Analysis of Individual Participant-Level Data.
OBJECTIVE: The effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions. METHODS: Data were acquired from 6 global, community-based cohorts of participants with and those without knee OA. Eligible participants had no evidence of knee OA or rheumatoid arthritis at baseline. Participants were followed up for 5-12 years for incident outcomes including the following: 1) radiographic knee OA (Kellgren-Lawrence [K/L] grade ≥2), 2) painful radiographic knee OA (radiographic OA with knee pain), and 3) OA-related knee pain. Self-reported recreational physical activity included sports and walking/cycling activities and was quantified at baseline as metabolic equivalents of task (METs) in days per week. Risk ratios (RRs) were calculated and pooled using individual participant data meta-analysis. Secondary analysis assessed the association between physical activity, defined as time (hours per week) spent in recreational physical activity and incident knee OA outcomes. RESULTS: Based on a total of 5,065 participants, pooled RR estimates for the association of MET days per week with painful radiographic OA (RR 1.02 [95% confidence interval (95% CI) 0.93-1.12]), radiographic OA (RR 1.00 [95% CI 0.94-1.07]), and OA-related knee pain (RR 1.00 [95% CI 0.96-1.04]) were not significant. Similarly, the analysis of hours per week spent in physical activity also showed no significant associations with all outcomes. CONCLUSION: Our findings suggest that whole-body, physiologic energy expenditure during recreational activities and time spent in physical activity were not associated with incident knee OA outcomes.
Foot and ankle pain and risk of incident knee osteoarthritis and knee pain: Data from the Multicentre Osteoarthritis Study.
OBJECTIVES: To examine whether foot and/or ankle pain increases the risk of knee OA. DESIGN: We utilised longitudinal data from the Multicentre Osteoarthritis Study (MOST); a community-based cohort of risk factors for knee OA. Participants without frequent knee pain (clinic visit only) and radiographic knee OA (RKOA) at baseline and, with no evidence of inflammatory musculoskeletal disease and a history of knee-related surgery were followed for up to 84-months for incident outcomes; i) RKOA (Kellgren-Lawrence (KL) ≥2), ii) symptomatic RKOA (RKOA and frequent pain in the same knee) and iii) frequent knee pain only. At baseline, ankle and foot symptoms were assessed, with knee radiographs and symptoms also assessed at 30, 60 and 84-months. Our exposures included baseline ankle, foot, and ankle and foot pain (participant-level). Associations between foot and/or ankle pain and incident outcomes were assessed using multiple logistic regression, with adjustment for participant characteristics and ankle/foot pain. RESULTS: No statistically significant associations were observed between ankle, foot and, ankle and foot pain and incident RKOA, respectively. Ankle pain with (2.30, 95% CI 1.13 to 4.66) and without foot pain (OR: 2.53, 95% CI 1.34 to 4.80) were associated with increased odds of incident symptomatic RKOA and frequent knee pain. No statistically significant associations were observed between foot pain and these outcomes. CONCLUSIONS: Ankle pain should be a focus point, more so than foot pain, in the management of knee OA. Future studies should include additional ankle joint-specific symptom questions to better elucidate the knee OA biomechanical pathway.
Monitoring work-related physical activity and estimating lower-limb loading: a proof-of-concept study.
BACKGROUND: Physical activity (PA) is important to general health and knee osteoarthritis (OA). Excessive workplace PA is an established risk factor for knee OA however, appropriate methods of measurement are unclear. There is a need to examine and assess the utility of new methods of measuring workplace PA and estimating knee load prior to application to large-scale, knee OA cohorts. Our aims, therefore, were to monitor workplace PA and estimate lower-limb loading across different occupations in health participants. METHODS: Twenty-four healthy adults, currently working full-time in a single occupation (≥ 35 h/week) and free of musculoskeletal disease, comorbidity and had no history of lower-limb injury/surgery (past 12-months) were recruited across New South Wales (Australia). A convenience sample was recruited with occupations assigned to levels of workload; sedentary, light manual and heavy manual. Metrics of workplace PA including tasks performed (i.e., sitting), step-count and lower-limb loading were monitored over 10 working days using a daily survey, smartwatch, and a smartphone. RESULTS: Participants of light manual occupations had the greatest between-person variations in mean lower-limb load (from 2 to 59 kg*m/s3). Lower-limb load for most participants of the light manual group was similar to a single participant in heavy manual work (30 kg*m/s3) and was at least three times greater than the sedentary group (2 kg*m/s3). The trends of workplace PA over working hours were largely consistent, per individual, but rare events of extreme loads were observed across all participants (up to 760 kg*m/s3). CONCLUSIONS: There are large interpersonal variations in metrics of workplace PA, particularly among light and heavy manual occupations. Our estimates of lower-limb loading were largely consistent with pre-conceived levels of physical demand. We present a new approach to monitoring PA and estimating lower-limb loading, which could be applied to future occupational studies of knee OA.
