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Background Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood. Methods We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison. Results Both regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding. Conclusions HSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups. Clinical Trials Registration NCT03467074., The Journal of Infectious Diseases, 225 (8), ISSN:0022-1899, ISSN:1537-6613

Biallelic mutations in ZMPSTE24 are known to be associated with autosomal recessive mandibuloacral dysplasia with type B lipodystrophy (MADB) and lethal restrictive dermopathy (RD), respectively. Disease manifestation is depending on the remaining enzyme activity of the mutated ZMPSTE24 protein. To date, complete loss of function has exclusively been reported in RD cases. In this study, we identified a novel N-terminal homozygous frameshift mutation (c.28_29insA) in a consanguineous family segregating with MADB. An in-depth analysis of the mutated sequence revealed, that the one base pair insertion creates a novel downstream in-frame start codon, which supposedly serves as an alternative translation initiation site (TIS). This possible rescue mechanism would explain the relatively mild clinical outcome in the studied individuals. Our findings demonstrate the necessity for careful interpretation of N-terminal variants potentially effecting translation initiation.

iLoc is an ultrasound ranging based indoor localization system deployed at the iHomeLab at Lucerne University of Applied Sciences and the Embedded Systems Lab at Stuttgart University of Applied Sciences. The system tracks humans in AAL scenarios which bear an ultrasound transmitter for example in the form of a name badge. The transmitter can be localized with an average accuracy well below 1 meter, by means of wired reference nodes distributed in the lab rooms. A small battery may suffice for several month of transmitter operation. The original deployment consists of wired nodes. Data and power is supplied via the IPoK fieldbus. Configuration data, i.e. node positions, are measured manually and entered in a database. The system participated at the first EvAAL competition 2011 and reached best accuracy score. iLoc+, A modified system comprising battery powered wireless nodes and an automatic configuration procedure was used at the second EvAAL Competition 2012. Both solutions are compared with focus on obtained accuracy and installation effort, using data from the respective competitions. Results of the comparison are discussed and possible optimizations are outlined. The implications may also be relevant for other positioning technologies in the AAL sector.

Antibody titers are commonly used as surrogate markers for serological protection against influenza and other pathogens. Detailed knowledge of antibody production pre- and post-vaccination is required to understand vaccine-induced immunity. This article describes a reliable point-by-point protocol to determine influenza-specific antibody titers. The first protocol describes a method to specify the antigen amounts required for hemagglutination, which standardizes the concentrations for subsequent usage in the second protocol (hemagglutination assay, HA assay). The second protocol describes the quantification of influenza-specific antibody titers against different viral strains by using a serial dilution of human serum or cell culture supernatants (hemagglutination inhibition assay, HI assay). As an applied example, we show the antibody response of a healthy cohort, which received a trivalent inactivated influenza vaccine. Additionally, the cross-reactivity between the different influenza viruses is shown and methods to minimize cross-reactivity by using different types of animal red blood cells (RBCs) are explained. The discussion highlights advantages and disadvantages of the presented assays and how the determination of influenza-specific antibody titers can improve the understanding of vaccine-related immunity.

