Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

Influence of hormone replacement therapy on proteomic pattern in serum of postmenopausal women

OBJECTIVES: Proteomics approaches to cardiovascular biology and disease hold the promise of identifying specific proteins and peptides or modification thereof to assist in the identification of novel biomarkers. METHOD: By using surface-enhanced laser desorption and ionization time of flight mass spectroscopy (SELDI-TOF-MS) serum peptide and protein patterns were detected enabling to discriminate between postmenopausal women with and without hormone replacement therapy (HRT). RESULTS: Serum of 13 HRT and 27 control subjects was analyzed and 42 peptides and proteins could be tentatively identified based on their molecular weight and binding characteristics on the chip surface. By using decision tree-based Biomarker Patternstrade mark Software classification and regression analysis a discriminatory function was developed allowing to distinguish between HRT women and controls correctly and, thus, yielding a sensitivity of 100% and a specificity of 100%. The results show that peptide and protein patterns have the potential to deliver novel biomarkers as well as pinpointing targets for improved treatment. The biomarkers obtained represent a promising tool to discriminate between HRT users and non-users. CONCLUSION: According to a tentative identification of the markers by their molecular weight and binding characteristics, most of them appear to be part of the inflammation induced acute-phase response

Matrix models for quantifying competitive intransitivity from species abundance data

In a network of competing species, a competitive intransitivity occurs when the ranking of competitive abilities does not follow a linear hierarchy (A > B > C but C > A). A variety of mathematical models suggests that intransitive networks can prevent or slow down competitive exclusion and maintain biodiversity by enhancing species coexistence. However, it has been difficult to assess empirically the relative importance of intransitive competition because a large number of pairwise species competition experiments are needed to construct a competition matrix that is used to parameterize existing models. Here we introduce a statistical framework for evaluating the contribution of intransitivity to community structure using species abundance matrices that are commonly generated from replicated sampling of species assemblages. We provide metrics and analytical methods for using abundance matrices to estimate species competition and patch transition matrices by using reverse-engineering and a colonization-competition model. These matrices provide complementary metrics to estimate the degree of intransitivity in the competition network of the sampled communities. Benchmark tests reveal that the proposed methods could successfully detect intransitive competition networks, even in the absence of direct measures of pairwise competitive strength. To illustrate the approach, we analyzed patterns of abundance and biomass of five species of necrophagous Diptera and eight species of their hymenopteran parasitoids that co-occur in beech forests in Germany. We found evidence for a strong competitive hierarchy within communities of flies and parasitoids. However, for parasitoids, there was a tendency towards increasing intransitivity in higher weight classes, which represented larger resource patches. These tests provide novel methods for empirically estimating the degree of intransitivity in competitive networks from observational datasets. They can be applied to experimental measures of pairwise species interactions, as well as to spatio-temporal samples of assemblages in homogenous environments or environmental gradients.

Simultaneous detection and discrimination of virulent and benign Dichelobacter nodosus in sheep of flocks affected by foot rot and in clinically healthy flocks by competitive real-time PCR.

Ovine foot rot caused by Dichelobacter nodosus is affecting sheep worldwide. The current diagnostic methods are difficult and cumbersome. Here, we present a competitive real-time PCR based on allelic discrimination of the protease genes aprV2 and aprB2. This method allows direct detection and differentiation of virulent and benign D. nodosus from interdigital skin swabs in a single test. Clinically affected sheep harbored high loads of only virulent strains, whereas healthy sheep had lower loads of predominantly benign strains.

Extent and distribution of calcification of both the aortic annulus and the left ventricular outflow tract predict aortic regurgitation after transcatheter aortic valve replacement

