Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Broadband multizone sound rendering by jointly optimizing the sound pressure and particle velocity.

In this paper, a recently proposed approach to multizone sound field synthesis, referred to as joint pressure and velocity matching (JPVM), is investigated analytically using a spherical harmonics representation of the sound field. The approach is motivated by the Kirchhoff-Helmholtz integral equation and aims at controlling the sound field inside the local listening zones by evoking the sound pressure and particle velocity on surrounding contours. Based on the findings of the modal analysis, an improved version of JPVM is proposed, which provides both better performance and lower complexity. In particular, it is shown analytically that the optimization of the tangential component of the particle velocity vector, as is done in the original JPVM approach, is very susceptible to errors and thus not pursued anymore. Furthermore, the analysis provides fundamental insights as to how the spherical harmonics used to describe three-dimensional sound fields translate into two-dimensional basis functions as observed on the contours surrounding the zones. By means of simulations, it is verified that discarding the tangential component of the particle velocity vector ultimately leads to an improved performance. Finally, the impact of sensor noise on the reproduction performance is assessed.

The effect of food quality during growth on spatial memory consolidation in adult pigeons.

Poor environmental conditions experienced during early development can have negative long-term consequences on fitness. Animals can compensate for negative developmental effects through phenotypic plasticity by diverting resources from non-vital to vital traits such as spatial memory to enhance foraging efficiency. We tested in young feral pigeons (Columba livia) how diets of different nutritional value during development affect the capacity to retrieve food hidden in a spatially complex environment, a process we refer to as 'spatial memory'. Parents were fed with either high- or low-quality food from egg laying until young fledged, after which all young pigeons received the same high-quality diet until memory performance was tested at 6 months of age. The pigeons were trained to learn a food location out of 18 possible locations in one session, and then their memory of this location was tested 24 h later. Birds reared with the low-quality diet made fewer errors in the memory test. These results demonstrate that food quality during development has long-lasting effects on memory, with a moderate nutritional deficit improving spatial memory performance in a foraging context. It might be that under poor feeding conditions resources are redirected from non-vital to vital traits, or pigeons raised with low-quality food might be better in using environmental cues such as the position of the sun to find where food was hidden.

Psychometric Properties of the German Version of the Pain Vigilance and Awareness Questionnaire (PVAQ) in Pain-Free Samples and Samples with Acute and Chronic Pain.

PURPOSE: The way individuals attend to pain is known to have a considerable impact on the experience and chronification of pain. One method to assess the habitual "attention to pain" is the Pain Vigilance and Awareness Questionnaire (PVAQ). With the present study, we aimed to test the psychometric properties of the German version of the PVAQ across pain-free samples and across patients with acute and chronic pain. METHOD: Two samples of pain-free individuals (student sample (N = 255)/non-student sample (N = 362)) and two clinical pain samples (acute pain patients (N = 105)/chronic pain patients (N = 36)) were included in this cross-sectional evaluation of the German PVAQ. Factor structure was assessed using exploratory and confirmatory factor analyses. Reliability was assessed using internal consistency (Cronbach's alpha). Construct validity was tested by assessing correlations between PVAQ and theoretically related constructs. RESULTS: Exploratory factor analysis (non-student sample) and confirmatory factor analysis (student sample, acute pain patient sample) suggested that a two-factor solution best fitted our data ("attention to pain," "attention to changes in pain"). Internal consistency ranged from acceptable to good in all four samples. As hypothesized, the PVAQ correlated significantly with theoretically related constructs in all four samples, suggesting good construct validity in pain-free individuals and in pain patients. CONCLUSION: The German PVAQ shows good psychometric properties across samples of pain-free individuals and patients suffering from pain that are comparable to PVAQ versions of other languages. Thus, the German PVAQ seems to be a measure of pain vigilance equally valid as found in other countries.

The spatial coherence of noise fields evoked by continuous source distributions.