Homogeneous nucleation of ice in supercooled water droplets is a stochastic process. In its classical description, the growth of the ice phase requires the emergence of a critical embryo from random fluctuations of water molecules between the water bulk and ice-like clusters, which is associated with overcoming an energy barrier. For heterogeneous ice nucleation on ice-nucleating surfaces both, stochastic and deterministic descriptions are in use. Deterministic (singular) descriptions are often favored because the temperature dependence of ice nucleation on a substrate usually dominates the stochastic time dependence, and the ease of representation facilitates the incorporation in climate models. Conversely, classical nucleation theory (CNT) describes heterogeneous ice nucleation as a stochastic process with a reduced energy barrier for the formation of a critical embryo in the presence of an ice-nucleating surface. This reduction is conveniently parameterized in terms of a contact angle α between the ice phase immersed in liquid water and the heterogeneous surface area. This study investigates various ice-nucleating agents in immersion mode by subjecting them to repeated freezing cycles to elucidate and discriminate the time and temperature dependences of heterogeneous ice nucleation. Freezing rates determined from such refreeze experiments are presented for Hoggar Mountain dust, birch pollen washing water and Arizona Test Dust (ATD) and nonadecanol coatings. For the analysis of the experimental data with CNT we assumed the same active site to be always responsible for freezing. Three different CNT-based parame-terizations were used to describe rate coefficients for heterogeneous ice nucleation as a function of temperature, all leading to very similar results: for Hoggar Mountain dust, ATD and larger nonadecanol coated water droplets, the experimentally determined increase of freezing rate with decreasing temperature is too shallow to be described properly by CNT using the contact angle as the only fit parameter. Birch pollen washing water and small nonadecanol coated water droplets show the reverse behavior with temperature dependencies of freezing rates steeper than predicted by CNT formulations. Good agreement of observations and calculations can be obtained when a prefactor β is introduced to the rate coefficient as second fit parameter. Thus, the following microphysical picture emerges: Heterogeneous freezing occurs on ice-nucleating sites that need a minimum (critical) surface area to host embryos of critical size to grow into a crystal. Fits based on CNT suggest that the critical active site area is in the range of 10–50 nm2 depending on sample, temperature, and CNT-based parameterization. Two fitting parameters are needed to characterize individual active sites. The contact angle lowers the energy barrier that has to be overcome to form the critical embryo on the site compared to the homogeneous case where the critical embryo develops in the volume of water. The prefactor β is needed to adjust the calculated slope of freezing rate increase with decreasing temperature to the measured one. When it is large, there are many nucleation attempts and nucleation occurs immediately when the temperature is low enough so that the active site can accommodate a critical embryo. This is the case for active sites of birch pollen washing water and the small droplets coated with nonadecanol. If the prefactor is low, the number of nucleation attempts is low and the increase of freezing rate with decreasing temperature is shallow. This is the case for Hoggar Mountain dust, the large droplets coated with nonadecanol, and ATD. Different hypotheses why the value of the prefactor depends on the nature of the active sites are discussed.

Twelve natural dust samples from eight dust source regions on four continents were investigated with respect to their ice nucleation activity, revealing no significant differences between source regions. Dust collection sites were distributed across Africa, South America, the Middle East and Antarctica. Mineralogical compositions have been determined by means of X-ray diffraction. All samples proved to be mixtures of minerals, with major contributions from quartz, calcite, clay minerals, K-feldspars and (Na, Ca)-feldspars. Reference samples of these minerals were investigated with the same methods as the natural dust samples. Furthermore, Arizona Test Dust (ATD) was re-evaluated as a benchmark. Immersion freezing of emulsion and bulk samples was investigated by differential scanning calorimetry. For emulsion measurements, water droplets with a diameter of about 2 µm, containing different amounts of dust between 0.5 wt% and 50 wt% were cooled until all droplets were frozen. These measurements characterize the average freezing behaviour of particles, as they are sensitive to the average active sites present in a dust sample. In addition, bulk measurements were conducted with one single 1 mm diameter droplet consisting of a 5 wt% aqueous suspension of the dusts/minerals. These measurements allow the investigation of the best particles/sites available in a dust. All natural dusts except for the Antarctica and ATD samples froze in a remarkably narrow temperature range with the heterogeneously frozen fraction reaching 10 % between 244 and 250 K, 25 % between 242 and 246 K, and 50 % between 239 and 244 K. Bulk freezing occurred between 255 and 265 K. In contrast to the natural dusts, the reference minerals reveal ice nucleation temperatures with 2–3 times larger scatter. Calcite, dolomite, dolostone and muscovite can be considered inactive as ice nuclei (IN). For microcline samples 50 % heterogeneously frozen fraction occurred above 245 K for all tested suspension concentrations, and a microcline mineral showed bulk freezing temperatures even above 270 K. This makes microcline (KAlSi3O8) an exceptionally good IN, superior to all other analysed K-feldspars, (Na, Ca)-feldspars and the clay minerals. However, microcline is not abundant in the investigated natural dust samples. While K-feldspars were identified in five of the seven investigated natural source regions, only one sample contained microcline, and then only as a minor fraction. In summary, the mineralogical composition can explain the observed freezing behaviour of five of the investigated 12 natural dust samples, and partly for six samples, leaving the freezing efficiency of only one sample not easily explained in terms of its mineral reference components. While this suggests that mineralogical composition is a major determinant of ice nucleation ability, in practice most natural samples consist of a mixture of minerals, and this mixture seems to lead to remarkably similar ice nucleation abilities, regardless of their exact composition, so that global models, in a first approximation, may represent mineral dust as a single species with respect to ice nucleation activity. However, more sophisticated representations of ice nucleation by mineral dusts should rely on the mineralogical composition based on a source scheme of dust emissions.