Aims: We sought to analyse local distribution of aortic annulus and left ventricular outflow tract (LVOT) calcification in patients undergoing transcatheter aortic valve replacement (TAVR) and its impact on aortic regurgitation (AR) immediately after device placement. Methods and results: A group of 177 patients with severe aortic stenosis undergoing multislice computed tomography of the aortic root followed by TAVR were enrolled in this single-centre study. Annular and LVOT calcifications were assessed per cusp using a semi-quantitative grading system (0: none; 1 [mild]: small, non-protruding calcifications; 2 [moderate]: protruding [>1 mm] or extensive [>50% of cusp sector] calcifications; 3 [severe]: protruding and extensive calcifications). Any calcification of the annulus or LVOT was present in 107 (61%) and 63 (36%) patients, respectively. Prevalence of annulus/LVOT calcifications in the left coronary cusp was 42% and 25%, respectively, in the non-coronary cusp 28% and 13%, in the right coronary cusp 13% and 5%. AR grade 2 to 4 assessed by the method of Sellers immediately after TAVR device implantation was observed in 55 patients (31%). Multivariate regression analysis revealed that the overall annulus calcification (OR [95% CI] 1.48 [1.10-2.00]; p=0.0106), the overall LVOT calcification (1.93 [1.26-2.96]; p=0.0026), any moderate or severe LVOT calcification (5.37 [1.52-18.99]; p=0.0092), and asymmetric LVOT calcification were independent predictors of AR. Conclusions: Calcifications of the aortic annulus and LVOT are frequent in patients undergoing TAVR, and both the distribution and the severity of calcifications appear to be independent predictors of aortic regurgitation after device implantation. - See more at: http://www.pcronline.com/eurointervention/77th_issue/126/#sthash.Hzodgju5.dpuf

Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Disease.

BACKGROUND Limited information exists describing the results of transcatheter aortic valve (TAV) replacement in patients with bicuspid aortic valve (BAV) disease (TAV-in-BAV). OBJECTIVES This study sought to evaluate clinical outcomes of a large cohort of patients undergoing TAV-in-BAV. METHODS We retrospectively collected baseline characteristics, procedural data, and clinical follow-up findings from 12 centers in Europe and Canada that had performed TAV-in-BAV. RESULTS A total of 139 patients underwent TAV-in-BAV with the balloon-expandable transcatheter heart valve (THV) (n = 48) or self-expandable THV (n = 91) systems. Patient mean age and Society of Thoracic Surgeons predicted risk of mortality scores were 78.0 ± 8.9 years and 4.9 ± 3.4%, respectively. BAV stenosis occurred in 65.5%, regurgitation in 0.7%, and mixed disease in 33.8% of patients. Incidence of type 0 BAV was 26.7%; type 1 BAV was 68.3%; and type 2 BAV was 5.0%. Multislice computed tomography (MSCT)-based TAV sizing was used in 63.5% of patients (77.1% balloon-expandable THV vs. 56.0% self-expandable THV, p = 0.02). Procedural mortality was 3.6%, with TAV embolization in 2.2% and conversion to surgery in 2.2%. The mean aortic gradient decreased from 48.7 ± 16.5 mm Hg to 11.4 ± 9.9 mm Hg (p < 0.0001). Post-implantation aortic regurgitation (AR) grade ≥2 occurred in 28.4% (19.6% balloon-expandable THV vs. 32.2% self-expandable THV, p = 0.11) but was prevalent in only 17.4% when MSCT-based TAV sizing was performed (16.7% balloon-expandable THV vs. 17.6% self-expandable THV, p = 0.99). MSCT sizing was associated with reduced AR on multivariate analysis (odds ratio [OR]: 0.19, 95% confidence intervals [CI]: 0.08 to 0.45; p < 0.0001). Thirty-day device safety, success, and efficacy were noted in 79.1%, 89.9%, and 84.9% of patients, respectively. One-year mortality was 17.5%. Major vascular complications were associated with increased 1-year mortality (OR: 5.66, 95% CI: 1.21 to 26.43; p = 0.03). CONCLUSIONS TAV-in-BAV is feasible with encouraging short- and intermediate-term clinical outcomes. Importantly, a high incidence of post-implantation AR is observed, which appears to be mitigated by MSCT-based TAV sizing. Given the suboptimal echocardiographic results, further study is required to evaluate long-term efficacy.

Feasibility and outcomes of combined transcatheter aortic valve replacement with other structural heart interventions in a single session: a matched cohort study

Background Concurrent cardiac diseases are frequent among elderly patients and invite simultaneous treatment to ensure an overall favourable patient outcome. Aim To investigate the feasibility of combined single-session percutaneous cardiac interventions in the era of transcatheter aortic valve implantation (TAVI). Methods This prospective, case–control study included 10 consecutive patients treated with TAVI, left atrial appendage occlusion and percutaneous coronary interventions. Some in addition had patent foramen ovale or atrial septal defect closure in the same session. The patients were matched in a 1:10 manner with TAVI-only cases treated within the same time period at the same institution regarding their baseline factors. The outcome was validated according to the Valve Academic Research Consortium (VARC) criteria. Results Procedural time (126±42 vs 83±40 min, p=0.0016), radiation time (34±8 vs 22±12 min, p=0.0001) and contrast dye (397±89 vs 250±105 mL, p<0.0001) were higher in the combined intervention group than in the TAVI-only group. Despite these drawbacks, no difference in the VARC endpoints was evident during the in-hospital period and after 30 days (VARC combined safety endpoint 32% for TAVI only and 20% for combined intervention, p=1.0). Conclusions Transcatheter treatment of combined cardiac diseases is feasible even in a single session in a high-volume centre with experienced operators.

