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Background: Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany.
Material and Methods: We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness.
Results: Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses.
Conclusions: Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.
Synthetische Cannabinoide sind strukturell variable Substanzen, die an die gleichen CB1- und CB2-Rezeptoren binden wie ∆9-THC und bei Konsumenten vergleichbare Symptome auslösen. Die psychoaktiven Substanzen werden Kräutermischungen beigemengt und gelten unter Konsumenten vermeintlich als ungefährlich. Aufgrund erhöhter Bindungsaffinitäten zu den Cannabinoidrezeptoren sind viele synthetische Cannabinoide potenter als ∆9-THC und lösen daher stärkere Symptome aus als der Konsum von ∆9-THC. Der Konsum von synthetischen Cannabinoiden führt zu zentraler Sedierung und Beeinträchtigungen in der Feinmotorik; dies ist nicht mit dem sicheren Führen eines Fahrzeugs kompatibel. Durch die strukturelle Varianz von synthetischen Cannabinoiden und ein stetig wechselndes Spektrum aktuell auf dem Drogenmarkt erhältlicher Substanzen ist der generelle Nachweis des Konsums von synthetischen Cannabinoiden limitiert. Bislang sind synthetische Cannabinoide in Blut oder Urin nur bei bekannter Struktur und vorhandenen Referenzmaterialien mit Sicherheit nachweisbar. Studien zur Prävalenz von synthetischen Cannabinoiden sind rar und basieren häufig auf Umfragen, da auf Probenanalysen basierende Studien meist nicht alle aktuellen synthetischen Cannabinoiden erfassen. In der vorliegenden Arbeit wurde die Prävalenz von synthetischen Cannabinoiden unter Fällen aus Verkehrs- und Kriminaldelikten des Jahres 2010 in Hessen bestimmt, um zu zeigen wie häufig synthetische Cannabinoide in forensischen Analysen unentdeckt bleiben. Die analytische Methode wurde entwickelt sowie validiert und war für alle 31 synthetischen Cannabinoide, die bis 2011 auf dem Drogenmarkt erhältlich waren, sensitiv. Eine repräsentative Stichprobe bestehen aus 20% aller Blutproben (422 aus 2201) des Jahres 2010 wurde nachuntersucht. Weitere Auswertungen wurden auf Basis von Fallakten durchgeführt. Unter den analysierten Blutproben enthielten 12 Proben synthetische Cannabinoide, woraus für das Jahr 2010 eine Prävalenz von synthetischen Cannabinoiden unter Fällen aus Verkehrs- und Kriminaldelikten von 2,8% ermittelt wurde. Das am häufigsten detektierte synthetische Cannabinoid war JWH-122. Die Konzentrationen lagen überwiegend im niedrigen Bereich (unter 1 ng/ml bis 3 ng/ml). In einem Fall wurde eine vergleichsweise hohe Konzentration des JWH-122 mit circa 73 ng/ml gemessen, wobei neben Apathie keine weiteren Symptome dokumentiert wurden. Alle Konsumenten waren männlich; das Alter lag in 11 Fällen zwischen 18 und 38 Jahren (median 22 Jahre) und die Konsumenten waren Verdächtige von Verkehrsdelikten. Eine weitere positiv getestete Blutprobe stammte aus einem Kriminaldelikt; der Verdächtige war 46 Jahre alt. Die Auswertung der Konsummuster zeigte in 10 von 12 Fällen (83,3%) einen Mischkonsum. Nur in zwei Fällen lag ausschließlicher Konsum von synthetischen Cannabinoiden vor. Die Kombination von synthetischen Cannabinoiden mit ∆9-THC oder Alkohol war mit je vier Fällen häufig. In sechs Fällen wurde eine Vielfalt anderer psychoaktiver Drogen oder Medikamente in den Blutproben nachgewiesen. Die dokumentierten Ausfallserscheinungen waren meist moderat und ließen sich durch die Effekte von Cannabinoiden, Alkohol oder anderen gefundenen Drogen oder Medikamenten erklären. Im Fall eines Konsumenten hat sich nach den Angaben in ärztlichen und polizeilichen Berichten durch den nachgewiesenen Konsum von synthetischen Cannabinoiden eine vorbestehende Psychose verschlimmert. Fazit: Durch die geringe Prävalenz synthetischer Cannabinoide, fehlende routinemäßige Erfassbarkeit sowie Häufigkeit des Mischkonsums müssen Träger von rechtsmedizinischen Instituten in Ausstattung und Personal investieren, um den modernen Ansprüche an die Leistungsfähigkeit gerecht zu werden.
