HIV-Infektion, antiretrovirale Therapie und Endothel

Zusammenfassung: Die hochaktive antiretrovirale Kombinationstherapie hat zu einer eindrücklichen Verbesserung der Prognose der HIV-Infektion geführt. Insbesondere unter Proteaseinhibitoren beobachtet man jedoch metabolische Veränderungen wie eine vermehrte Insulinresistenz und Veränderungen des Lipidmetabolismus. Bezüglich der Auswirkung der antiretroviralen Therapie auf die kardiovaskuläre Prognose der HIV-infizierten Personen sind die Studienresultate widersprüchlich. In der großen D:A:D-Kohortenstudie fand sich unter Therapie mit Proteaseinhibitoren und Nicht-Nukleosid-Reverse-Transkriptase-Inhibitoren eine Zunahme der Myokardinfarktinzidenz. Die Mechanismen, die zu dieser Progression der Arteriosklerose führen, sind jedoch nicht konklusiv geklärt. Als Ursache können direkte Effekte des HI-Virus respektive der Infektion auf die Gefäße, aber auch durch die antiretrovirale Therapie induzierte direkte oder indirekte Effekte verantwortlich sein. Virale Bestandteile (gp120, TAT) erhöhen prothrombotische Faktoren, Sauerstoffradikale und die Expression von Adhäsionsmolekülen auf Endothelzellen. Die flussabhängige Vasodilatation ist bei HIV-Infizierten vermindert und korreliert mit dem Virustiter. Proteaseinhibitoren vermindern die eNOS-Expression, steigern die Expression des CD36-Scavenger-Rezeptors und führen zu vermehrter Bildung reaktiver Sauerstoffspezies, Apoptose, Endothelin-1-Expression und Proliferation von glatten Muskelzellen. Die meisten klinischen Studien zeigen eine Endotheldysfunktion bei Patienten unter Proteaseinhibitortherapie. Indinavir induziert bei gesunden Probanden eine Endotheldysfunktion, was auf die direkte Rolle der Medikamente als Ursache hinweist. Unter Statintherapie konnte eine Verbesserung der Gefäßfunktion beobachtet werden. Die Daten aus Studien am Endothel liefern verschiedene mechanistische Hinweise, welche die gesteigerte Inzidenz kardiovaskulärer Ereignisse bei HIV-Infizierten erklären könnten. Viele Fragen sind jedoch noch offe

Application of Optimal Control to CPMG Refocusing Pulse Design

We apply optimal control theory (OCT) to the design of refocusing pulses suitable for the CPMG sequence that are robust over a wide range of B0 and B1 offsets. We also introduce a model, based on recent progress in the analysis of unitary dynamics in the field of quantum information processing (QIP), that describes the multiple refocusing dynamics of the CPMG sequence as a dephasing Pauli channel. This model provides a compact characterization of the consequences and severity of residual pulse errors. We illustrate the methods by considering a specific example of designing and analyzing broadband OCT refocusing pulses of length 10 t180 that are constrained by the maximum instantaneous pulse power. We show that with this refocusing pulse, the CPMG sequence can refocus over 98% of magnetization for resonance offsets up to 3.2 times the maximum RF amplitude, even in the presence of +/- 10% RF inhomogeneity.Comment: 23 pages, 10 figures; Revised and reformatted version with new title and significant changes to Introduction and Conclusions section

Treatment with higher dosages of heart failure medication is associated with improved outcome following cardiac resynchronization therapy