Mid-term results of aortic root replacement using a self-assembled biological composite graft.

OBJECTIVES To report the mid-term results of aortic root replacement using a self-assembled biological composite graft, consisting of a vascular tube graft and a stented tissue valve. METHODS Between January 2005 and December 2011, 201 consecutive patients [median age 66 (interquartile range, IQR, 55-77) years, 31 female patients (15.4%), median logistic EuroSCORE 10 (IQR 6.8-23.2)] underwent aortic root replacement using a stented tissue valve for the following indications: annulo-aortic ectasia or ascending aortic aneurysm with aortic valve disease in 162 (76.8%) patients, active infective endocarditis in 18 (9.0%) and acute aortic dissection Stanford type A in 21 (10.4%). All patients underwent clinical and echocardiographic follow-up. We analysed survival and valve-related events. RESULTS The overall in-hospital mortality rate was 4.5%. One- and 5-year cardiac-related mortality rates were 3 and 6%, and overall survival was 95 ± 1.5 and 75 ± 3.6%, respectively. The rate of freedom from structural valve failure was 99% and 97 ± 0.4% at the 1- and 5-year follow-up, respectively. The incidence rates of prosthetic valve endocarditis were 3 and 4%, respectively. During a median follow-up of 28 (IQR 14-51) months, only 2 (1%) patients required valve-related redo surgery due to prosthetic valvular endocarditis and none suffered from thromboembolic events. One percent of patients showed structural valve deterioration without any clinical symptoms; none of the patients suffered greater than mild aortic regurgitation. CONCLUSIONS Aortic root replacement using a self-assembled biological composite graft is an interesting option. Haemodynamic results are excellent, with freedom from structured valve failure. Need for reoperation is extremely low, but long-term results are necessary to prove the durability of this concept.

Decision-making in aortic root surgery in Marfan syndrome: bleeding, thromboembolism and risk of reintervention after valve-sparing or mechanical aortic root replacement†

OBJECTIVES Valve-sparing root replacement (VSRR) is thought to reduce the rate of thromboembolic and bleeding events compared with aortic root replacement using a mechanical aortic root replacement (MRR) with a composite graft by avoiding oral anticoagulation. But as VSRR carries a certain risk for subsequent reinterventions, decision-making in the individual patient can be challenging. METHODS Of 100 Marfan syndrome (MFS) patients who underwent 169 aortic surgeries and were followed at our institution since 1995, 59 consecutive patients without a history of dissection or prior aortic surgery underwent elective VSRR or MRR and were retrospectively analysed. RESULTS VSRR was performed in 29 (David n = 24, Yacoub n = 5) and MRR in 30 patients. The mean age was 33 ± 15 years. The mean follow-up after VSRR was 6.5 ± 4 years (180 patient-years) compared with 8.8 ± 9 years (274 patient-years) after MRR. Reoperation rates after root remodelling (Yacoub) were significantly higher than after the reimplantation (David) procedure (60 vs 4.2%, P = 0.01). The need for reinterventions after the reimplantation procedure (0.8% per patient-year) was not significantly higher than after MRR (P = 0.44) but follow-up after VSRR was significantly shorter (P = 0.03). There was neither significant morbidity nor mortality associated with root reoperations. There were no neurological events after VSRR compared with four stroke/intracranial bleeding events in the MRR group (log-rank, P = 0.11), translating into an event rate of 1.46% per patient-year following MRR. CONCLUSION The calculated annual failure rate after VSRR using the reimplantation technique was lower than the annual risk for thromboembolic or bleeding events. Since the perioperative risk of reinterventions following VSRR is low, patients might benefit from VSRR even if redo surgery may become necessary during follow-up.

Mitral valve replacement in patients under 65 years of age: mechanical or biological valves?

