Marfan syndrome and related connective tissue disorders in the current era in Switzerland in 103 patients: medical and surgical management and impact of genetic testing

INTRODUCTION Marfan syndrome (MFS) and related connective tissue disorders (CTDs) are increasingly recognised. Genetic testing has greatly improved the diagnostic outcome/power over the last two decades. In this study we describe a multicentre cohort of adults with MFS and related CTDs, with a particular focus on results from genetic testing. METHODS All patients with MFS and related CTDs were identified from the databases of five centres in the canton of Zurich. Echocardiographic and clinical findings including systemic Marfan score, use of medication and genetic results were retrospectively analysed. MFS was diagnosed using the revised Ghent criteria (including FBN1 genetic testing if available); other CTDs (Loeys-Dietz syndrome) were diagnosed by genetic testing only. RESULTS A cohort of 103 patients were identified (62 index patients, 41 relatives of family members): 96 patients with MFS and 7 patients with other CTD, 54 males (52%), median age 23 years (range 1–75). The median systemic Marfan score was 5 (range 0–18). Only 40 patients (40/103, 39%) fulfilled criteria for systemic involvement (≥7 points). A history of aortic dissection was present in 14 out of 103 patients (14%). Echocardiographic data were available for all: aortic root enlargement (Z-score ≥2 in adults, Z-score ≥3 in children) was found in 49 patients (48%) and mitral valve prolapse in 64 (62%). Genetic testing had been performed in 80 patients (78%); FBN1 mutations were present in 69 patients (86%); other pathogenic mutations could be identified in seven patients (9%); no disease-causing mutation was found in four patients, three of them fulfilling the Ghent criteria of MFS. Of the mutation-positive patients, 33 had a systemic score of ≥7 and 43 had a systemic score of ≥5. Revised Ghent criteria were fulfilled in 70 patients: in 69 patients with FBN1 mutations and 1 patient with another CTD. Recommended treatment (beta-blocker, angiotensin receptor blocker) was taken by 63% of patients. CONCLUSIONS In this cohort a high percentage of patients fulfilling the revised Ghent criteria for MFS underwent genetic testing, often leading to or confirming the diagnosis of MFS. Other CTDs could be discriminated best by genetic testing. With respect to the diagnosis of MFS and related CTDs, the usefulness of the systemic score is limited, showing the importance of genetic testing, which enabled definitive diagnosis in 95% of tested patients. Patient education on medical treatment still has to be improved. (Trial registration no: KEK-ZH-Nr. 2013-0241)

● Original Contribution doi:10.1016/j.ultrasmedbio.2006.03.010 UNSUPERVISED IMAGE CLASSIFICATION OF MEDICAL ULTRASOUND DATA BY MULTIRESOLUTION ELASTIC REGISTRATION

Abstract—Thousands of medical images are saved in databases every day and the need for algorithms able to handle such data in an unsupervised manner is steadily increasing. The classification of ultrasound images is an outstandingly difficult task, due to the high noise level of these images. We present a detailed description of an algorithm based on multiscale elastic registration capable of unsupervised, landmark-free classification of cardiac ultrasound images into their respective views (apical four chamber, two chamber, parasternal long axis and short axis views). We validated the algorithm with 90 unselected, consecutive echocardiographic images recorded during daily clinical work. When the two visually very similar apical views (four chamber and two chamber) are combined into one class, we obtained a 93.0 % correct classification ( � 2 � 123.8, p < 0.0001, cross-validation 93.0%; � 2 � 131.1, p < 0.0001). Classification into the 4 classes reached a 90.0 % correct classification ( � 2 � 205.4, p < 0.0001, cross-validation 82.2%; � 2 � 165.9, p < 0.0001). (E-mail

Pharmacokinetics and pharmacodynamics of sildenafil in a patient treated with human immunodeficiency virus protease inhibitors

We describe a 44-year-old male patient with human immunodeficiency virus (HIV) infection and pulmonary arterial hypertension who was treated with several protease inhibitors and with sildenafil. In order to guide treatment with sildenafil, the pharmacokinetics and dynamics of sildenafil were monitored at various time points. In comparison with healthy subjects, the maximal concentration in plasma (Cmax), area under the curve (AUC), and elimination half-life of sildenafil were approximately doubled in the patient. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 hours, the pulmonary arterial hypertension and physical performance of the patient improved significantly. We conclude that the elimination of sildenafil is impaired in patients treated with protease inhibitors, but to a lesser extent than predicted from single-dose studies reported in the literature. Patients treated concomitantly with protease inhibitors and sildenafil need close monitoring of plasma levels, pharmacodynamics, and toxicity of sildenafil in order to be treated optimally

Use of the wearable cardioverter-defibrillator - the Swiss experience

INTRODUCTION Sudden cardiac death caused by malignant arrhythmia can be prevented by the use of defibrillators. Although the wearable cardioverter defibrillator (WCD) can prevent such an event, its role in clinical practice is ill defined. We investigated the use of the WCD in Switzerland with emphasis on prescription rate, therapy adherence and treatment rate. MATERIALS AND METHODS The Swiss WCD Registry is a retrospective observational registry including patients using a WCD. Patients were included from the first WCD use in Switzerland until February 2018. Baseline characteristics and data on WCD usage were examined for the total study population, and separately for each hospital. RESULTS From 1 December 2011 to 18 February 2018, a total of 456 patients (67.1% of all WCDs prescribed in Switzerland and 81.1% of all prescribed in the participating hospitals) were included in the registry. Up to 2017 there was a yearly increase in the number of prescribed WCDs to a maximum of 271 prescriptions per year. The mean age of patients was 57 years (± 14), 81 (17.8%) were female and mean left ventricular ejection fraction (EF) was 32% (± 13). The most common indications for WCD use were new-onset ischaemic cardiomyopathy (ICM) with EF ≤35% (206 patients, 45.2%), new-onset nonischaemic cardiomyopathy (NICM) with EF ≤35% (115 patients, 25.2%), unknown arrhythmic risk (83 patients, 18.2%), bridging to implantable cardioverter-defibrillator implantation or heart transplant (37 patients, 8.1%) and congenital/inherited heart disease (15 patients, 3.3%). Median wear duration was 58 days (interquartile range [IQR] 31–94) with a median average daily wear time of 22.6 hours (IQR 20–23.2). Seventeen appropriate therapies from the WCD were delivered in the whole population (treatment rate: 3.7%) to a total of 12 patients (2.6% of all patients). The most common underlying heart disease in patients with a treatment was ICM (13/17, 76.5%). There were no inappropriate treatments. CONCLUSION The use of WCDs has increased in Switzerland over the years for a variety of indications. There is high therapy adherence to the WCD, and a treatment rate comparable to previously published registry data. &nbsp

Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected

Evolocumab and clinical outcomes in patients with cardiovascular disease

peer reviewedBACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. © 2017 Massachusetts Medical Society