Optimising treatment of younger, active knee osteoarthritis patients:Surgical options and functional outcomes

The main objective of this thesis is to facilitate the shared-decision making for the best surgical treatment strategy in relatively young and active knee osteoarthritis (OA) patients, based on their individual expectations and activity goals. We investigated three topics: I) current functional outcomes, including participation in sports and work, of joint preserving alternatives to knee arthroplasty (KA), II) prognostic factors for patient relevant outcomes, such as return to sport and work, after knee osteotomy and KA, and III) strategies to optimize outcomes like goal attainment and patient satisfaction in this relatively young and active group of KA patients. The results reported in this thesis support the use of knee joint sparing alternatives to KA in the treatment of relatively young, active patients. Individual activity goals, and prognostic factors for patient relevant outcomes, such as preoperative sports participation and being the family’s breadwinner, should be taken into account when deciding which treatment option is best for each specific patient. Finally, if patients go on to require a knee arthroplasty, goal-oriented and personalized rehabilitation should be offered

Structural Studies of Lanthanide Double Perovskites

This project focuses on the examination of the structures of lanthanide containing double perovskites of the type Ba2LnB'O6-d (Ln = lanthanide or Y3+ and B' = Nb5+, Ta5+, Sb5+ and/or Sn4+) using synchrotron X-ray and neutron powder diffraction. The first part of this project examined the relative stability of R3 rhombohedral and I4/m tetragonal structures as the intermediate phase adopted by the series Ba2LnB'O6 (Ln = lanthanide (III) or Y3+ and B' = Nb5+, Ta5+ or Sb5+). It was found that I4/m tetragonal symmetry was favoured when B' was a transition metal with a small number of d electrons, such as Nb5+ or Ta5+. This is due to the presence of p-bonding in these compounds. In the Ba2LnNbO6 and Ba2LnTaO6 series R3 rhombohedral symmetry was, however, favoured over I4/m tetragonal symmetry when Ln = La3+ or Pr3+ due to the larger ionic radius of these cations. The incompatibility of the d0 and d10 B'-site cations in this family of compounds was indicated by significant regions of phase segregation in the two series Ba2Eu1-xPrxNb1-xSbxO6 and Ba2NdNb1-xSbxO6. In the second part of this project the compounds in the series Ba2LnSnxB'1-xO6-d (Ln = Pr, Nd or Tb and B' = Nb5+ or Sb5+) were examined to understand the relative stability of oxygen vacancies in these materials compared to the oxidation of the lanthanide cations and to determine if any oxygen vacancy ordering occurred. It was found, using a combination of structural characterisation, X ray Absorption Near Edge Structure and Ultra-Violet, Visible and Near Infrared spectroscopies, that with Ln = Pr or Tb increased Sn4+ doping results in a change in the oxidation state of the Ln3+ cations to Ln4+. This leads to those series containing little or no oxygen vacancies. A loss of B site cation ordering was found to accompany this oxidation state change and phase segregation was found to occur in the Ba2PrSnxSb1-xO6-d series most likely due to the Pr3+ and Pr4+ cations segregating into different phases. The Nd3+ cations in the series Ba2NdSnxSb1-xO6-d, however, can not oxidise to the tetravalent state so the number of oxygen vacancies rises with increasing x. It was found that oxygen vacancies concentrate onto the axial site of the compounds with x = 0.6 and 0.8 at ambient temperature. In Ba2Sn0.6Sb0.4O5.7 the oxygen vacancies were found to change to concentrating on the equatorial site at higher temperatures and it is suggested that this oxygen vacancy ordering plays a role in the adoption of I2/m monoclinic symmetry

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy.

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity

Modelling and characterisation of a ultrasound-actuated needle for improved visibility in ultrasound-guided regional anaesthesia and tissue biopsy