Background Cardiac resynchronization therapy (CRT) is associated with improved morbidity and mortality in patients with chronic heart failure (CHF) on optimal medical therapy. The impact of CHF medication optimization following CRT, however, has never been comprehensively evaluated. In the current study, we therefore investigated the effect of CHF medication dosage on morbidity and mortality in CHF patients after CRT implantation. Methods and results Chronic heart failure medication was assessed in 185 patients after CRT implantation. During an overall mean follow-up of 44.6 months, 83 patients experienced a primary endpoint (death, heart transplantation, assist device implantation, or hospitalization for CHF). Treatment with higher dosages of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blockers (ARBs) (P = 0.001) and beta-blockers (P < 0.001) as well as with lower dosages of loop diuretics (P < 0.001) was associated with a reduced risk for the primary combined endpoint as well as for all-cause mortality. Echocardiographic super-responders to CRT were treated with higher average dosages of ACE-I/ARBs (68.1 vs. 52.4%, P < 0.01) and beta-blockers (59 vs. 42.2%, P < 0.01). During follow-up, the average dosage of loop diuretics was decreased by 20% in super-responders, but increased by 30% in non-super-responders (P < 0.03). Conclusion The use of higher dosages of neurohormonal blockers and lower dosages of diuretics is associated with reduced morbidity and mortality following CRT implantation. Our data imply a beneficial effect of increasing neurohormonal blockade whenever possible following CRT implantatio

Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling

Aims Chronic right ventricular (RV) pacing may impose ventricular dyssynchrony leading to LV remodelling and is associated with increased morbidity and mortality. Upgrading patients with chronic RV pacing to cardiac resynchronization therapy (CRT) may be considered to restore synchronicity and prevent these deleterious effects. Methods and results A total of 172 patients from two tertiary centres were analysed over a mean follow-up of 21.7 and 23.5 months after primary CRT implantation (n = 102) and CRT upgrade (n = 70), respectively. In the latter group, mean duration of RV pacing before CRT upgrade was 80.3 months, and ventricular stimulation was >95%. A significant improvement in left ventricular (LV) ejection fraction (10 and 11% absolute increase in primary CRT vs. upgrades, respectively), LV end-diastolic diameter index (−0.15 cm/m2 vs. −0.2 cm/m2), and LV end-systolic diameter (−6.0 vs. −7.0 mm) was observed in both groups, which did not differ between primary CRT recipients and CRT upgrades. Response to CRT upgrade was independent of the underlying rhythm, QRS duration, duration of prior RV pacing, or LV function and size at baseline. Of note, even seven of nine patients with RV pacing >12 years responded favourably to CRT. Conclusion The current study demonstrates that CRT reverses LV remodelling in heart failure patients with chronic RV pacing in a similar way as in primary CRT recipients, even after very long periods of RV pacing. Our data, therefore, may have important implications for the treatment of pacemaker-dependent patients with heart failure, and support the use of CRT in this settin

Rivaroxaban postmarketing risk of liver injury

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been marketed worldwide since 2008 for the primary and secondary prevention and treatment of thromboembolic disorders. Although liver injury was observed in premarketing trials of rivaroxaban, there are no published postmarketing cases of liver injury associated with rivaroxaban. METHODS: Report of 14 cases of liver injury associated with rivaroxaban, including two with liver biopsy, and search queries in three large international pharmacovigilance databases for comparable cases. RESULTS: Formal causality assessment classified rivaroxaban as the "highly probable", "probable" and "possible" cause in 4, 7 and 3 patients, respectively. Search results from three large international pharmacovigilance databases revealed a considerable number of additional hepatic adverse events where rivaroxaban was reported as a suspected cause. CONCLUSIONS: We interpret the presented information as a relevant safety signal that should be followed by pharmacoepidemiological studies in order to reliably estimate absolute and relative risks of liver injury associated with rivaroxaban in support of rational risk-benefit assessment. Meanwhile, incident symptoms and signs of liver disease in patients treated with rivaroxaban should be considered as a potential adverse drug reaction, and if no other likely cause can be identified rivaroxaban should be stopped as soon as possible

Improvement of antibiotic prescription in outpatient care: a cluster-randomized intervention study using a sentinel surveillance network of physicians.