The current state of the osteoarthritis drug development pipeline: a comprehensive narrative review of the present challenges and future opportunities.
In this narrative review article, we critically assess the current state of the osteoarthritis (OA) drug development pipeline. We discuss the current state-of-the-art in relation to the development and evaluation of candidate disease-modifying OA drugs (DMOADs) and the limitations associated with the tools and methodologies that are used to assess outcomes in OA clinical trials. We focus on the definition of DMOADs, highlight the need for an updated definition in the form of a consensus statement from all the major stakeholders, including academia, industry, regulatory agencies, and patient organizations, and provide a summary of the results of recent clinical trials of novel DMOAD candidates. We propose that DMOADs should be more appropriately targeted and investigated according to the emerging clinical phenotypes and molecular endotypes of OA. Based on the findings from recent clinical trials, we propose key topics and directions for the development of future DMOADs.
Association between Markers of Synovial Inflammation, Matrix Turnover and Symptoms in Knee Osteoarthritis: A Cross-Sectional Study.
To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually. Knee symptoms were assessed using WOMAC at all visits. We examined the cross-sectional association between knee symptoms and three MRI-based and three serum markers of synovitis and matrix turnover, respectively. A total of 447 participants were included in the serum and 136 participants in the MRI analyses. MRI-defined medial perimeniscal synovitis was positively associated with knee pain and, suprapatellar and medial perimeniscal synovitis with knee function in multivariate analysis. We observed a statistically significant, negative association between a higher concentration of serum C3M and CRPM and knee pain, respectively. Furthermore, the highest CRPM quartile was negatively associated with knee function. Our findings suggest that, in established painful radiographic KOA, MRI-defined medial perimeniscal and suprapatellar synovitis were positively associated with knee symptoms. Serum-based C3M and CRPM markers were negatively associated with knee symptoms. Pain fluctuations are common in KOA and a better understanding of the relationship between markers of synovitis and matrix turnover and knee symptoms would facilitate a more accurate assessment of temporal changes in disease progression.
An open-label, single-arm trial of cryoneurolysis for improvements in pain, activities of daily living and quality of life in patients with symptomatic ankle osteoarthritis.
OBJECTIVE: Cryoneurolysis, cold-induced reversible conduction block of peripheral nerves, is an effective treatment for reducing knee osteoarthritis (OA) symptoms and opioid use following knee arthroplasty. There are however, limited data concerning its use for ankle OA. Our aim was to assess clinically significant long-term symptomatic relief of ankle OA with cryoneurolysis. METHOD: This single-center, open-label trial included participants aged >18 years with radiographic tibiotalar OA, unilateral ankle pain ≥5/10 on Numerical Rating Scale (NRS), and with no ankle surgery within 6-months of screening. Following ultrasound-guided cryoneurolysis of nerves in the participant's pain distribution (sural, saphenous, superficial and/or deep fibular nerves), outcomes were assessed at clinic visits (6, 12 and 24-weeks) and by telephone interview (3, 9, 18-weeks). The primary endpoint was change in Foot and Ankle Outcome Score (FAOS) (pain subscale) at 12-weeks. Change in quality of life (FAOS-QoL), activities of daily living (FAOS-ADL), NRS-pain, and physical performance measures were also assessed. Longitudinal mixed models were constructed to evaluate changes from baseline at 6, 12- and 24-weeks post-treatment. RESULTS: Forty participants enrolled (50% female, mean ± SD age 63.0 ± 12.8 years). At 12-weeks post treatment, FAOS-pain (20.8, p