AbstractClear needle visualisation is recognised as an unmet need for ultrasound guided percutaneous needle procedures including regional anaesthesia and tissue biopsy. With inadequate needle visibility, these procedures may result in serious complications or a failed operation. This paper reports analysis of the modal behaviour of a previously proposed ultrasound-actuated needle configuration, which may overcome this problem by improving needle visibility in colour Doppler imaging. It uses a piezoelectric transducer to actuate longitudinal resonant modes in needles (outer diameter 0.8–1.2mm, length>65mm). The factors that affect the needle’s vibration mode are identified, including the needle length, the transducer’s resonance frequency and the gripping position. Their effects are investigated using finite element modelling, with the conclusions validated experimentally. The actuated needle was inserted into porcine tissue up to 30mm depth and its visibility was observed under colour Doppler imaging. The piezoelectric transducer is able to generate longitudinal vibration with peak-to-peak amplitude up to 4μm at the needle tip with an actuating voltage of 20Vpp. Actuated in longitudinal vibration modes (distal mode at 27.6kHz and transducer mode at 42.2kHz) with a drive amplitude of 12–14Vpp, a 120mm needle is delineated as a coloured line in colour Doppler images, with both needle tip and shaft visualised. The improved needle visibility is maintained while the needle is advanced into the tissue, thus allowing tracking of the needle position in real time. Moreover, the needle tip is highlighted by strong coloured artefacts around the actuated needle generated by its flexural vibration. A limitation of the technique is that the transducer mode requires needles of specific lengths so that the needle’s resonance frequency matches the transducer. This may restrict the choice of needle lengths in clinical applications

Breast MRI in nonpalpable breast lesions: a randomized trial with diagnostic and therapeutic outcome – MONET – study

<p>Abstract</p> <p>Background</p> <p>In recent years there has been an increasing interest in MRI as a non-invasive diagnostic modality for the work-up of suspicious breast lesions. The additional value of Breast MRI lies mainly in its capacity to detect multicentric and multifocal disease, to detect invasive components in ductal carcinoma in situ lesions and to depict the tumor in a 3-dimensional image. Breast MRI therefore has the potential to improve the diagnosis and provide better preoperative staging and possibly surgical care in patients with breast cancer. The aim of our study is to assess whether performing contrast enhanced Breast MRI can reduce the number of surgical procedures due to better preoperative staging and whether a subgroup of women with suspicious nonpalpable breast lesions can be identified in which the combination of mammography, ultrasound and state-of-the-art contrast-enhanced Breast MRI can provide a definite diagnosis.</p> <p>Methods/Design</p> <p>The MONET – study (<b><it>M</it></b>R mammography <b><it>O</it></b>f <b><it>N</it></b>onpalpable Br<b><it>E</it></b>ast <b><it>T</it></b>umors) is a randomized controlled trial with diagnostic and therapeutic endpoints. We aim to include 500 patients with nonpalpable suspicious breast lesions who are referred for biopsy. With this number of patients, the expected 12% reduction in surgical procedures due to more accurate preoperative staging with Breast MRI can be detected with a high power (90%). The secondary outcome is the positive and negative predictive value of contrast enhanced Breast MRI. If the predictive values are deemed sufficiently close to those for large core biopsy then the latter, invasive, procedure could possibly be avoided in some women. The rationale, study design and the baseline characteristics of the first 100 included patients are described.</p> <p>Trial registration</p> <p>Study protocol number NCT00302120</p

Recommendations for the use of bioresorbable vascular scaffolds in percutaneous coronary interventions

Background To eliminate some of the potential late limitations of permanent metallic stents, the bioresorbable coronary stents or ‘bioresorbable vascular scaffolds’ (BVS) have been developed. Methods We reviewed all currently available clinical data on BVS implantation. Results Since the 2015 position statement on the appropriateness of BVS in percutaneous coronary interventions, several large randomised trials have been presented. These have demonstrated that achieving adequate 1 and 2 year outcomes with these first-generation BVS is not straightforward. These first adequately powered studies in non-complex lesions showed worse results if standard implan- tation techniques were used for these relatively thick scaffolds. Post-hoc analyses hypothesise that outcomes similar to current drug-eluting stents are still possible if aggressive lesion preparation, adequate sizing and high-pressure postdilatation are implemented rigorously. As long as this has not been confirmed in prospective studies the usage should be restricted to experienced centres with continuous outcome monitoring. For more complex lesions, results are even more disappointing and usage should be discouraged. When developed, newer generation scaffolds with thinner struts or faster resorption rates are expected to improve outcomes. In the meantime prolonged dual antiplatelet therapy (DAPT, beyond one year) is recommended in an individu-alised approach for patients treated with current generation BVS. Conclusion The new 2017 recommendations downgrade and limit the use of the current BVS to experienced centres within dedicated registries using the updated implantation protocol and advise the prolonged usage of DAPT. In line with these recommendations the manufacturer does not supply devices to the hospitals without such registries in place

Author Correction:The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy (Scientific Reports, (2020), 10, 1, (9819), 10.1038/s41598-020-66656-9)

The title in the original version of this Article contained a typographical error of ‘unresponsive’. The error has now been corrected in the PDF and HTML versions of the Article

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856)