Efficacy and safety of rechallenge with [177Lu]Lu-PSMA-I&T radioligand therapy in metastatic castration resistant prostate cancer.

BACKGROUND: The purpose of this study was to evaluate the safety and outcome of rechallenge [177Lu]Lu-PSMA-I&T in newly progressed mCRPC patients after response to initial [177Lu]Lu-PSMA radioligand therapy (PRLT). METHODS: We retrospectively included 18 patients who underwent rechallenge with [177Lu]Lu-PSMA-I&T. All patients presented with (i) newly progressed disease after response to initial PRLT; (ii) a [68Ga]Ga-PSMA-11 PET/CT confirming the presence of PSMA-positive metastases; iii) ECOG performance status 0-1. Adverse events were graded according to CTCAE v5.0. Response was assessed by PSA and classified according to PCWG3 recommendations. For patients who underwent restaging with [68Ga]Ga-PSMA-11 PET/CT, imaging response was categorised according to adapted PERCIST v1.0. In patients with discordant [68Ga]Ga-PSMA-11 PET/CT and PSA, other available imaging modalities were evaluated to confirm disease status. Overall survival (OS) was calculated from the first cycle of initial PRLT and rechallenge PRLT, respectively, until last patient contact or death. RESULTS: Patients were initially treated with a median of 5 cycles (range 4-7) and were rechallenged after a median of 9 months (range 3-13). Each patient received a median of 4 (range 2-7) rechallenge cycles (median cumulative activity 26.1 GBq). None of the patients experienced life-threatening G4 adverse events during either treatment period. Grade 3 adverse events included one case of anaemia, one case of thrombocytopenia, and one case of renal failure. In 8/18 patients long-term toxicities were evaluated. Serious toxicities (≥ Grade 3) occurred in 3/8 patients (n = 1 G4 thrombocytopenia, n = 1 G4 renal failure and n = 1 pancytopenia and G4 renal failure). Best PSA50%-response was observed in 44% of patients and PSA-disease control was confirmed in 56% of patients at the last cycle. Of the 12/18 patients restaged by imaging, 6/12 (50%) patients had disease control (partial response/stable disease), 1/12 had a mixed response, and 5/12 had progression. After a median follow-up time of 25 months (range 14-44), 10 patients had died, 7 were still alive, and one patient was lost at follow-up. The median OS was 29 months (95%CI, 14.3-43.7 months) for the initial treatment and 11 months (95%CI, 8.1-13.8 months) for the first rechallenge course. CONCLUSION: More than half of patients benefit from rechallenge PRLT. Our analysis suggests that rechallenge may prolong survival in selected patients, with an acceptable safety profile.

The trial tax and the intersection of race/ethnicity, gender, and age in criminal court sentencing.

OBJECTIVE: Prior research consistently demonstrates that defendants convicted at trial are sentenced more harshly than those who plead guilty. Additionally, a vast literature has shown that Black and Hispanic defendants, and especially young minority males, are particularly disadvantaged in sentencing, though these effects may be conditional on various legal and case-processing factors. However, it remains unclear how the mode of conviction might moderate these inequalities according to offenders' combined race/ethnicity, gender, and age. HYPOTHESES: I expected that mode of conviction would moderate the joint effects of race/ethnicity, gender, and age on the imposition of a sentence to prison and on sentence length such that young minority males convicted at trial would receive more severe punishments than members of other subgroups. METHOD: The analyses made use of data on defendants sentenced for noncapital felony crimes in Florida circuit courts over a 12-year period (N = 1,076,500). Hurdle regression models and marginal effects analysis were used. RESULTS: Greater sentencing disparities in absolute as well as relative terms between young minority males and other race/ethnicity, gender, and age subgroups were found among trial cases than among plea cases. Further, Black and Hispanic males were subjected to trial taxes that were substantially larger than those of other subgroups. CONCLUSIONS: These findings suggest that defendants who plead guilty are generally sentenced according to predictable and standardized "going rates" of punishment, whereas the enhanced discretion afforded judges in trial cases as well as racialized "bad facts" about defendants that emerge at trial may drive inequalities in punishment. Thus, extralegal sentencing disparities tied to mode of conviction are an area in which criminal justice reform efforts might be directed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A GoldenBraid cloning system for synthetic biology in social amoebae.