PURPOSE OF REVIEW There is controversy regarding the optimal choice of prosthetic valves in patients less than 65 years of age requiring mitral valve replacement (MVR). Recently, trends for valve replacement are moving towards biological prosthesis also in younger patients, which is justified by the fact that a later valve-in-valve procedure is feasible in the case of degeneration of the tissue valve. This strategy is increasingly recommended in aortic valve surgery but is questionable for MVR. The purpose of this review is to evaluate current guidelines and analyse evidence for biological MVR in patients under 65 years. RECENT FINDINGS There are differences between guidelines of the American Heart Association and those of the European Society of Cardiology concerning the choice of prostheses in patients undergoing MVR. Although the European Society of Cardiology recommends a mechanical mitral valve in patients under 65 years of age, the American Heart Association does not provide detailed advice for these patients. Mitral valve replacement with biological valves in patients under 65 years is associated with higher rates of reoperation due to structural valve deterioration. In addition, several studies showed a decreased survival after biological MVR. SUMMARY Evidence for biological MVR in patients less than 65 years without comorbidities or contraindication for oral anticoagulation does not exist. Recommendations for patients less than 65 years of age should not be blurred by current 'en-vogue' methods for promising but not yet proven valve-in-valve strategies.

Aortic valve replacement and concomitant procedures with the Perceval valve: results of European trials.

BACKGROUND The Perceval (Sorin Group, Milan, Italy) is a self-anchoring sutureless aortic valve prosthesis. We report the short- to midterm results of combined aortic valve replacement (AVR) with concomitant procedures in elderly patients undergoing operation as part of 3 consecutive prospective multicenter European studies. METHODS From April 2007 to February 2013, 243 patients (mean age, 79.7 ± 5.1 years; female patients, 61%; median EuroSCORE, 9%) underwent AVR with concomitant procedures. The concomitant procedures were coronary artery bypass grafting (CABG) (182 cases), septal myectomy (21 cases), CABG + other procedures (18 cases), and 22 other procedures. Primary and secondary end points included implant feasibility and safety (for mortality and morbidity) and efficacy (New York Heart Association [NYHA] class improvement and hemodynamic results) of the prosthesis at the different follow-up periods. Data were expressed as mean ± standard deviation. Kaplan-Meier analysis was performed for survival analysis. RESULTS Mean aortic cross-clamp and extracorporeal circulation (ECC) times were 50.7 ± 22.8 minutes and 78.9 ± 32.3 minutes, respectively. Thirty-day mortality was 2.1%. Mean postoperative gradient and effective orifice area were 10.1 ± 4.7 mm Hg and 1.5 ± 0.4 cm(2) and 8.9 ± 5.6 mm Hg and 1.6 ± 0.4 cm(2), respectively, at 1 year. There were early explantations, 4 of which resulted from paravalvular leaks. One additional valve explantation resulted from aortic root bleeding, probably caused by excessively extensive decalcification. In the late period, there was 1 mild paravalvular leak and no intravalvular insufficiency. No migration, dislodgement, or degeneration of the valve occurred during follow-up. Median follow-up was 444 days. CONCLUSIONS These trials confirm the safety and efficacy of the Perceval sutureless aortic valve, especially in elderly patients requiring AVR + concomitant procedures. In this patient group, sutureless valves may be advantageous compared to transcatheter valve implantations as concomitant procedures other than percutaneous coronary artery angioplasty are not always possible in the latter.

German Total Ankle Replacement Register of the German Foot and Ankle Society (D. A. F.) - presentation of design and reliability of the data as well as first results