Correlation of lumbar lateral recess stenosis in magnetic resonance imaging and clinical symptoms
(2017)
Aim: To assess the correlation of lateral recess stenosis (LRS) of lumbar segments L4/5 and L5/S1 and the Oswestry Disability Index (ODI).
Methods: Nine hundred and twenty-seven patients with history of low back pain were included in this uncontrolled study. On magnetic resonance images (MRI) the lateral recesses (LR) at lumbar levels L4/5 and L5/S1 were evaluated and each nerve root was classified into a 4-point grading scale (Grade 0-3) as normal, not deviated, deviated or compressed. Patient symptoms and disability were assessed using ODI. The Spearman’s rank correlation coefficient was used for statistical analysis (P < 0.05).
Results: Approximately half of the LR revealed stenosis (grade 1-3; 52% at level L4/5 and 42% at level L5/S1) with 2.2% and 1.9% respectively reveal a nerve root compression. The ODI score ranged from 0%-91.11% with an arithmetic mean of 34.06% ± 16.89%. We observed a very weak statistically significant positive correlation between ODI and LRS at lumbar levels L4/5 and L5/S1, each bilaterally (L4/5 left: rho < 0.105, P < 0.01; L4/5 right: rho < 0.111, P < 0.01; L5/S1 left: rho 0.128, P < 0.01; L5/S1 right: rho < 0.157, P < 0.001).
Conclusion: Although MRI is the standard imaging tool for diagnosing lumbar spinal stenosis, this study showed only a weak correlation of LRS on MRI and clinical findings. This can be attributed to a number of reasons outlined in this study, underlining that imaging findings alone are not sufficient to establish a reliable diagnosis for patients with LRS.
Sex differences in the relationship between conduct disorder and cortical structure in adolescents
(2017)
Objective: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure.
Method: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status−matched controls (14–18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume.
Results: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset.
Conclusion: We found both similarities and differences between males and females in CD–cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.
Background: Minimally invasive coronary artery bypass grafting (MICS CABG) has been introduced to abstain from median sternotomy due to related comorbidities. The aim of this study is to report the long term results of three different MICS CABG strategies: Partial lower sternotomy (PLS), totally endoscopic coronary artery bypass grafting (TECAB) and anterolateral thoracotomy (ALT). Moreover we aimed to compare these surgical approaches in terms of quality of pain and pain intensity.
Methods: From 1997 to 2006, 126 patients underwent MICS CABG surgeries in our department through different surgical approaches: 43 PLS, 63 TECAB and 20 ALT. Preoperative characteristics were similar between groups. There were 90 males (71.4%) and 36 (28.6%) females with a mean age of 62±11 years (Range 36 to 90).
Results: There was no in-hospital mortality. Conversion to minithoracotomy was necessary in 2 (1.6%) patients and conversion to sternotomy was performed in 1 (0.8%) patient. Length of hospital stay was comparable in patients who underwent PLS or TECAB, but both groups had significantly shorter hospital stays than ALT patients (p<0.05). Two patients in group ALT developed temporary neurological complications postoperatively, which was significantly higher than that in groups TECAB (n=0) and PLS (n=0) (p<0.05). Mean follow-up was 12.2±2.1 (range 7.2 to 16.1) years with completed in 81.7 % of the patients. There were 17 late deaths. Freedom from graft problems was 87.5%, 86.5% and 94.7%; freedom from percutaneous coronary interventions (PCI) was 78.1%, 82.7% and 68.4% and freedom from Re-CABG was 100%, 96.1% and 94.7% in PLS, TECAB and ALT group, respectively. Pain intensity was similar between all three groups.
Conclusion: MICS CABG can be performed safely and effectively. Short and long-term outcomes of MICS CABG are comparable with those of the conventional CABG. There were no major differences regarding pain intensity between all three groups, although all three minimally invasive techniques have completely different surgical accesses.
The yeast bc1 complex (complex III) and cytochrome oxidase (complex IV) are mosaics of core subunits encoded by the mitochondrial genome and additional nuclear-encoded proteins imported from the cytosol. Both complexes build in the mitochondrial inner membrane various supramolecular assemblies. The formation of the individual complexes and their supercomplexes depends on the activity of dedicated assembly factors. We identified a so far uncharacterized mitochondrial protein (open reading frame YDR381C-A) as an important assembly factor for complex III, complex IV, and their supercomplexes. Therefore, we named this protein Cox interacting (Coi) 1. Deletion of COI1 results in decreased respiratory growth, reduced membrane potential, and hampered respiration, as well as slow fermentative growth at low temperature. In addition, coi1Δ cells harbour reduced steady-state levels of subunits of complexes III and IV as well as of the assembled complexes and supercomplexes. Interaction of Coi1 with respiratory chain subunits seems transient, as it appears to be a stoichiometric subunit neither of complex III nor of complex IV. Collectively, this work identifies a novel protein that plays a role in the assembly of the mitochondrial respiratory chain.
