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Hox genes are critical regulators of skeletal development and Hox9-13 paralogs, specifically, are necessary for appendicular development along the proximal to distal axis. Loss of function of both Hoxa11 and Hoxd11 results in severe malformation of the forelimb zeugopod. In the radius and ulna of these mutants, chondrocyte development is perturbed, growth plates are not established, and skeletal growth and maturation fails. In compound mutants in which one of the four Hox11 alleles remains wild-type, establishment of a growth plate is preserved and embryos develop normally through newborn stages, however, skeletal phenotypes become evident postnatally. During postnatal development, the radial and ulnar growth rate slows compared to wild-type controls and terminal bone length is reduced. Growth plate height is decreased in mutants and premature growth plate senescence occurs along with abnormally high levels of chondrocyte proliferation in the reserve and proliferative zones. Compound mutants additionally develop an abnormal curvature of the radius, which causes significant distortion of the carpal elements. The progressive bowing of the radius appears to result from physical constraint caused by the disproportionately slower growth of the ulna than the radius. Collectively, these data are consistent with premature depletion of forelimb zeugopod progenitor cells in the growth plate of Hox11 compound mutants, and demonstrate a continued function for Hox genes in postnatal bone growth and patterning.

Purpose. The outcome of recanalization in patients with chronic symptomatic intracranial vertebral artery (ICVA) total occlusion is poor. This paper reports the technical feasibility and long-term outcome of ICVA stenting in patients with chronic symptomatic total occlusion. Methods. Retrospective review of our prospectively maintained intracranial intervention database to identify patients with symptomatic total occlusion of ICVA with revascularization attempted >1 month after index ischemic event. Results. Eight patients (mean age 58 years) were identified. One had stroke and 7 had recurrent transient ischemic attacks. Four had bilateral ICVA total occlusion and 4 had unilateral ICVA total occlusion with severe stenosis contralaterally. Seven of 8 patients underwent endovascular recanalization, which was achieved in 6. Periprocedural complications included cerebellum hemorrhage, arterial dissection, perforation, and subacute in-stent thrombosis which occurred in 3 patients. One patient died of cerebellum hemorrhage. The other patients improved clinically after endovascular therapy. Conclusions. Stent-supported recanalization of ICVA total occlusion is technically feasible, and may become a viable treatment option in selected patients.

Background: Thoracoabdominal periprocedural occlusion/reperfusion injury of the spinal cord (SCII/R) can lead to devastating paraplegia, underscoring the critical need for effective interventions. However, our knowledge of optimal medical strategies and their efficacy remains limited. Preclinical investigations have shown promise in harnessing adult stem cells, including pluripotent and multipotent stem cells such as mesenchymal stem cells (MSCs), to address SCII/R by enhancing neuro-inflammation, axonal growth, and myelination. Particularly, growth factors derived from adipose tissue-derived MSCs (ADSCs) have been proposed to facilitate recovery. Despite advancements, achieving complete recovery remains a formidable challenge. Therefore, gaining a more profound insight into the role of ADSCs in alleviating SCII/R-induced paraplegia, including optimizing the delivery systems for therapies, is imperative. Materials and methods: In this study, we assessed the impact of subpial allogeneic rat adipose tissue-derived MSCs (rADSCs) transplantation on paraplegia using a rat SCII/R model induced by ephemeral aortic occlusion, known as the Taira-Marsala model. rADSCs were isolated from adipose tissue of male Sprague-Dawley rats, cultured, characterized, and cryopreserved. One week following the induction of paraplegia, rADSCs (n = 6) or physiological saline (n = 6) were transplanted. Hind limb motor function was evaluated before treatment and at 3-, 7-, and 14-days post-treatment using the Basso-Beattie-Bresnahan scoring system. Results: The rADSC-treated group demonstrated a significant improvement in hind limb motor function compared to the saline-treated group (p