In this work, analytic expressions for the spatial coherence of noise fields are derived in the modal domain with the aim of providing a sparse representation. For this purpose, the sound field in a region of interest is expressed in terms of a given pressure distribution on a virtual surrounding cylindrical or spherical surface. According to the Huygens-Fresnel principle, the sound pressure on this surface is represented by a continuous distribution of elementary line or point sources, where orthogonal basis functions characterize the spatial properties. To describe spatially windowed pressure distributions with arbitrary angular extensions, orthogonal basis functions of limited angular support are proposed. As special cases, circular and spherical pressure distributions with uncorrelated source modes of equal power are investigated. It is shown that these distributions result, respectively, in cylindrically isotropic and spherically isotropic, i.e., diffuse noise fields. The analytic expressions derived in this work allow for a prediction of the spatial coherence between arbitrary positions within the region of interest, such that no microphones need to be placed at the actual points of interest. Simulation results are presented to validate the derived relations.

Full counting statistics of laser excited Rydberg aggregates in a one-dimensional geometry.

We experimentally study the full counting statistics of few-body Rydberg aggregates excited from a quasi-one-dimensional atomic gas. We measure asymmetric excitation spectra and increased second and third order statistical moments of the Rydberg number distribution, from which we determine the average aggregate size. Estimating rates for different excitation processes we conclude that the aggregates grow sequentially around an initial grain. Direct comparison with numerical simulations confirms this conclusion and reveals the presence of liquidlike spatial correlations. Our findings demonstrate the importance of dephasing in strongly correlated Rydberg gases and introduce a way to study spatial correlations in interacting many-body quantum systems without imaging.

[Psychological prophylaxis training for coping with postoperative pain. Long-term effects]. / Psychologisches Prophylaxetraining zur Bewältigung postoperativer Schmerzen. Langfristige Effekte.

INTRODUCTION: The present study was performed to investigate the effect of multidimensional psychological prophylaxis training focusing on coping with cognitive-emotional pain on recovery within the first 12 months after surgery. The training included the following three components: (1) education about pain, analgesia and psychological aspects of coping with pain, (2) training for coping with pain and (3) body-centered relaxation. MATERIAL AND METHODS: In the study 48 young male patients (surgical correction of a chest malformation) were assessed 1 day before surgery, at discharge and 3, 6 and 12 months postoperatively concerning postoperative pain intensity and pain disability as well as pain anxiety, pain catastrophizing and pain hypervigilance. Additionally, 24 of these patients received training on cognitive-emotional coping with pain 1 day before surgery and 1-3 days after surgery (each session 1 h). RESULTS: The proportion of patients with clinically relevant improvement was significantly higher in the training group compared to the control group. This was the case for acute pain intensity (approximately 1 week after surgery), pain disability 3 months later and pain anxiety 12 months after surgery. CONCLUSION: The resurgence of pain anxiety after 12 months could only be found in the control group and could be due to the upcoming surgical removal of the transsternal metal implant. The prophylaxis training can therefore be seen as a protective factor for long-term management of surgery-related consequences and future pain experiences.

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Unified approach to probing Coulomb effects in tunnel ionization for any ellipticity of laser light.

We present experimental data that show significant deviations from theoretical predictions for the location of the center of the electron momenta distribution at low values of ellipticity ε of laser light. We show that these deviations are caused by significant Coulomb focusing along the minor axis of polarization, something that is normally neglected in the analysis of electron dynamics, even in cases where the Coulomb correction is otherwise taken into account. By investigating ellipticity-resolved electron momenta distributions in the plane of polarization, we show that Coulomb focusing predominates at lower values of ellipticity of laser light, while Coulomb asymmetry becomes important at higher values, showing that these two complementary phenomena can be used to probe long-range Coulomb interaction at all polarizations of laser light. Our results suggest that both the breakdown of Coulomb focusing and the onset of Coulomb asymmetry are linked to the disappearance of Rydberg states with increasing ellipticity.

Spontaneous avalanche ionization of a strongly blockaded Rydberg gas.

