Nanovesicle-based therapy is increasingly being pursued as a safe, cell-free strategy to combat various immunological, musculoskeletal and neurodegenerative diseases. Small secreted extracellular vesicles (sEVs) obtained from multipotent mesenchymal stromal cells (MSCs) are of particular interest for therapeutic use since they convey anti-inflammatory, anti-scarring and neuroprotective activities to the recipient cells. Cell-derived vesicles (CDVs) produced by a proprietary extrusion process are surrounded by a lipid bilayer membrane with correct membrane topology, display biological activities similar to MSC-derived EVs and may find specific application for organ-targeted drug delivery systems. Translation of nanovesicle-based therapeutics into clinical application requires quantitative and reproducible analysis of bioactivity and stability, and the potential for GMP-compliant manufacturing. Manufacturing and regulatory considerations as well as preclinical models to support clinical translation will be discussed

Chronic pain is recognised as a problem worldwide. Interdisciplinary multimodal pain therapy (MMPT) is currently the gold standard of treatment. The aim of the present prospective observational study is to research whether chronic pain patients form an intention for lifestyle change during a 4-week-long treatment at the Outpatient Clinic for Pain Therapy and Conservative Orthopedics in Heidelberg, Germany, and how sustainable this change is after 3 months. In addition, we theorized a connection between standardised survey endpoints and the number of therapy units perceived as helpful (TPAH). Finally, the effect of socio-demographic factors on patient perceptions were put into perspective. Clinical data was collected via 3-part-questionnaires from 95 German-speaking patients at 4 checkpoints between 05/2020 and 11/2021 at admission (T1), after 2 weeks (T2), at discharge (T3) and 3 months post-treatment (T4). The questionnaires consisted of already established scores for surveying chronic pain patients, such as the von Korff Chronification Scale, ODI, HADS, PSEQ/FESS, and FABQ, a grading scale for each therapy unit, and free answers. Patients were most likely to implement Group Walking in their everyday lives. A higher number of TPAH neither lowered nor improved significantly the change in lifestyle, but both a higher number and bigger lifestyle changes improved significantly the scores across the standardised surveys. Furthermore, no significant change in intention happened between the second and the fourth week. Physical components were perceived throughout as more helpful. The results of this research support the efficacy of MMPT in multi-faceted improving of the patient's well-being and lowering the possibility for pain chronification. A higher number of TPAH could be translated as having more available techniques to combat chronic pain in everyday life. The number of TPAH and the amount of lifestyle change both influence positively the survey scores, yet no connection between them was found. A third factor could be the reason for this constellation. The possibility that the more mental therapies are offered, the more likely it is for those to be perceived as helpful, cannot be excluded either. Further research is required on both topics

Introduction. Civilian fractures have been extensively studied with in an attempt to develop classification systems, which guide optimal fracture management, predict outcome or facilitate communication. More recently, biomechanical analyses have been applied in order to suggest mechanism of injury after the traumatic insult, and predict injuries as a result of a mechanism of injury, with particular application to the field so forensics. However, little work has been carried out on military fractures, and the application of civilian fracture classification systems are fraught with error. Explosive injuries have been sub-divided into primary, secondary and tertiary effects. The aim of this study was to 1. determine which effects of the explosion are responsible for combat casualty extremity bone injury in 2 distinct environments; a) in the open and b) enclosed space (either in vehicle or in cover) 2. determine whether patterns of combat casualty bone injury differed between environments Invariably, this has implications for injury classification and the development of appropriate mitigation strategies. Method. All ED records, case notes, and radiographs of patients admitted to the British military hospital in Afghanistan were reviewed over a 6 month period Apr 08-Sept 08 to identify any fracture caused by an explosive mechanism. Paediatric cases were excluded from the analysis. All radiographs were independently reviewed by a Radiologist, a team of Military Orthopaedic Surgeons and a team of academic Biomechanists, in order to determine the fracture classification and predict the mechanism of injury. Early in the study it became clear that due to the complexity of some of the injuries it was inappropriate to consider bones separately and the term ‘Zone of Insult’ (ZoI) was developed to identify separate areas of injury. Results. 62 combat casualties with 115 ZoIs (mean 1.82 zones) were identified in this study. 34 casualties in the open sustained 56 ZoIs (mean 1.65); 28 casualties in the enclosed group sustained 59 ZoIs (mean 2.10). There was no statistical difference in the mean ZoIs per casualty in the open vs enclosed group (Student t-test, p=0.24). Open fractures were more prevalent in the open group compared to the enclosed group (48/59 vs 20/49, Chi-squared test p<0.001). Of the casualties in the open, 1 zone of injury was due to the primary effects of blast, 10 a combination of primary and secondary blast zones, 23 due to secondary effects and 24 from the tertiary effects of blast. In contrast, there were no primary or combined primary and secondary blast zones and only 2 secondary blast zones in the enclosed group. Tertiary blast effects predominated in the enclosed group, accounting for 96% of injury zones (57/59). Analysis of the pattern of injury revealed that there were a higher proportion of lower limb injuries in the Enclosed group (54/59) compared to the Open group (40/58, Chi-squared p<0.05). In the Open group the mechanism of lower limb injury was more evenly distributed amongst mixed primary and secondary blast effects (10), secondary (10) and tertiary (20). In the enclosed group, lower limb injuries were almost exclusively caused by tertiary blast effects (47/48). A similar pattern was also seen in the Upper limb with 4/5 in the enclosed group was injured by tertiary effects compared to 4/18 in the Open Group. In the open group fragmentation injury was the predominant cause of injury (13/18). Conclusions. This data clearly demonstrates two distinct injury groups based upon the casualties' environment. The enclosed environment afforded by buildings and vehicles appears to mitigate the primary and secondary effects of the explosion. However, tertiary blast effects were the predominant mechanism of injury, with severe axial loading to the lower extremity being a characteristic of the fractures seen. In contrast, secondary fragments from the explosion were more likely to result in fractures of casualties caught in the open. The development of future mitigation strategies must be focused on reducing all the different mechanisms of injury caused by an explosion. This will require a better understanding on the effects of bone in high strain environments. This method of forensic biomechanics involving clinicians and engineers, combined with accurate physical and numerical simulations can form the basis in reducing the injury burden to the combat soldier