Spinal cord injury (SCI) has limited treatment options for regaining function. Adipose-derived stem cells (ADSCs) show promise owing to their ability to differentiate into multiple cell types, promote nerve cell survival, and modulate inflammation. This review explores ADSC therapy for SCI, focusing on its potential for improving function, preclinical and early clinical trial progress, challenges, and future directions.Preclinical studies have demonstrated ADSC transplantation's effectiveness in promoting functional recovery, reducing cavity formation, and enhancing nerve regrowth and myelin repair. To improve ADSC efficacy, strategies including genetic modification and combination with rehabilitation are being explored. Early clinical trials have shown safety and feasibility, with some suggesting motor and sensory function improvements.Challenges remain for clinical translation, including optimizing cell survival and delivery, determining dosing, addressing tumor formation risks, and establishing standardized protocols. Future research should focus on overcoming these challenges and exploring the potential for combining ADSC therapy with other treatments, including rehabilitation and medication.

Chronic wounds represent a significant global burden, afflicting millions with debilitating complications. Despite standard care, impaired healing persists due to factors like persistent inflammation and impaired tissue regeneration. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) offer an innovative regenerative medicine approach, delivering stem cell-derived therapeutic cargo in engineered nanoscale delivery systems. This review examines pioneering bioengineering strategies to engineer MSC-EVs into precision nanotherapeutics for chronic wounds. Emerging technologies like CRISPR gene editing, microfluidic manufacturing, and biomimetic delivery systems are highlighted for their potential to enhance MSC-EV targeting, optimize therapeutic cargo enrichment, and ensure consistent clinical-grade production. However, key hurdles remain, including batch variability, rigorous safety assessment for potential tumorigenicity, immunogenicity, and biodistribution profiling. Crucially, collaborative frameworks harmonizing regulatory science with bioengineering and patient advocacy hold the key to expediting global clinical translation. By overcoming these challenges, engineered MSC-EVs could catalyze a new era of off-the-shelf regenerative therapies, restoring hope and healing for millions afflicted by non-healing wounds.

Abstract Introduction Cenegermin is approved for treatment of neurotrophic keratopathy (NK) and has been studied in patients with stage 2 or 3 NK. This study evaluated the efficacy and safety of cenegermin in adults with stage 1 NK. Methods This was a phase IV, multicenter, prospective, open-label, uncontrolled trial. Adults with stage 1 NK (Mackie criteria) and decreased corneal sensitivity (≤ 4 cm) received 1 drop of cenegermin 20 mcg/ml in the affected eye(s) 6 times/day for 8 weeks with a 24-week follow-up. Results Of 37 patients, corneal epithelial healing was observed in 84.8% (95% confidence interval [CI] 68.1–94.9%; P

Introduction: The environmentally acquired aerobic spore-forming (EAS-Fs) bacteria that are ubiquitous in nature (e.g., soil) are transient colonisers of the mammalian gastro-intestinal tract. Without regular exposure, their numbers quickly diminish. These species of bacteria have been suggested to be essential to the normal functioning of metabolic and immunogenic health. The modern Western lifestyle restricts exposure to these EAS-Fs, possibly explaining part of the pathogenesis of many Western diseases. To date, the only animal studies that address specific microbiome modelling are based around germ-free animals. We have designed a new animal model that specifically restricts exposure to environmental sources of bacteria. Methodology: A new protocol, termed Super Clean, which involves housing mice in autoclaved individually ventilated cages (IVCs), with autoclaved food/water and strict ascetic handling practice was first experimentally validated. The quantification of EAS-Fs was assessed by heat-treating faecal samples and measuring colony-forming units (CFUs). This was then compared to mice in standard conditions. Mice were housed in their respective groups from birth until 18 months. Stool samples were taken throughout the experiment to assess for abundance in transiently acquired environmental bacteria. Clinical, biochemical, histological, and gene expression markers were analysed for diabetes, hypercholesterolaemia, obesity, inflammatory bowel disease, and non-alcoholic fatty liver disease (the “diseases of the West”). Results: Our results show that stringent adherence to the Super Clean protocol produces a significantly decreased abundance of aerobic spore-forming Bacillota after 21 days. This microbiomic shift was correlated with significantly increased levels of obesity and impaired glucose metabolism. There was no evidence of colitis, liver disease or hypercholesterolaemia. Conclusions: This new murine model successfully isolates EAS-Fs and has potential utility for future research, allowing for an investigation into the clinical impact of living in relative hygienic conditions.