We report the sudden and spontaneous evolution of an initially correlated gas of repulsively interacting Rydberg atoms to an ultracold plasma. Under continuous laser coupling we create a Rydberg ensemble in the strong blockade regime, which at longer times undergoes an ionization avalanche. By combining optical imaging and ion detection, we access the full information on the dynamical evolution of the system, including the rapid increase in the number of ions and a sudden depletion of the Rydberg and ground state densities. Rydberg-Rydberg interactions are observed to strongly affect the dynamics of plasma formation. Using a coupled rate-equation model to describe our data, we extract the average energy of electrons trapped in the plasma, and an effective cross section for ionizing collisions between Rydberg atoms and atoms in low-lying states. Our results suggest that the initial correlations of the Rydberg ensemble should persist through the avalanche. This would provide the means to overcome disorder-induced heating, and offer a route to enter new strongly coupled regimes.

Sub-Poissonian statistics of Rydberg-interacting dark-state polaritons.

We observe individual dark-state polaritons as they propagate through an ultracold atomic gas involving Rydberg states coupled via an electromagnetically induced transparency resonance. Strong long-range interactions between Rydberg excitations give rise to a blockade between polaritons, resulting in large optical nonlinearities and modified polariton number statistics. By combining optical imaging and high-fidelity detection of the Rydberg polaritons we investigate both aspects of this coupled atom-light system. We map out the full nonlinear optical response as a function of atomic density and follow the temporal evolution of polaritons through the atomic cloud. In the blockade regime, the statistical fluctuations of the polariton number drop well below the quantum noise limit. The low level of fluctuations indicates that photon correlations modified by the strong interactions have a significant backaction on the Rydberg atom statistics.

Evaluation of two minimally invasive techniques for electroencephalogram recording in wild or freely behaving animals.

Insight into the function of sleep may be gained by studying animals in the ecological context in which sleep evolved. Until recently, technological constraints prevented electroencephalogram (EEG) studies of animals sleeping in the wild. However, the recent development of a small recorder (Neurologger 2) that animals can carry on their head permitted the first recordings of sleep in nature. To facilitate sleep studies in the field and to improve the welfare of experimental animals, herein, we test the feasibility of using minimally invasive surface and subcutaneous electrodes to record the EEG in barn owls. The EEG and behaviour of four adult owls in captivity and of four chicks in a nest box in the field were recorded. We scored a 24-h period for each adult bird for wakefulness, slow-wave sleep (SWS), and rapid-eye movement (REM) sleep using 4 s epochs. Although the quality and stability of the EEG signals recorded via subcutaneous electrodes were higher when compared to surface electrodes, the owls' state was readily identifiable using either electrode type. On average, the four adult owls spent 13.28 h awake, 9.64 h in SWS, and 1.05 h in REM sleep. We demonstrate that minimally invasive methods can be used to measure EEG-defined wakefulness, SWS, and REM sleep in owls and probably other animals.

Nanoscale probing of charge transport in an organic field-effect transistor at cryogenic temperatures.

We studied charge transport in a field-effect transistor based on an anthracene crystal by single-molecule spectroscopy at cryogenic temperatures. When applying a control voltage to the gate, source and drain electrodes, we observe spectral drifts of the probe molecules' lines, which follow strongly non-exponential (stretched) kinetics, from seconds to tens of minutes. Applying a gate voltage alone, we find a dependence of the spectral shift as the logarithm of time. When an additional source-drain voltage is applied, the spectral shift follows a power law of time, similar to the elementary step of conduction in amorphous solids, postulated in the continuous-time random walk theory of Scher and Montroll.

Interaction enhanced imaging of individual Rydberg atoms in dense gases.

We propose a new all-optical method to image individual Rydberg atoms embedded within dense gases of ground state atoms. The scheme exploits interaction-induced shifts on highly polarizable excited states of probe atoms, which can be spatially resolved via an electromagnetically induced transparency resonance. Using a realistic model, we show that it is possible to image individual Rydberg atoms with enhanced sensitivity and high resolution despite photon-shot noise and atomic density fluctuations. This new imaging scheme could be extended to other impurities such as ions, and is ideally suited to equilibrium and dynamical studies of complex many-body phenomena involving strongly interacting particles. As an example we study blockade effects and correlations in the distribution of Rydberg atoms optically excited from a dense gas.

Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab.

Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aß) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer's disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD.

Coherent population trapping with controlled interparticle interactions.