A luminescence immunoassay (LIA) was developed for the diagnosis of bovine spongiform encephalopathy (BSE) in brain tissue using two different monoclonal antibodies for capture and detection of the protease-resistant fragment of the pathological prion protein (PrP27-30). PrP27-30 currently represents the most reliable marker for the infectious particle (denominated prion) causing transmissible spongiform encephalopathies (TSEs). Internal and official validation studies of this assay are described using brain homogenates from ascertained BSE positive and negative cows. Using more than 300 positive and 1400 negative bovine or ovine samples, an excellent sensitivity and specificity of 100% were demonstrated. More than 1000-fold dilutions of a BSE positive homogenate still resulted in a clear positive signal. In combination with a simple homogenisation procedure for the preparation of the samples, this assay lends itself for large scale screening of cattle and sheep for TSEs using complete automation of the process.

e14523 Background: Cancer patients (pts) are at risk to develop complications when infected with seasonal influenza viruses. Current guidelines propose that pts on PD-1 directed therapies may receive concurrent inactivated influenza immunization if not medically contraindicated. In this observational study, we aimed to assess the vaccine induced immune response and safety of immunotherapy and influenza vaccine. Methods: Metastatic cancer pts treated with at least one dose of either nivolumab or pembrolizumab were vaccinated with a trivalent inactive influenza vaccination between October and November 2015. Partners of the pts were vaccinated and included in our analysis as age-matched controls. Antibody titers against vaccine virus strains were measured by hemagglutination inhibition assay at days 7, 30, 60 and 180. Cytokine/chemokine profile and changes in peripheral immune cells were assessed in cancer pts at the same time points. Immune-related adverse events (irAE) were documented according to CTCAE v4.0. Results: We included 23 pts and 7 age-matched healthy controls. Median time between initiation of PD-1 inhibition and influenza vaccination was 74 days (range, 44-57). 22 pts were treated with nivolumab and 1 pt with pembrolizumab. 16 pts had a diagnosis of non-small cell lung cancer, 3 pts had renal cell carcinoma and 3 pts a malignant melanoma. In total, 12 pts (52.2%) experienced an irAE. 6 pts (26.1%) had grade 3 or 4 (G3/4) irAEs. This frequency seems to be higher than reported in the literature. G3/4 irAEs include colitis (n = 2), encephalitis (n = 1), vasculitis (n = 1), pneumonitis (n = 1), peripheral neuritis (n = 1). There was no major difference over time in the generation of antibody titers against strains in the vaccine. Peripheral leukocyte counts and cytokine/inflammatory chemokine levels were unchanged after vaccination. We did not observe unexpected local toxicities at the injection site. Conclusions: The seasonal influence vaccination reaches a protective range in these pts. Unexpectedly, however, an increased rate of clinically relevant irAEs was observed. Confirmation in a larger population and mechanistic understanding is required.

The maturation of the iliac apophysis (Risser sign) and of the bones of the hand and wrist of 34 girls with scoliosis with 46 pairs of data were analyzed to get information upon their predictive value for further growth and development of the scoliotic curve. A strong correlation was found between the Risser sign and the maturation of the hand and wrist (r = 0.74, p less than 0.005). The prognostic value of the Risser sign (r = -0.57) for further height gain is superior to chronological age only (r = -0.52), the maturation of the hand and wrist (r = -0.62) however is superior to the Risser sign. It can be assumed that this also holds for their prognostic value for the progression of the scoliotic curve. We feel that in the clinician routine for girls with scoliosis the determination of the skeletal maturity from X-rays of the hand is sufficient and with its probably unavoidable irradiation risks to the gonads the determination of the Risser sign should be abandoned.

Cherrypickers are a useful class of machines that lift people to great heights. However, a major drawback of cherrypickers is that they oscillate when they move. Understanding the dynamics and stability of these machines is crucial for efficient and safe operation. To this end, a small-scale cherrypicker was constructed for experimental dynamic analysis and educational use. Experimental results confirm the benefits of the vibration-control techniques developed for this machine. The cherrypicker was used during Fall 2010 as an experimental apparatus in an advanced graduate controls course taught simultaneously at the Georgia Institute of Technology and the Massachusetts Institute of Technology. Details of its educational use are discussed.

iLoc is an ultrasound ranging based indoor localization system which is deployed at the iHomeLab laboratory. For example, the system can be used for visitor tracking: Visitors get an electronic name badge comprising an ultrasound transmitter. This badge can be localized with an average accuracy of less than 10 cm deviation in its spatial position, by means of reference nodes distributed in the lab rooms. Depending on the position update rate, a small battery may suffice for several month of tag operation. Other advantages when compared to existing ultrasound ranging systems (like CRICKET, CALMARI, BAT) are for example the simple deployment with its 2 wire “IPoK” bus system. In this paper we report on the system itself and on the participating of iLoc at the first EvAAL indoor localization competition.