Building Cox-Type Structured Hazard Regression Models with Time-Varying Effects

In recent years, flexible hazard regression models based on penalised splines have been developed that allow us to extend the classical Cox-model via the inclusion of time-varying and nonparametric effects. Despite their immediate appeal in terms of flexibility, these models introduce additional difficulties when a subset of covariates and the corresponding modelling alternatives have to be chosen. We present an analysis of data from a specific patient population with 90-day survival as the response variable. The aim is to determine a sensible prognostic model where some variables have to be included due to subject-matter knowledge while other variables are subject to model selection. Motivated by this application, we propose a twostage stepwise model building strategy to choose both the relevant covariates and the corresponding modelling alternatives within the choice set of possible covariates simultaneously. For categorical covariates, competing modelling approaches are linear effects and time-varying effects, whereas nonparametric modelling provides a further alternative in case of continuous covariates. In our data analysis, we identified a prognostic model containing both smooth and time-varying effects

Mitochondrial protein import

Transport of nuclear-encoded precursor proteins into mitochondria includes proteolytic cleavage of aminoterminal targeting sequences in the mitochondrial matrix. We have isolated the processing activity from Neurospora crassa. The final preparation (enriched ca. 10,000-fold over cell extracts) consists of two proteins, the matrix processing peptidase (MPP, 57 kd) and a processing enhancing protein (PEP, 52 kd). The two components were isolated as monomers. PEP is about 15-fold more abundant in mitochondria than MPP. It is partly associated with the inner membrane, while MPP is soluble in the matrix. MPP alone has a low processing activity whereas PEP alone has no apparent activity. Upon recombining both, full processing activity is restored. Our data indicate that MPP contains the catalytic site and that PEP has an enhancing function. The mitochondrial processing enzyme appears to represent a new type of “signal peptidase,” different from the bacterial leader peptidase and the signal peptidase of the endoplasmic reticulum

Cyclosporin A-binding protein (cyclophilin) of Neurospora crassa

Cyclophilin (cyclosporin A-binding protein) has a dual localization in the mitochondria and in the cytosol of Neurospora crassa. The two forms are encoded by a single gene which is transcribed into mRNAs having different lengths and 5' termini (approximately 1 and 0.8 kilobases). The shorter mRNA specifies the cytosolic protein consisting of 179 amino acids. The longer mRNA is translated into a precursor polypeptide with an amino-terminal extension of 44 amino acids which is cleaved in two steps upon entry into the mitochondrial matrix. Neurospora cyclophilin shows about 60% sequence homology to human and bovine cyclophilins

Acute and long-term survival in chronically critically ill surgical patients: a retrospective observational study

Introduction Various cohort studies have shown that acute ( short-term) mortality rates in unselected critically ill patients may have improved during the past 15 years. Whether these benefits also affect acute and long-term prognosis in chronically critically ill patients is unclear, as are determinants relevant to prognosis. Methods We conducted a retrospective analysis of data collected from March 1993 to February 2005. A cohort of 390 consecutive surgical patients requiring intensive care therapy for more than 28 days was analyzed. Results The intensive care unit ( ICU) survival rate was 53.6%. Survival rates at one, three and five years were 61.8%, 44.7% and 37.0% among ICU survivors. After adjustment for relevant covariates, acute and long-term survival rates did not differ significantly between 1993 to 1999 and 1999 to 2005 intervals. Acute prognosis was determined by disease severity during ICU stay and by primary diagnosis. However, only the latter was independently associated with long-term prognosis. Advanced age was an independent prognostic determinant of poor short-term and long-term survival. Conclusion Acute and long-term prognosis in chronically critically ill surgical patients has remained unchanged throughout the past 12 years. After successful surgical intervention and intensive care, long-term outcome is reasonably good and is mainly determined by age and underlying disease

Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models

BACKGROUND Proteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use. METHODS Using a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: 1.2~g/kg per day) during the first 11~days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet). RESULTS Of 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49~g/kg IQR 0.27-0.66, standard intake 0.99~g/kg IQR 0.89- 1.09, and high intake 1.41~g/kg IQR 1.29-1.60. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95{\%} CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95{\%} CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome. CONCLUSIONS Provision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase. Study registration ID number ISRCTN17829198

Nonparametric change point estimation for survival distributions with a partially constant hazard rate