We investigate coherent population trapping in a strongly interacting ultracold Rydberg gas. Despite the strong van der Waals interactions and interparticle correlations, we observe the persistence of a resonance with subnatural linewidth at the single-particle resonance frequency as we tune the interaction strength. This narrow resonance cannot be understood within a mean-field description of the strong Rydberg-Rydberg interactions. Instead, a many-body density matrix approach, accounting for the dynamics of interparticle correlations, is shown to reproduce the observed spectral features.

Genetic basis of differential opsin gene expression in cichlid fishes.

Visual sensitivity can be tuned by differential expression of opsin genes. Among African cichlid fishes, seven cone opsin genes are expressed in different combinations to produce diverse visual sensitivities. To determine the genetic architecture controlling these adaptive differences, we analysed genetic crosses between species expressing different complements of opsin genes. Quantitative genetic analyses suggest that expression is controlled by only a few loci with correlations among some genes. Genetic mapping identifies clear evidence of trans-acting factors in two chromosomal regions that contribute to differences in opsin expression as well as one cis-regulatory region. Therefore, both cis and trans regulation are important. The simple genetic architecture suggested by these results may explain why opsin gene expression is evolutionarily labile, and why similar patterns of expression have evolved repeatedly in different lineages.

Strong coupling in a single quantum dot-semiconductor microcavity system.

Cavity quantum electrodynamics, a central research field in optics and solid-state physics, addresses properties of atom-like emitters in cavities and can be divided into a weak and a strong coupling regime. For weak coupling, the spontaneous emission can be enhanced or reduced compared with its vacuum level by tuning discrete cavity modes in and out of resonance with the emitter. However, the most striking change of emission properties occurs when the conditions for strong coupling are fulfilled. In this case there is a change from the usual irreversible spontaneous emission to a reversible exchange of energy between the emitter and the cavity mode. This coherent coupling may provide a basis for future applications in quantum information processing or schemes for coherent control. Until now, strong coupling of individual two-level systems has been observed only for atoms in large cavities. Here we report the observation of strong coupling of a single two-level solid-state system with a photon, as realized by a single quantum dot in a semiconductor microcavity. The strong coupling is manifest in photoluminescence data that display anti-crossings between the quantum dot exciton and cavity-mode dispersion relations, characterized by a vacuum Rabi splitting of about 140 microeV.

Middle-molecule clearance at 20 and 35 ml/kg/h in continuous venovenous hemodiafiltration.

BACKGROUND: Of 5 clinical trials testing dose response of continuous renal replacement therapy (CRRT) in acute kidney injury, 2 showed a benefit, 2 showed none, and 1 appeared equivocal. However, blood-membrane interactions may dominate macromolecule transport in continuous venovenous hemodiafiltration, reducing the impact of dose adjustment. The dosing arms in the Acute Renal Failure Trial Network (ATN) study may have delivered similar clearances for middle molecules. METHODS: We simulated the 2 CRRT doses in the ATN study using a synthetic polydisperse macromolecular probe in bovine blood. Clearance of tracers between 10 and 100 kDa molecular weight was measured during 6 h of therapy. RESULTS: Middle-molecule clearance differed by less than 2 ml/min between the 2 dosing arms. CONCLUSION: The CRRT prescription used in the ATN study appears to have achieved dose separation for small molecules while holding middle-molecule clearance nearly constant. This may explain the outcome difference between the ATN study and earlier studies, and suggests subsequent trial designs.

Gender aspects in skin diseases.

Gender differences in medicine have been recognized in anatomy, physiology, as well as in epidemiology and manifestations of various diseases. With respect to skin disorders, males are generally more commonly afflicted with infectious diseases while women are more susceptible to psychosomatic problems, pigmentary disorders, certain hair diseases, and particularly autoimmune as well as allergic diseases. Significantly, more female sex-associated dermatoses can be identified than the male sex-associated dermatoses. Dermatoses in the genital area differ between men and women. Gender differences also exist in the occurrence and prognosis of certain skin malignancies. The mechanisms underlying gender differences in skin diseases remain largely unknown. Differences in the skin structure and physiology, effect of sex hormones, ethnic background, sociocultural behaviour and environmental factors may interact to exert the influences. A better understanding of gender differences in human health and diseases will allow the development of novel concepts for prevention, diagnosis and therapy of skin diseases.