PCSK9 inhibitors: emerging treatment to lower cholesterol?

The achievement rate of recommended low-density lipoprotein cholesterol (LDL-C) targets of < 1.8 mmol/l for secondary prevention in very high risk patients is difficult. Observational studies reported that loss of function mutation of the PCS9 was associated with LDL-C decrease level and reduction of cardiovascular events. Monoclonal antibodies to PCSK9 (REGN727 and AMG 145, PSCK9 inhibitors) have been tested in clinical studies of phase I and II and showed LDL-C level reduction of 60-70% compared to placebo. This approach appears safe and well-tolerated. The PCSK9 inhibitors are now tested in large phase III clinical studies to assess the long-term safety and efficacy of this new promising approach.

The trouble with quality filtering based on relative Cramér-Rao lower bounds.

Cramér Rao Lower Bounds (CRLB) have become the standard for expression of uncertainties in quantitative MR spectroscopy. If properly interpreted as a lower threshold of the error associated with model fitting, and if the limits of its estimation are respected, CRLB are certainly a very valuable tool to give an idea of minimal uncertainties in magnetic resonance spectroscopy (MRS), although other sources of error may be larger. Unfortunately, it has also become standard practice to use relative CRLB expressed as a percentage of the presently estimated area or concentration value as unsupervised exclusion criterion for bad quality spectra. It is shown that such quality filtering with widely used threshold levels of 20% to 50% CRLB readily causes bias in the estimated mean concentrations of cohort data, leading to wrong or missed statistical findings-and if applied rigorously-to the failure of using MRS as a clinical instrument to diagnose disease characterized by low levels of metabolites. Instead, absolute CRLB in comparison to those of the normal group or CRLB in relation to normal metabolite levels may be more useful as quality criteria. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Blind Deconvolution via Lower-Bounded Logarithmic Image Priors

In this work we devise two novel algorithms for blind deconvolution based on a family of logarithmic image priors. In contrast to recent approaches, we consider a minimalistic formulation of the blind deconvolution problem where there are only two energy terms: a least-squares term for the data fidelity and an image prior based on a lower-bounded logarithm of the norm of the image gradients. We show that this energy formulation is sufficient to achieve the state of the art in blind deconvolution with a good margin over previous methods. Much of the performance is due to the chosen prior. On the one hand, this prior is very effective in favoring sparsity of the image gradients. On the other hand, this prior is non convex. Therefore, solutions that can deal effectively with local minima of the energy become necessary. We devise two iterative minimization algorithms that at each iteration solve convex problems: one obtained via the primal-dual approach and one via majorization-minimization. While the former is computationally efficient, the latter achieves state-of-the-art performance on a public dataset.

A new model construction by making a detour via intuitionistic theories II: Interpretability lower bound of Feferman's explicit mathematics T0

We partially solve a long-standing problem in the proof theory of explicit mathematics or the proof theory in general. Namely, we give a lower bound of Feferman’s system T0 of explicit mathematics (but only when formulated on classical logic) with a concrete interpretat ion of the subsystem Σ12-AC+ (BI) of second order arithmetic inside T0. Whereas a lower bound proof in the sense of proof-theoretic reducibility or of ordinalanalysis was already given in 80s, the lower bound in the sense of interpretability we give here is new. We apply the new interpretation method developed by the author and Zumbrunnen (2015), which can be seen as the third kind of model construction method for classical theories, after Cohen’s forcing and Krivine’s classical realizability. It gives us an interpretation between classical theories, by composing interpretations between intuitionistic theories.

Modified natural cycle in vitro fertilization an alternative in vitro fertilization treatment with lower costs per achieved pregnancy but longer treatment time

OBJECTIVE To analyze the cost and time requirement per achieved pregnancy in optimized modified natural cycle in vitro fertilization (mNC-IVF) based on a treatment protocol with very few consultations and to compare those with conventional gonadotropin-stimulated aVF (clVF) cycles. STUDY DESIGN Mono centric prospective trial. Eighty infertile patients each received 1 modified mNC-IVF cycle using low doses of the clomiphene citrate. Based on the number of consultations and the clinical pregnancy rate per cycle, the total costs and required time to achieve a pregnancy were analyzed and compared with cIVF. Calculations for cIVF were based on standard therapy protocols and outcomes of European registries. RESULTS Patients (21-42 years old, 35.4 +/- 4.7 years) undergoing mNC-IVF required on average 1.2 consultations before follicle aspiration. Pregnancy rate per transfer and per initiated cycle were 25% and 13.6%, respectively. Multiple pregnancies did not occur. According to the calculations, total costs per pregnancy rate were around 15% lower with mNC-IVF as compared to cIVF. In contrast, time to achieve an equal pregnancy rate was calculated to take around 30% longer with mNC-IVF as compared to cIVF. CONCLUSION mNC-IVF using very low dosages of clomiphene citrate avoids multiple pregnancies and is less expensive but more time consuming per achieved pregnancy when compared to clVF.