INTRODUCTION Even though arthroplasty of the ankle joint is considered to be an established procedure, only about 1,300 endoprostheses are implanted in Germany annually. Arthrodeses of the ankle joint are performed almost three times more often. This may be due to the availability of the procedure - more than twice as many providers perform arthrodesis - as well as the postulated high frequency of revision procedures of arthroplasties in the literature. In those publications, however, there is often no clear differentiation between revision surgery with exchange of components, subsequent interventions due to complications and subsequent surgery not associated with complications. The German Orthopaedic Foot and Ankle Association's (D. A. F.) registry for total ankle replacement collects data pertaining to perioperative complications as well as cause, nature and extent of the subsequent interventions, and postoperative patient satisfaction. MATERIAL AND METHODS The D. A. F.'s total ankle replacement register is a nation-wide, voluntary registry. After giving written informed consent, the patients can be added to the database by participating providers. Data are collected during hospital stay for surgical treatment, during routine follow-up inspections and in the context of revision surgery. The information can be submitted in paper-based or online formats. The survey instruments are available as minimum data sets or scientific questionnaires which include patient-reported outcome measures (PROMs). The pseudonymous clinical data are collected and evaluated at the Institute for Evaluative Research in Medicine, University of Bern/Switzerland (IEFM). The patient-related data remain on the register's module server in North Rhine-Westphalia, Germany. The registry's methodology as well as the results of the revisions and patient satisfaction for 115 patients with a two year follow-up period are presented. Statistical analyses are performed with SAS™ (Version 9.4, SAS Institute, Inc., Cary, NC, USA). RESULTS About 2½ years after the register was launched there are 621 datasets on primary implantations, 1,427 on follow-ups and 121 records on re-operation available. 49 % of the patients received their implants due to post-traumatic osteoarthritis, 27 % because of a primary osteoarthritis and 15 % of patients suffered from a rheumatic disease. More than 90 % of the primary interventions proceeded without complications. Subsequent interventions were recorded for 84 patients, which corresponds to a rate of 13.5 % with respect to the primary implantations. It should be noted that these secondary procedures also include two-stage procedures not due to a complication. "True revisions" are interventions with exchange of components due to mechanical complications and/or infection and were present in 7.6 % of patients. 415 of the patients commented on their satisfaction with the operative result during the last follow-up: 89.9 % of patients evaluate their outcome as excellent or good, 9.4 % as moderate and only 0.7 % (3 patients) as poor. In these three cases a component loosening or symptomatic USG osteoarthritis was present. Two-year follow-up data using the American Orthopedic Foot and Ankle Society Ankle and Hindfoot Scale (AOFAS-AHS) are already available for 115 patients. The median AOFAS-AHS score increased from 33 points preoperatively to more than 80 points three to six months postoperatively. This increase remained nearly constant over the entire two-year follow-up period. CONCLUSION Covering less than 10 % of the approximately 240 providers in Germany and approximately 12 % of the annually implanted total ankle-replacements, the D. A. F.-register is still far from being seen as a national registry. Nevertheless, geographical coverage and inclusion of "high-" (more than 100 total ankle replacements a year) and "low-volume surgeons" (less than 5 total ankle replacements a year) make the register representative for Germany. The registry data show that the number of subsequent interventions and in particular the "true revision" procedures are markedly lower than the 20 % often postulated in the literature. In addition, a high level of patient satisfaction over the short and medium term is recorded. From the perspective of the authors, these results indicate that total ankle arthroplasty - given a correct indication and appropriate selection of patients - is not inferior to an ankle arthrodesis concerning patients' satisfaction and function. First valid survival rates can be expected about 10 years after the register's start.

A Simple Guideline Reduces the Need for Red Blood Cell Transfusions in Swiss Hospitals: A Prospective, Multicentre, Before-and-After Study in Elective Hip and Knee Replacement

INTRODUCTION Optimising the use of blood has become a core task of transfusion medicine. Because no general guidelines are available in Switzerland, we analysed the effects of the introduction of a guideline on red blood cell (RBC) transfusion for elective orthopaedic surgery. METHODS Prospective, multicentre, before-and-after study comparing the use of RBCs in adult elective hip or knee replacement before and after the implementation of a guideline in 10 Swiss hospitals, developed together with all participants. RESULTS We included 2,134 patients, 1,238 in 7 months before, 896 in 6 months after intervention. 57 (34 or 2.7% before, 23 or 2.6% after) were lost before follow-up visit. The mean number of transfused RBC units decreased from 0.5 to 0.4 per patient (0.1, 95% CI 0.08-0.2; p = 0.014), the proportion of transfused patients from 20.9% to 16.9% (4%, 95% C.I. 0.7-7.4%; p = 0.02), and the pre-transfusion haemoglobin from 82.6 to 78.2 g/l (4.4 g/l, 95% C. I. 2.15-6.62 g/l, p < 0.001). We did not observe any statistically significant changes in in-hospital mortality (0.4% vs. 0%) and morbidity (4.1% vs. 4.0%), median hospital length of stay (9 vs. 9 days), follow-up mortality (0.4% vs. 0.2%) and follow-up morbidity (6.9% vs. 6.0%). CONCLUSIONS The introduction of a simple transfusion guideline reduces and standardises the use of RBCs by decreasing the haemoglobin transfusion trigger, without negative effects on the patient outcome. Local support, training, and monitoring of the effects are requirements for programmes optimising the use of blood.