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[Emerio Boykins]

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The realization that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs to create more effective vaccines. Early clinical trials exploring autologous DCs that were loaded with antigens ex vivo to induce T-cell responses have provided proof of principle. Here, we discuss how direct targeting of antigens to DC surface receptors in vivo might replace laborious and expensive ex vivo culturing, and facilitate large-scale application of DC-based vaccination therapies.

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Clinical trials exploring DC-based vaccines mostly involve autologous DCs that are cultured and loaded with antigens ex vivo, which is a costly procedure. Targeting antigens to DC surface receptors in vivo bypasses the necessity for ex vivo DC culturing, allowing large-scale application of DC-based vaccination therapy.

Preclinical mouse studies for targeted delivery of antigens to DCs in vivo show successful induction of humoral and cellular responses. Targeting tumour antigens to DC surface receptors has been shown to protect mice from growing tumours and even cure them of existing tumours.

Advancing knowledge on the intracellular routing of antigen allows for the design of more potent vaccines. The use of powerful DC maturation stimuli, agents that facilitate antigen to escape from endosomes or means to prevent rapid antigen degradation have been shown to enhance humoral responses, cellular responses, or both.

The realization that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs to create more effective vaccines. Early clinical trials exploring autologous DCs that were loaded with antigens ex vivo to induce T-cell responses have provided proof of principle. Here, we discuss how direct targeting of antigens to DC surface receptors in vivo might replace laborious and expensive ex vivo culturing, and facilitate large-scale application of DC-based vaccination therapies.

The standard proteasome is composed of 14 α and β subunits, of which three, β1, β2 and β5, are involved in peptide-bond cleavage. Interferon-γ induces the expression of the immunosubunits β1i, β2i and β5i that can replace the catalytic subunits of the standard proteasome to generate the immunoproteasome, which has distinct cleavage-site preferences.

(Immunoreceptor tyrosine-based activation motif). A structural motif containing a tyrosine residue that is found in the cytoplasmic tails of several signalling molecules. The consensus sequence consists of Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by Src tyrosine kinases and subsequent binding of proteins containing SRC homologue 2 domains.

(Immunoreceptor tyrosine-based inhibitory motif). A structural motif found in the cytoplasmic domains of many receptors that negatively regulates intracellular signalling complexes. The consensus sequence consists of Ile/Val-Xaa-Tyr-Xaa-Xaa-Leu/Val.

(TLRs). A family of membrane-spanning proteins that recognize structurally conserved molecules that are shared by various microorganisms. Signalling through TLRs generally results in immune activation.

Having affinity for, and thus accumulating in, lysosomes. Lysosomotropic weak bases that are capable of crossing biological membranes selectively accumulate in acidic compartments by protonation, thereby affecting organelle pH and function.

A further increase in the number of total hip arthroplasty (THA) is predicted, in particular the number of young THA patients has raised and with it their demands. There is no standardized evidence-based rehabilitation program and no reliable guidelines for sports activities after THA. Stretching and strengthening gymnastics are routinely performed in rehabilitation and aerobics as a sport after THA. The aim of the investigation was to determine the in vivo force and moments acting on the hip prosthesis during gymnastics and aerobic exercises to provide a source for evidence-based recommendations. Hip joint loads were measured in six patients with instrumented hip implants. The resulting force FRes, bending moment MBend at the neck and torsional moment MTors at the stem were examined during seven strengthening (with two different resistance bands) and four stretching gymnastic exercises and seven aerobic exercises with and without an aerobic step board compared to the loads during the reference activity walking. The stretching and strengthening gymnastics exercises and the aerobic exercises with and without a board demonstrated in their median peak force and moments mostly lower or similar values compared to walking. Significantly increased loads were recorded for the flexor stretching exercise in monopod stand (Fres and MBend), the strengthening abduction exercise on the chair (MTors) and the strengthening flexion exercise with the stronger resistance band (MTors). We also found a significant increase in median peak values in aerobic exercises with a board for the "Basic Step" (ipsilateral started Fres and MTors; contralateral started MTors), "Kickstep ipsilateral started" (Fres and MTors) and "Over the Top contralateral started" (Fres). The in vivo loads in THA patients during frequently performed stretching, strengthening and aerobic exercises were demonstrated for the first time. It was proved that stretching gymnastic exercises are safe in terms of resulting force, bending and torque moments for THA patients, although an external assistance for stabilization may be considered. Strengthening gymnastics exercises are reliable in terms of Fres, MBend and MTors, but, based on our data, we recommend to adhere to the communicated specific postoperative restrictions and select the resistance bands with lower tension. Aerobic exercises without an aerobic board can be considered as reliable activity in terms of force and moments for THA patients. Aerobic exercises with a board are not recommended for the early postoperative period and in our opinion need to be adapted to the individual muscular and coordinative resources.