Information theory provides a formal framework within which information processing and its disorders can be described. However, information theory has rarely been applied to modeling aspects of the cognitive neuroscience of schizophrenia. The goal of this article is to highlight the benefits of an approach based on information theory, including its recent extensions, for understanding several disrupted neural goal functions as well as related cognitive and symptomatic phenomena in schizophrenia. We begin by demonstrating that foundational concepts from information theory—such as Shannon information, entropy, data compression, block coding, and strategies to increase the signal-to-noise ratio—can be used to provide novel understandings of cognitive impairments in schizophrenia and metrics to evaluate their integrity. We then describe more recent developments in information theory, including the concepts of infomax, coherent infomax, and coding with synergy, to demonstrate how these can be used to develop computational models of schizophrenia-related failures in the tuning of sensory neurons, gain control, perceptual organization, thought organization, selective attention, context processing, predictive coding, and cognitive control. Throughout, we demonstrate how disordered mechanisms may explain both perceptual/cognitive changes and symptom emergence in schizophrenia. Finally, we demonstrate that there is consistency between some information-theoretic concepts and recent discoveries in neurobiology, especially involving the existence of distinct sites for the accumulation of driving input and contextual information prior to their interaction. This convergence can be used to guide future theory, experiment, and treatment development.
Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to the peripheral blood is a complex mechanism that involves adhesive and chemotactic interactions of HSCs as well as their bone marrow microenvironment. In addition to a number of non-genetic factors, genetic susceptibilities also contribute to the mobilization outcome. Identification of genetic factors associated with HSC yield is important to better understand the mechanism behind HSC mobilization. In the present study, we enrolled 148 Korean participants (56 healthy donors and 92 patients) undergoing HSC mobilization for allogeneic or autologous HSC transplantation. Among a total of 53 polymorphisms in 33 candidate genes, one polymorphism (rs11264422) in relaxin/insulin-like family peptide receptor 4 (RXFP4) gene was significantly associated with a higher HSC yield after mobilization in Koreans. However, in a set of 101 Europeans, no association was found between circulating CD34+ cell counts and rs11264422 genotype. Therefore, we suggest that the ethnic differences in subjects’ genetic background may be related to HSC mobilization. In conclusion, the relaxin—relaxin receptor axis may play an important role in HSC mobilization. We believe that the results of the current study could provide new insights for therapies that use relaxin and HSC populations, as well as a better understanding of HSC regulation and mobilization at the molecular level.
Oxygenation-sensitive spin relaxation time T2′ and relaxation rate R2′ (1/T2′) are presumed to be markers of the cerebral oxygen extraction fraction (OEF) in acute ischemic stroke. In this study, we investigate the relationship of T2′/R2′ with dynamic susceptibility contrast-based relative cerebral blood flow (rCBF) in acute ischemic stroke to assess their plausibility as surrogate markers of the ischemic penumbra. Twenty-one consecutive patients with internal carotid artery and/or middle cerebral artery occlusion were studied at 3.0 T. A physiological model of the cerebral vasculature (VM) was used to process PWI raw data in addition to a conventional deconvolution technique. T2′, R2′, and rCBF values were extracted from the ischemic core and hypoperfused areas. Within hypoperfused tissue, no correlation was found between deconvolved rCBF and T2′ (r = −0.05, p = 0.788), or R2′ (r = 0.039, p = 0.836). In contrast, we found a strong positive correlation with T2′ (r = 0.444, p = 0.006) and negative correlation with R2′ (r = −0.494, p = 0.0025) for rCBFVM, indicating increasing OEF with decreasing CBF and that rCBF based on the vascular model may be more closely related to metabolic disturbances. Further research to refine and validate these techniques may enable their use as MRI-based surrogate markers of the ischemic penumbra for selecting stroke patients for interventional treatment strategies.
A randomised, double-blind, placebo-controlled trial of trichuris suis ova in active crohn's disease
(2017)
BACKGROUND AND AIMS To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD].
METHODS Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment.
RESULTS Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns.
CONCLUSIONS Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD.