Novel Treatments with Small Molecules in Psoriatic Arthritis

Current treatment options for patients with active psoriatic arthritis (PsA) include synthetic disease-modifying antirheumatic drugs and biologic agents. Propelled by increased understanding of immunopathogenesis of PsA, new therapeutic agents targeting different biologic pathways have been evaluated. This article discusses novel small-molecule, orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA. This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase (JAK) inhibitors. Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA. Tofacitinib, an oral inhibitor of JAK3, JAK1, and, to a lesser degree, JAK2, approved for the treatment of rheumatoid arthritis in several countries, has demonstrated positive results in psoriasis in phase II studies. Studies in PsA are ongoing. With these new developments, treatment options will continue to improve in the future.     

In Vivo Deformation and Strain Measurements in Human Bone Using Digital Volume Correlation (DVC) and 3T Clinical MRI

Strains within bone play an important role in the remodelling process and the mechanisms of fracture. The ability to assess these strains in vivo can provide clinically relevant information regarding bone health, injury risk, and can also be used to optimise treatments. In vivo bone strains have been investigated using multiple experimental techniques, but none have quantified 3D strains using non-invasive techniques. Digital volume correlation based on clinical MRI (DVC-MRI) is a non-invasive technique that has the potential to achieve this. However, before it can be implemented, uncertainties associated with the measurements must be quantified. Here, DVC-MRI was evaluated to assess its potential to measure in vivo strains in the talus. A zero-strain test (two repeated unloaded scans) was conducted using three MRI sequences, and three DVC approaches to quantify errors and to establish optimal settings. With optimal settings, strains could be measured with a precision of 200 με and accuracy of 480 με for a spatial resolution of 7.5 mm, and a precision of 133 με and accuracy of 251 με for a spatial resolution of 10 mm. These results demonstrate that this technique has the potential to measure relevant levels of in vivo bone strain and to be used for a range of clinical applications.     

Research on Microstructure and Mechanical Properties of Rheological Die Forging Parts of Al-6.54Zn-2.40Cu-2.35Mg-0.10Zr(-Sc) Alloy

High-strength aluminum alloy (mainly refers to the 7xxx series) is the optimum material for lightweight military equipment. However, this type of aluminum alloy is a wrought aluminum alloy. If it is directly formed by traditional casting methods, there will inevitably be problems such as coarseness, unevenness, looseness, and hot cracking in the structure, which will greatly affect the final performance of the part. Based on the internal cooling with annular electromagnetic stirring (IC-AEMS) method, a new technology of rheological die forging is developed in this paper, and the scale-reduced parts of a brake hub of Al-6.54Zn-2.40Cu-2.35Mg-0.10Zr aluminum alloy were prepared. The influence of IC-AEMS and the addition of rare element Sc on the structure and mechanical properties of the parts was studied. An optical microscope and scanning electron microscope (SEM) were used to observe the microstructure evolution, energy dispersive spectroscopy (EDS) was used to analyze the phase distribution and composition, and the mechanical properties of the parts were tested by uniaxial tensile tests. The results show that the addition of Sc element can effectively refine the grains and improve the strength and elongation of the material; the application of IC-AEMS improves the cooling rate of the melt, increases the effective nucleation rate, and the grains are further refined. Through process optimization, scale-reduced parts of a brake hub with good formability and mechanical properties can be obtained, the ultimate tensile strength is 597.2 ± 3.1 MPa, the yield strength is 517.8 ± 4.3 MPa, and the elongation is 13.7 ± 1.3%.     

Healthcare providers’ awareness of the information needs of their cardiac rehabilitation patients throughout the program continuum

Objective

To (1) describe cardiac rehabilitation (CR) participant information needs, (2) investigate whether CR providers are cognizant of patient's information needs and preferred delivery formats, and (3) investigate whether patient information needs change over the course of CR.

Methods

In this cross-sectional study, 306 CR patients and 28 CR providers completed a survey. The survey consisted of the Information Needs in CR (INCR) questionnaire, and items about preferred education delivery formats.

Results

Low-income CR participants had significantly greater information needs than high-income participants. CR providers were cognizant of patient information needs, except patients did desire more information on diagnosis and treatment than providers perceived (p < 0.01). Books, lectures and discussion were identified as the preferred delivery formats by both patients and providers. There were some significant differences in patient information needs over the course of the program, particularly in relation to concerns and risk factors.