Total hip arthroplasty (THA) is one of the most frequently performed surgical procedures in Germany with more than 240,000 surgeries in 2019 and a predicted increase by 27% in THA numbers by 20401,2. THA is considered a successful intervention, but some serious complications such as THA dislocation or aseptic loosening occur and may require revision surgery3,4. After THA, early mobilization is widely practiced and accelerated recovery and a lower rate of complications such as deep vein thrombosis and pneumonia are assumed compared with delayed mobilization5,6. In fact, full weight bearing after cementless THA was long discussed in contrast to cemented THA, but is nowadays common practice. Due to improved coating materials and implant design and soft-tissue preserving approaches in recent years, primary stability in cementless THA is considered appropriate7,8,9,10. Among the expanding number of patients with THA, the rising number in young patients (

In a 10-year follow-up after cementless THA, Innmann et al. found a constant activity level compared to preoperatively with a shift from high to low impact sports16. Hara et al. even found an increased activity level after THA17. One study even reported successful participation in ultra trail races by patients with hip replacement18.

Moderate physical activity is considered to improve implant longevity by stimulating bone metabolism leading to enhanced osteointegration and muscular stabilization of the joint with presumably reduced risk of dislocation19,20. However, it is also being discussed whether physical activity may increase wear and aseptic loosening by inducing mechanical strain, particularly torsion forces may affect the stability of the stem20,21,22,23. Ollivier et al. reported a higher THA revision rate in THA patients with high activity level24. Accordingly, avoiding high impact sports is discussed as a risk reduction to prevent excessive wear and subsequent aseptic loosening25,26. In contrast, a systematic review demonstrated no clear evidence of a relationship between high activity levels and early THA failure at midterm follow-up27. Furthermore, no significant literature reported on early activity after THA and increased rates of periprosthetic fractures or THA instability12.

Despite the increased patient expectations there are still no conclusive evidence-based guidelines from the professional orthopedic associations on which basis sport activities can be recommended12,15,19.

Many THA patients undergo postoperative rehabilitation programs with instructed physiotherapy exercises, often involving gymnastics and basic aerobic exercises28. This is intended to improve joint mobility, gait pattern and reinforce the muscles surrounding the prosthetic joint29,30. Despite the recent surge of general interest in physical activity and THA, the actual impact of gymnastics and aerobics on in vivo hip joint forces and moments has not yet been adequately investigated. In the past few years, more studies have been conducted on joint loads during activities of daily life, which are partly based on indirect measurements. Mathematical models are used to infer the hip loads from gait analysis data22,31,32,33. So far, there are investigations with instrumented implants measuring in vivo loads on the hip joint during basic physiotherapeutic and aquatic exercises34,35. Most of the basic physiotherapeutic procedures conducted were not deemed hazardous in terms of peak loads, but weight bearing exercises in the early postoperative phase were considered critical (with Fres peak values up to 441%bodyweight (BW) compared to reference walking with 266%BW). However, although gymnastics and aerobics with stretching and strengthening exercises as well as rhythmic movements are often performed as an activity in rehabilitative treatment concepts and as a leisure activity, the realistic in vivo loading on the prosthetic hip joint are still unknown28. Consequently this study was conducted to reduce the lack of evidence concerning hip joint loads during gymnastics and aerobics and to provide a source for evidence-based recommendations regarding sports and rehabilitation activities after THA. Therefore, the aim of our investigation was to determine the hip joint in vivo loading compared to the reference walking.

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