Watershed classification in the Lower Mekong Basin: Rapid economic growth - a source of increasing potential for conflict over resource use

In the Lower Mekon Basin the extraordinary pace of economic development and growth contradicts with environmental protection. On base of the Watershed Classification Project (WSCP) and the inclusion of a DTM for the entire LMB the potential degradation risk was derived for each land unit. The risks were grouped into five classes, where classes one and two are considered critical with regard to soil erosion when the land is cleared of natural resources. For practical use the database has an enormous potential for further spatial analysis in combination with other datasets, as for example the NCCR North-South uses the WSCP within two research projects.

Extratropical fronts in the lower troposphere-global perspectives obtained from two automated methods

In this study two commonly used automated methods to detect atmospheric fronts in the lower troposphere are compared in various synoptic situations. The first method is a thermal approach, relying on the gradient of equivalent potential temperature (TH), while the second method is based on temporal changes in the 10 m wind (WND). For a comprehensive objective comparison of the outputs of these methods of frontal identification, both schemes are firstly applied to an idealised strong baroclinic wave simulation in the absence of topography. Then, two case-studies (one in the Northern Hemisphere (NH) and one in the Southern Hemisphere (SH)) were conducted to contrast fronts detected by the methods. Finally, we obtain global winter and summer frontal occurrence climatologies (derived from ERA-Interim for 1979–2012) and compare the structure of these. TH is able to identify cold and warm fronts in strong baroclinic cases that are in good agreement with manual analyses. WND is particularly suited for the detection of strongly elongated, meridionally oriented moving fronts, but has very limited ability to identify zonally oriented warm fronts. We note that the areas of the main TH frontal activity are shifted equatorwards compared to the WND patterns and are located upstream of regions of main WND front activity. The number of WND fronts in the NH shows more interseasonal variations than TH fronts, decreasing by more than 50% from winter to summer. In the SH there is a weaker seasonal variation of the number of observed WND fronts, however TH front activity reduces from summer (DJF) to winter (JJA). The main motivation is to give an overview of the performance of these methods, such that researchers can choose the appropriate one for their particular interest.

Higher Visual Functions in the Upper and Lower Visual Fields: a pilot study in healthy subjects

Visual perception is not identical in the upper and lower visual hemifields. The mechanisms behind this difference can be found at the retinal, cortical, or higher attentional level. In this study, a new visual test battery, that involves real-time comparisons of complex visual stimuli, such as shape of objects, and speed of moving dot patterns, in the upper and lower visual hemifields, is presented. This study represents, to our knowledge, the first to implement such a visual test battery in an immersive environment composed of a hemisphere, in order to present visual stimuli in precise regions of the visual field. Ten healthy volunteers were tested in this pilot study. The results showed a higher accuracy in the image matching when the visual test was performed in the lower visual hemifield.

Early-Holocene afforestation processes in the lower subalpine belt of the Central Swiss Alps as inferred from macrofossil and pollen records

To reconstruct the vegetation history of the Upper Engadine, continuous sediment cores covering the past 11 800 years from Lej da Champfer and Lej da San Murezzan (Upper Engadine Valley, c. 1800 m a.s.l., southeastern Switzerland) have been analysed for pollen and plant macrofossils. The chronologies of the cores are based on 16 and 22 radiocarbon dates, respectively. The palaeobotanical records of both lakes are in agreement for the Holocene, but remarkable differences exist between the sites during the period 11 100 to 10 500 cal. BP, when Lej da Champfer was affected by re-sedimentation processes. Macrofossil data suggest that Holocene afforestation began at around 11400 cal. BP. A climatic deterioration, the Preboreal Oscillation, stopped and subsequently delayed the establishment of trees until c. 11000 cal. BP, when first Betula, then Pinus sylvestrislmugo, then Larix 300 years later, and finally Pinus cembra expanded within the lake catchment. Treeline was at c. 1500 m during the Younger Dryas (12 542- 11 550 cal. BP) in the Central Alps. Our results, along with other macrofossil studies from the Alps, suggest a nearly simultaneous afforestation (e.g., by Pinus sylvestris in the lower subalpine belt) between 1500 and 2340 m a.s.l. at around 11 400 to 11 300 cal. BP. We suggest that forest-limit species (e.g., Pinus cembra, Larix decidua) could expand faster at today's treeline (c. 2350 m a.s.l.), than 550 m lower. Earlier expansions at higher altitudes probably resulted from reduced competition with low-altitude trees (e.g. Pinus sylvestris) and herbaceous species. Comparison with other proxies such as oxygen isotopes, residual A14C, glacier fluctuations, and alpine climatic cooling phases suggests climatic sensitivity of vegetation during the early Holocene.