Osteoarthritis (OA) is a debilitating joint disease that severely affects elderly populations. At present there are no effective treatments for OA and mechanisms of disease progression are poorly understood. Previous work has identified that neuronal-Interleukin-16 (nIL-16) was significantly up-regulated in cartilage during the later stages of OA. Preliminary investigations identified co-localisation of nIL-16 with the Transient Receptor Potential cation ion-channel sub-Family-V-member-4 (TRPV4) in the primary cilium and the pericellular matrix of human OA chondrocytes. Perturbation of both TRPV4 and cilia are strongly associated with OA. We hypothesised that nIL-16 and TRPV4 work in tandem in a pathway that leads to chondrocyte hypertrophy and calcification that is seen in late OA and contributes to the loss of joint integrity. This makes it a promising target for development of a gene therapy to combat the disease. With the aim of elucidating the mechanism involved, nIl-16 knock-out cell lines generated using the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system will be used to knock out nIl-16 PDZ domains to investigate whether this is the mechanism in which nIL-16 functions to anchor TRPV4 to the membrane of chondrocytes at the primary cilium. This work will be carried out using an immortalized hTERT mesenchymal stromal cell (MSC) cell line and effects on terminal MSC chondrogenesis, where hypertrophy mimics the process of calcification seen in OA, will be used to define functional effects of the knockout. Cell lines will be made using the RALA peptide (Phion Therapeutics), a bioinspired nanoparticle, for delivery the CRISPR/Cas9 system

We studied 51 patients with osteo-articular tuberculosis who were divided into two groups. Group I comprised 31 newly-diagnosed patients who were given first-line antituberculous treatment consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Group II (non-responders) consisted of 20 patients with a history of clinical non-responsiveness to supervised uninterrupted antituberculous treatment for a minimum of three months or a recurrence of a previous lesion which on clinical observation had healed. No patient in either group was HIV-positive. Group II were treated with an immunomodulation regime of intradermal BCG, oral levamisole and intramuscular diphtheria and tetanus vaccines as an adjunct for eight weeks in addition to antituberculous treatment. We gave antituberculous treatment for a total of 12 to 18 months in both groups and they were followed up for a mean of 30.2 months (24 to 49). A series of 20 healthy blood donors served as a control group.

Twenty-nine (93.6%) of the 31 patients in group I and 14 of the 20 (70%) in group II had a clinicoradiological healing response to treatment by five months.

The CD4 cell count in both groups was depressed at the time of enrolment, with a greater degree of depression in the group-II patients (686 cells/mm³ (sd 261) and 545 cells/mm³ (sd 137), respectively; p < 0.05). After treatment for three months both groups showed significant elevation of the CD4 cell count, reaching a level comparable with the control group. However, the mean CD4 cell count of group II (945 cells/mm³ (sd 343)) still remained lower than that of group I (1071 cells/mm³ (sd 290)), but the difference was not significant. Our study has shown encouraging results after immunomodulation and antituberculous treatment in non-responsive patients. The pattern of change in the CD4 cell count in response to treatment may be a reliable clinical indicator.