We present a new method for estimating a change point in the hazard function of a survival distribution assuming a constant hazard rate after the change point and a decreasing hazard rate before the change point. Our method is based on fitting a stump regression to p-values for testing hazard rates in small time intervals. We present three real data examples describing survival patterns of severely ill patients, whose excess mortality rates are known to persist far beyond hospital discharge. For designing survival studies in these patients and for the definition of hospital performance metrics (e.g. mortality), it is essential to define adequate and objective end points. The reliable estimation of a change point will help researchers to identify such end points. By precisely knowing this change point, clinicians can distinguish between the acute phase with high hazard (time elapsed after admission and before the change point was reached), and the chronic phase (time elapsed after the change point) in which hazard is fairly constant. We show in an extensive simulation study that maximum likelihood estimation is not robust in this setting, and we evaluate our new estimation strategy including bootstrap confidence intervals and finite sample bias correction

Complex spectral line profiles resulting from cryogenic deformation of the SINFONI/SPIFFI diffraction gratings

The integral field spectrograph, spectrometer for infrared faint field imaging (SPIFFI), has complex line profile shapes that vary with wavelength and pixel scale, the origins of which have been sought since the instrument construction. SPIFFI is currently operational as part of SINFONI at the Very Large Telescope (VLT) and will be upgraded and incorporated into the VLT instrument enhanced resolution imager and spectrograph (ERIS). We conducted an investigation of the line profiles based on the measurements we could take with the instrument calibration unit, as well as laboratory measurements of spare SPIFFI optical components. Cryogenic measurements of a spare SPIFFI diffraction grating showed significant periodic deformation. These measurements match the cryogenic deformation expected from bimetallic bending stress based on a finite element analysis of the lightweighted grating blank. The periodic deformation of the grating surface gives rise to satellite peaks in the diffraction pattern of the grating. An optical simulation including the cryogenic grating deformation reproduces the behavior of the SPIFFI line profiles with both wavelength and pixel scale as measured with the instrument calibration unit. The conclusion is that cryogenic deformation of the diffraction gratings is responsible for the nonideal line profiles, and that the diffraction gratings should be replaced during the upgrade for optimal instrument performance.ISSN:2329-4221ISSN:2329-412

Evidence based medicine in physical medicine and rehabilitation (English version)

In the last twenty years the term “Evidence Based Medicine (EBM)” has spread into all areas of medicine and is often used for decision-making in the medical and public health sector. It is also used to verify the significance and/or the effectiveness of different therapies. The definition of EBM is to use the physician’s individual expertise, the patient’s needs and the best external evidence for each individual patient. Today, however, the term EBM is often wrongly used as a synonym for best “external evidence”. This leads not only to a misuse of evidence based medicine but suggests a fundamental misunderstanding of the model which was created by Gordon Guyatt, David Sackett and Archibald Cochrane. This problem becomes even greater the more social insurance institutions, public healthcare providers and politicians use external evidence alone as a main guideline for financing therapies in physical medicine and general rehabilitation without taking into account the physician’s expertise and the patient’s needs.The wrong interpretation of EBM can lead to the following problems: well established clinical therapies are either questioned or not granted and are therefore withheld from patients (for example physical pain management). Absence of evidence for individual therapy methods does not prove their ineffectiveness! In this short statement the significance of EBM in physical medicine and general rehabilitation will be analysed and discussed

Pathogenic Fungi Regulate Immunity by Inducing Neutrophilic Myeloid-Derived Suppressor Cells

Peer reviewedPublisher PD

ERIS: revitalising an adaptive optics instrument for the VLT

ERIS is an instrument that will both extend and enhance the fundamental diffraction limited imaging and spectroscopy capability for the VLT. It will replace two instruments that are now being maintained beyond their operational lifetimes, combine their functionality on a single focus, provide a new wavefront sensing module that makes use of the facility Adaptive Optics System, and considerably improve their performance. The instrument will be competitive with respect to JWST in several regimes, and has outstanding potential for studies of the Galactic Center, exoplanets, and high redshift galaxies. ERIS had its final design review in 2017, and is expected to be on sky in 2020. This contribution describes the instrument concept, outlines its expected performance, and highlights where it will most excel.Comment: 12 pages, Proc SPIE 10702 "Ground-Based and Airborne Instrumentation for Astronomy VII