Iodine-129: Sample preparation, quality control and analyses of pre-nuclear materials and of natural waters from Lower Saxony, Germany

Sample preparation procedures for AMS measurements of 129I and 127I in environmental materials and some methodological aspects of quality assurance are discussed. Measurements from analyses of some pre-nuclear soil and thyroid gland samples and of a systematic investigation of natural waters in Lower Saxony, Germany, are described. Although the up-to-now lowest 129I/127I ratios in soils and thyroid glands were observed, they are still suspect to contamination since they are significantly higher than the pre-nuclear equilibrium ratio in the marine hydrosphere. A survey on all available 129I/127I isotopic ratios in precipitation shows a dramatic increase until the middle of the 1980s and a stabilization since 1987 at high isotopic ratios of about (3.6–8.3)×10−7. In surface waters, ratios of (57–380)×10−10 are measured while shallow ground waters show with ratios of (1.3–200)×10−10 significantly lower values with a much larger spread. The data for 129I in soils and in precipitation are used to estimate pre-nuclear and modern 129I deposition densities.

Range of Motion of the Upper Extremity in a Healthy Pediatric Population: Introduction to Normative Data.

Objective In the pediatric population traumatic injuries of the upper extremity are common. After therapy a decision has to be made if the mobility of the joint lies within a normal range. The purpose of this study was to give an introduction to normative data. We investigate if there is a significant difference in the range of motion (ROM) between male and female probands and furthermore, if an effect of the age can be detected. Methods We performed an institutional review board-approved study of healthy girls and boys aged between 2 and 16 years without any medical history of an upper extremity fracture. We investigated the active ROM of the elbow, wrist, metacarpophalangeal, and interphalangeal joints. Furthermore, age, handedness, weight, and height were recorded. A total of 171 adolescents with a mean age of 10.6 years were included and separated into four cohorts by age: 2 to 5, 6 to 10, 11 to 13, and 14 to 16 years. Results We found significant differences between the genders in the age group from 11 to 13 years for the flexion of the elbow, the pronation, the flexion of the interphalangeal joint of the thumb, as well as the flexion of the metacarpophalangeal joints of digitus II to V. Furthermore, a significant difference in the same joints except from the elbow flexion could be demonstrated between the genders. Conclusion Our study contributes normative data for upper extremity ROM in the pediatric population and presents a gender-related difference in certain joints. Clinical Relevance Normative data for the ROM of upper extremity joints in children is helpful for the evaluation of pediatric orthopedic patients and provides the framework for therapeutic resolution. Since a great number of traumatic injuries in children affect the upper extremity, this information may help the physician to estimate the impact of the injury and decide on the therapeutic management.

Long-bone fractures in persons with spinal cord injury

STUDY DESIGN Retrospective data analysis. OBJECTIVES To document fracture characteristics, management and related complications in individuals with traumatic spinal cord injury (SCI). SETTING Rehabilitation centre for SCI individuals. METHOD Patients' records were reviewed. Patients with traumatic SCI and extremity fractures that had occurred after SCI were included. Patient characteristics, fractured bone, fracture localisation, severity and management (operative/conservative), and fracture-related complications were extracted. RESULTS A total of 156 long-bone fractures in 107 SCI patients (34 women and 73 men) were identified. The majority of patients were paraplegics (77.6%) and classified as American Spinal Injury Association Impairment Scale A (86.0%). Only the lower extremities were affected, whereby the femur (60.9% of all fractures) was fractured more frequently than the lower leg (39.1%). A total of 70 patients (65.4%) had one fracture, whereas 37 patients (34.6%) had two or more fractures. Simple or extraarticular fractures were most common (75.0%). Overall, 130 (83.3%) fractures were managed operatively. Approximately half of the femur fractures (48.2%) were treated with locking compression plates. In the lower leg, fractures were mainly managed with external fixation (48.8%). Conservative fracture management was applied in 16.7% of the cases and consisted of braces or a well-padded soft cast. Fracture-associated complications were present in 13.5% of the cases but did not differ significantly between operative (13.1%) and conservative (15.4%) fracture management. CONCLUSION SCI was associated with simple or extraarticular fractures of the distal femur and the lower leg. Fractures were mainly managed operatively with a low complication rate.