Introduction: Ageing tends to have a degenerative effect on the skin and emollient use may help maintain skin integrity in older people. In the hospital setting, skin conditions can sometimes be misinterpreted as minor and therefore regular emollient prescriptions are often incomplete or inaccurate.1 We undertook a quality improvement project to evaluate the prescribing of regular emollients in care of the elderly inpatients. Materials and methods: Baseline data were collected using electronic health records for patients in six care of the elderly wards at Northwick Park hospital. We undertook two Plan Do Study Act (PDSA) cycles to improve the accuracy and reduce the delay in regular emollient prescriptions on admission. Our interventions included posters clearly displayed in Accident and Emergency and on acute medical wards and discussions with pharmacists to alert admitting doctors when regular emollients were not prescribed appropriately over 3 months. Results and discussion: In the first PDSA cycle 156 patients were identified, out of which 46 were on regular emollients. The proportion of timely prescriptions was 26% with a mean delay of 11.5 days. In the second cycle 150 patients were identified, out of which 30 were on regular emollients. Following our interventions, the proportion of timely prescriptions rose to 30% and the mean delay time improved to 6.6 days. Conclusion: Our interventions resulted in increased timely prescriptions of regular emollients and reduced prescription delay time in care of the elderly inpatients. This project highlights the need to continue to raise awareness regarding the suboptimal emollient prescribing in elderly patients on admission and hence further cycles to sustain the improvements seen are planned.

Abstract Background Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. Methods Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. Results We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. Conclusions While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs.

Background Distal transradial access (dTRA) is an alternative to conventional forearm transradial access (fTRA) for coronary angiography (CAG). Differences in healing of the radial artery (RA) in the forearm have not been evaluated between these 2 access strategies. We sought to compare the mean difference in forearm RA intimal‐medial thickening (IMT) in patients randomized to dTRA versus fTRA. Methods and Results In this single‐center randomized clinical trial, 64 patients undergoing nonemergent CAG were randomized (1:1) to dTRA versus fTRA. Ultra–high‐resolution (55‐MHz) vascular ultrasound of the forearm and distal RA was performed pre‐CAG and at 90 days. The primary end point was the mean change in forearm RA IMT. Secondary end points included procedural characteristics, vascular injury, RA occlusion, and ipsilateral hand pain and function. Baseline demographics and clinical characteristics, mean forearm RA IMT, and procedural specifics were similar between the dTRA and fTRA cohorts. There was no difference in mean change in forearm RA IMT between the 2 cohorts (0.07 versus 0.07 mm; P=0.37). No RA occlusions or signs of major vascular injury were observed at 90 days. Ipsilateral hand pain and function (Borg pain scale score: 12 versus 11; P=0.24; Disabilities of the Arm, Shoulders, and Hand scale score: 6 versus 8; P=0.46) were comparable. Conclusions Following CAG, dTRA was associated with no differences in mean change of forearm RA IMT, hand pain, and function versus fTRA for CAG. Further investigation is warranted to elucidate mechanisms and predictors of RA healing and identify effective strategies to preserving RA integrity for repeated procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801901.

This article describes the arc of global measles and rubella elimination since 2000 from the perspective of the founding partners of the Measles Initiative. The Measles Initiative was formed in 2001 as a partnership among the American Red Cross, the Centers for Disease Control and Prevention, UNICEF, the United Nations Foundation, and the World Health Organization with the aim to reduce measles deaths in low-income countries. Recognizing rubella as the leading infectious disease cause of congenital abnormalities globally and achievement of measles and rubella elimination in the region of the Americas, the partnership was renamed the Measles and Rubella Initiative (MRI) in 2012. The goals of the MRI were at least a 95% reduction in global measles mortality and elimination of measles and rubella in at least five of the six WHO regions. In January 2023, the membership of the partnership was expanded to include the Bill and Melinda Gates Foundation (BMGF) and Gavi the Vaccine Alliance, and its name changed to the IA2030 Measles and Rubella Partnership. We describe the role the partnership has had in measles partner effectiveness and its impact on measles and rubella disease burden, including how the partnership has strategically adapted to the evolving immunization landscape. We conclude with lessons learned regarding the role global partnerships can play in furthering the impact of disease control programs within the current global immunization environment.