Conclusion

CR patients desire information in many areas, particularly regarding emergency/safety and diagnosis/treatment. CR providers were highly cognizant of patient information needs; however, these do change over time.

Practice implications

These findings could inform evaluation and improvement of CR education programming, to ensure programs are meeting patient information needs across all stages of recovery.     

Living in uncertain times: trajectories to death in residential care homes

Background

Older people living in care homes often have limited life expectancy. Practitioners and policymakers are increasingly questioning the appropriateness of many acute hospital admissions and the quality of end-of-life care provided in care homes.

Aim

To describe care home residents’ trajectories to death and care provision in their final weeks of life.

Design and setting

Prospective study of residents in six residential care homes in three sociodemographically varied English localities: Hertfordshire, Essex, and Cambridgeshire.

Method

Case note reviews and interviews with residents, care home staff, and healthcare professionals.

Results

Twenty-three out of 121 recruited residents died during the study period. Four trajectories to death were identified: ‘anticipated dying’ with an identifiable end-of-life care period and death in the care home (n = 9); ‘unexpected dying’ with death in the care home that was not anticipated and often sudden (n = 3); ‘uncertain dying’ with a period of diagnostic uncertainty or difficult symptom management leading to hospital admission and inpatient death (n = 7); and ‘unpredictable dying’ with an unexpected event leading to hospital admission and inpatient death (n = 4). End-of-life care tools were rarely used. Most residents who had had one or more acute hospital admission were still alive at the end of the study.

Conclusion

For some care home residents there was an identifiable period when they were approaching the end-of-life and planned care was put in place. For others, death came unexpectedly or during a period of considerable uncertainty, with care largely unplanned and reactive to events.     

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen

Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by persisting mucoid biofilms in hypoxic endobronchial mucus. These biofilms are surrounded by numerous polymorphonuclear leucocytes (PMNs), which consume a major part of present molecular oxygen (O₂) due to production of superoxide (O₂⁻). In this study, we show that the PMNs also consume O₂ for production of nitric oxide (NO) by the nitric oxide synthases (NOS) in the infected endobronchial mucus. Fresh expectorated sputum samples (n = 28) from chronically infected CF patients (n = 22) were analysed by quantifying and visualizing the NO production. NO production was detected by optode measurements combined with fluorescence microscopy, flow cytometry and spectrophotometry. Inhibition of nitric oxide synthases (NOS) with N^G-monomethyl-L-arginine (L-NMMA) resulted in reduced O₂ consumption (P < 0·0008, n = 8) and a lower fraction of cells with fluorescence from the NO-indicator 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) (P < 0·002, n = 8). PMNs stained with DAF-FM and the superoxide indicator hydroethidine (HE) and host cells with inducible NOS (iNOS) were identified in the sputum. In addition, the production of the stable end-products of NO in CF sputum was correlated with the concentration of PMNs; NO₃⁻ (P < 0·04, r = 0·66, n = 10) and NO₂⁻ (P< 0·006, r = 0·78, n = 11). The present study suggests that besides consumption of O₂ for production of reactive oxygen species, the PMNs in CF sputum also consume O₂ for production of NO.     

A novel T‐cell receptor mimic defines dendritic cells that present an immunodominant West Nile virus epitope in mice

We used a newly generated T‐cell receptor mimic monoclonal antibody (TCRm MAb) that recognizes a known nonself immunodominant peptide epitope from West Nile virus (WNV) NS4B protein to investigate epitope presentation after virus infection in C57BL/6 mice. Previous studies suggested that peptides of different length, either SSVWNATTAI (10‐mer) or SSVWNATTA (9‐mer) in complex with class I MHC antigen H‐2D^b, were immunodominant after WNV infection. Our data establish that both peptides are presented on the cell surface after WNV infection and that CD8⁺ T cells can detect 10‐ and 9‐mer length variants similarly. This result varies from the idea that a given T‐cell receptor (TCR) prefers a single peptide length bound to its cognate class I MHC. In separate WNV infection studies with the TCRm MAb, we show that in vivo the 10‐mer was presented on the surface of uninfected and infected CD8α⁺CD11c⁺ dendritic cells, which suggests the use of direct and cross‐presentation pathways. In contrast, CD11b⁺CD11c^? cells bound the TCRm MAb only when they were infected. Our study demonstrates that TCR recognition of peptides is not limited to certain peptide lengths and that TCRm MAbs can be used to dissect the cell‐type specific mechanisms of antigen presentation in vivo.