OBJECTIVES: To assess the effectiveness of implementing guidelines, coupled with individual feedback, on antibiotic prescribing behaviour of primary care physicians in Switzerland. METHODS: One hundred and forty general practices from a representative Swiss sentinel network of primary care physicians participated in this cluster-randomized prospective intervention study. The intervention consisted of providing guidelines on treatment of respiratory tract infections (RTIs) and uncomplicated lower urinary tract infections (UTIs), coupled with sustained, regular feedback on individual antibiotic prescription behaviour during 2 years. The main aims were: (i) to increase the percentage of prescriptions of penicillins for all RTIs treated with antibiotics; (ii) to increase the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics; (iii) to decrease the percentage of quinolone prescriptions for all cases of exacerbated COPD (eCOPD) treated with antibiotics; and (iv) to decrease the proportion of sinusitis and other upper RTIs treated with antibiotics. The study was registered at ClinicalTrials.gov (NCT01358916). RESULTS: While the percentage of antibiotics prescribed for sinusitis or other upper RTIs and the percentage of quinolones prescribed for eCOPD did not differ between the intervention group and the control group, there was a significant increase in the percentage of prescriptions of penicillins for all RTIs treated with antibiotics [57% versus 49%, OR=1.42 (95% CI 1.08-1.89), P=0.01] and in the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics [35% versus 19%, OR=2.16 (95% CI 1.19-3.91), P=0.01] in the intervention group. CONCLUSIONS: In our setting, implementing guidelines, coupled with sustained individual feedback, was not able to reduce the proportion of sinusitis and other upper RTIs treated with antibiotics, but increased the use of recommended antibiotics for RTIs and UTIs, as defined by the guidelines

Prediction of permeability and formation factor of sandstone with hybrid lattice Boltzmann/finite element simulation on microtomographic images

In Fontainebleau sandstone, the evolution of transport properties with porosity is related to changes in both the size and connectivity of the pore space. Microcomputed tomography can be used to characterize the relevant geometric attributes, with the resolution that is sufficiently refined for realistic simulation of transport properties based on the 3D image. In this study, we adopted a hybrid computation scheme that is based on a hierarchical multi-scale approach. The specimen was partitioned into cubic sub-volumes for pore-scale simulation of hydraulic permeability and formation factor using the lattice Boltzmann method. The pore-scale results were then linked with finite element simulation in a homogenized scheme to compute and upscale the transport properties to specimen scale. The simulated permeability and formation factor have magnitude and anisotropy that are in good agreement with experimental rock physics data. Together with simulated and measured values of connected porosity and specific surface area, they provide useful insights into how pore geometry controls the evolution of the transport properties

Improvement of antibiotic prescription in outpatient care: a cluster-randomized intervention study using a sentinel surveillance network of physicians

Objectives To assess the effectiveness of implementing guidelines, coupled with individual feedback, on antibiotic prescribing behaviour of primary care physicians in Switzerland. Methods One hundred and forty general practices from a representative Swiss sentinel network of primary care physicians participated in this cluster-randomized prospective intervention study. The intervention consisted of providing guidelines on treatment of respiratory tract infections (RTIs) and uncomplicated lower urinary tract infections (UTIs), coupled with sustained, regular feedback on individual antibiotic prescription behaviour during 2 years. The main aims were: (i) to increase the percentage of prescriptions of penicillins for all RTIs treated with antibiotics; (ii) to increase the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics; (iii) to decrease the percentage of quinolone prescriptions for all cases of exacerbated COPD (eCOPD) treated with antibiotics; and (iv) to decrease the proportion of sinusitis and other upper RTIs treated with antibiotics. The study was registered at ClinicalTrials.gov (NCT01358916). Results While the percentage of antibiotics prescribed for sinusitis or other upper RTIs and the percentage of quinolones prescribed for eCOPD did not differ between the intervention group and the control group, there was a significant increase in the percentage of prescriptions of penicillins for all RTIs treated with antibiotics [57% versus 49%, OR = 1.42 (95% CI 1.08-1.89), P = 0.01] and in the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics [35% versus 19%, OR = 2.16 (95% CI 1.19-3.91), P = 0.01] in the intervention group. Conclusions In our setting, implementing guidelines, coupled with sustained individual feedback, was not able to reduce the proportion of sinusitis and other upper RTIs treated with antibiotics, but increased the use of recommended antibiotics for RTIs and UTIs, as defined by the guideline