Background Visual perception has been defined as the first step to a football player’s decision-making process and it plays an important role in performance in sport. The skill of focussing to prioritize relevant cues has been also considered crucial in sport. This pilot study aims to explore the visual behaviour and attentional effort of three football players (mean age 19 ± 0 years old) in specific-role positions; Right-winger (RW), Centre-Midfielder (CM) and Left-Back (LB), in the five seconds before receiving the ball from their teammate. Methods Twenty-two male football players performed an 11v11 game, where 24 game sequences (trials) from which 166 fixations were recorded and analysed via the Tobii Pro eye-movement registration glasses and software. The gaze behaviour dependent variables were the mean of fixation duration (FD), time to first fixation (TTF), both measured in milliseconds (ms), and the number of fixations (NF) on eight areas of interest (AOIs). AOIs include teammate with and without the ball, opponent without the ball, space around teammate with and without the ball, space around opponent without the ball, ball and undefined. The mean pupil diameter (PD) correlates to the attentional effort and was measured in millimetres (mm). Results Descriptive statistics showed nonregular search rate data between the participants in FD, TTF, NF on the AOIs. Mean FD on the ball: (CM, 270 ms), (RW, 570 ms), (CM, 380 ms). They also presented differences in the mean PD during play; (CM: 2.90 mm ± 0.26), (RW: 2.74 mm ± 0.30), (LB 2.77mm ± 0.27). Conclusions Albeit the sample size was small, the findings demonstrated a promising way to measure the on-field perceptual-cognitive abilities of football players according to their specific positions, since different playing roles revealed to present distinctive visual and attentional patterns. This could potentially assist in tailoring players ‘visual and focus training.

Background Visual perception has been defined as the first step to a football player’s decision-making process and it plays an important role in performance in sport. The skill of focussing to prioritize relevant cues has been also considered crucial in sport. This pilot study aims to explore the visual behaviour and attentional effort of three football players (mean age 19 ± 0 years old) in specific-role positions; Right-winger (RW), Centre-Midfielder (CM) and Left-Back (LB), in the five seconds before receiving the ball from their teammate. Methods Twenty-two male football players performed an 11v11 game, where 24 game sequences (trials) from which 166 fixations were recorded and analysed via the Tobii Pro eye-movement registration glasses and software. The gaze behaviour dependent variables were the mean of fixation duration (FD), time to first fixation (TTF), both measured in milliseconds (ms), and the number of fixations (NF) on eight areas of interest (AOIs). AOIs include teammate with and without the ball, opponent without the ball, space around teammate with and without the ball, space around opponent without the ball, ball and undefined. The mean pupil diameter (PD) correlates to the attentional effort and was measured in millimetres (mm). Results Descriptive statistics showed nonregular search rate data between the participants in FD, TTF, NF on the AOIs. Mean FD on the ball: (CM, 270 ms), (RW, 570 ms), (CM, 380 ms). They also presented differences in the mean PD during play; (CM: 2.90 mm ± 0.26), (RW: 2.74 mm ± 0.30), (LB 2.77mm ± 0.27). Conclusions Albeit the sample size was small, the findings demonstrated a promising way to measure the on-field perceptual-cognitive abilities of football players according to their specific positions, since different playing roles revealed to present distinctive visual and attentional patterns.

Renewable energy provides a low-carbon alternative to power generation in the UK. However, the resultant supply varies on daily, weekly and seasonal cycles, such that for green energies to be fully exploited new grid-scale energy storage systems must be implemented. Two pilot facilities in Germany and the United States have demonstrated the potential of the Earth as a battery to store compressed air, using off-peak surplus energy. Natural accumulations of salt (halite deposits) in the UK represent a large and untapped natural storage reservoir for compressed air with the ability to provide instantaneous green energy to meet peak demand. To realise the potential of this emerging technology, a detailed knowledge of the relationship between mechanics, chemistry and geological properties is required to optimise cavern design, storage potential and economic feasibility. The variable stresses imposed on the rock matrix by gas storage, combined with the cyclic nature of cavern pressurisation are barriers to deployment that need to be addressed to enable large-scale adoption of schemes. Well-designed field experiments are a lynchpin for advancing research in this area, especially when supported by state-of-the-art characterisation and modelling techniques. The research facility at STFC’s Boulby Underground Laboratory presents the ideal location to tackle these fundamental issues to optimise “Battery Earth”.

Abstract Background The coexistence of calcium pyrophosphate dihydrate crystal deposition (CPP) and synovial chondromatosis (SC) in the temporomandibular joint (TMJ) is rarely reported. CPP disease (CPPD) is complex arthritis synonymous with excessive pyrophosphate production and variable aberrations in mineral and organic phase metabolism of the joint cartilage, leading to local inundated CPP and crystal deposition of partially deciphered predispositions. Meanwhile, SC is a rare benign synovial joint proliferative disease of unclear etiology and has a low risk of malignant transformation. However, SC manifests severe joint disability and dysfunction because of connective tissue metaplasia of the synovial membrane, which forms cartilaginous nodules with or without calcifications or ossifications. These nodules often detach and form intra-articular loose bodies and very rarely within extraarticular spaces. Case presentation We report the case of a 61-year-old man to expand the body of literature on these unusual coexisting arthropathies of the TMJ. The patient presented to our hospital in 2020 with complaints of pain in the right TMJ and trismus for over 6 months. Radiographic assessments of the TMJ provided a preoperative provisional diagnosis of SC. However, the histopathology of the open biopsy revealed tumor-like lesions comprising several deposits of rhomboid and rod-shaped crystals that displayed positive birefringence in polarized light, confirming a coexistence of CPPD. A second-stage operation was performed for the complete removal of the loose bodies and chalk-like lesions including synovectomy. No evidence of recurrence was recorded after a follow-up of nearly 1.5 years. Conclusions Isolated CPPD and SC of the TMJ are prevalent in the literature however, monoarticular coexistence of these diseases is rare, due to the lack of consistency in the diagnostic criteria in clinical practice. Moreover, optimal treatment depends on several considerations. This report delineated the molecular etiopathology and underscored the need for continued deciphering of the causal mechanisms of coexisting CPPD and SC of the TMJ. In addition, the importance of confirmatory testing for accurate diagnosis, and appropriate management of these diseases were discussed.

Current trends indicate a growing interest among healthcare specialists and the public in the use of regenerative medicine-based approaches for skin regeneration. The approaches are categorised in either cell-based or cell-free therapies and are reportedly safe and effective. Cell-based therapies include mesenchymal stem cells (MSCs), tissue induced pluripotent stem cells (iPSCs), fibroblast-based products, and blood-derived therapies, such as those employing platelet-rich plasma (PRP) products. Cell-free therapies primarily involve the use of MSC-derived extracellular vesicles/exosomes. MSCs are isolated from various tissues, such as fat, bone marrow, umbilical cord, menstrual blood, and foetal skin, and expanded ex vivo before transplantation. In cell-free therapies, MSC exosomes, MSC-derived cultured media, and MSC-derived extracellular vesicles are collected from MSC-conditioned media or supernatant. In this review, a literature search of the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus was conducted using several combinations of terms, such as ‘stem’, ‘cell’, ‘aging’, ‘wrinkles’, ‘nasolabial folds’, ‘therapy’, ‘mesenchymal stem cells’, and ‘skin’, to identify relevant articles providing a comprehensive update on the different regenerative medicine-based therapies and their application to skin regeneration. In addition, the regulatory perspectives on the clinical application of some of these therapies in Japan are highlighted.

Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as “stem cell,” “alopecia,” “hair loss,” “Androgenetic alopecia,” “male-pattern hair loss,” “female-pattern hair loss,” “regenerative hair growth,” “cell therapy,” “mesenchymal stem cells,” “MSC-derived extracellular vesicles,” “MSC-derived exosomes,” and “platelet-rich plasma” and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.