GoldenBraid is a rapid, modular, and robust cloning system used to assemble and combine genetic elements. Dictyostelium amoebae represent an intriguing synthetic biological chassis with tractable applications in development, chemotaxis, bacteria-host interactions, and allorecognition. We present GoldenBraid as a synthetic biological framework for Dictyostelium, including a library of 250 DNA parts and assemblies and a proof-of-concept strain that illustrates cAMP-chemotaxis with four fluorescent reporters coded by one plasmid.

Annual precipitation explains variability in dryland vegetation greenness globally but not locally.

Dryland vegetation productivity is strongly modulated by water availability. As precipitation patterns and variability are altered by climate change, there is a pressing need to better understand vegetation responses to precipitation variability in these ecologically fragile regions. Here we present a global analysis of dryland sensitivity to annual precipitation variations using long-term records of normalized difference vegetation index (NDVI). We show that while precipitation explains 66% of spatial gradients in NDVI across dryland regions, precipitation only accounts for <26% of temporal NDVI variability over most (>75%) dryland regions. We observed this weaker temporal relative to spatial relationship between NDVI and precipitation across all global drylands. We confirmed this result using three alternative water availability metrics that account for water loss to evaporation, and growing season and precipitation timing. This suggests that predicting vegetation responses to future rainfall using space-for-time substitution will strongly overestimate precipitation control on interannual variability in aboveground growth. We explore multiple mechanisms to explain the discrepancy between spatial and temporal responses and find contributions from multiple factors including local-scale vegetation characteristics, climate and soil properties. Earth system models (ESMs) from the latest Coupled Model Intercomparison Project overestimate the observed vegetation sensitivity to precipitation variability up to threefold, particularly during dry years. Given projections of increasing meteorological drought, ESMs are likely to overestimate the impacts of future drought on dryland vegetation with observations suggesting that dryland vegetation is more resistant to annual precipitation variations than ESMs project.

Three-dimensional transfer function of optical microscopes in reflection mode.

Three-dimensional (3D) transfer functions build the basis for a comprehensive characterization of optical imaging systems in the spatial frequency domain. Utilizing the projection-slice theorem, the 2D modulation transfer function of an incoherent imaging system can be derived from a 3D transfer function by integration with respect to the axial spatial frequency. For a diffraction limited microscope with homogeneous incoherent pupil illumination, the modulation transfer function equals the 2D autocorrelation function of a circular disc. However, until now to the best of our knowledge no 3D transfer function has been published, which exactly leads to the 2D modulation transfer function of a diffraction limited microscope in reflection mode. In this article, we derive a formula, which after integration with respect to the axial spatial frequency coordinate perfectly fits to the diffraction limited 2D modulation transfer function. The inverse three-dimensional Fourier transform of the 3D transfer function results in a complex-valued 3D point spread function, from which the depth of field, the lateral resolution and, in addition, the corresponding 3D point spread function of both, a conventional and an interference microscope, can be obtained.

Optical microscopes are probably the most wide-spread optical instruments in science and technology. While in biological applications microscopes are mostly operated in transmission mode, reflection-type microscopes dominate in materials science. A further important field of application of reflection microscopy is the reconstruction of the three-dimensional (3D) surface topography of an object. This kind of 3D microscopy obtains 3D image stacks by axially scanning through the focus. While in a conventional bright-field microscope point scatterers are necessary to enable height discrimination, interference microscopy even works on specularly reflecting surfaces. In both cases, according to optical systems theory the physical behaviour of the microscope is fully represented by a 3D point spread function in the object space or, equivalently, by the corresponding 3D transfer function in the spatial frequency domain. In order to be consistent with microscopic imaging theory, integrating the 3D transfer function along the axial spatial frequency is required to result in the well-known modulation transfer function of a diffraction limited optical imaging system. Since to the best of our knowledge no formula for the calculation of the 3D transfer function of a microscope operated in reflection mode has been published, we derive a mostly analytical formula, which is perfectly consistent with the modulation transfer function of a diffraction limited system. The inverse three-dimensional Fourier transform of the 3D transfer function results in a complex-valued 3D point spread function, from which the depth of field, the lateral resolution and, in addition, the corresponding 3D point spread function of both, a conventional and an interference microscope, can be obtained. Utilizing the rotational symmetry of the 3D transfer function we present a computationally efficient formula for the numerical calculation of the 3D point spread function.

3D modeling of coherence scanning interferometry on 2D surfaces using FEM.

Despite the fact that optical profilers, such as coherence scanning interferometers, are frequently used for fast and contactless topography measurements in various fields of application, measured profiles still suffer from the wave characteristics of light, which leads to systematic deviations that are still not sufficiently investigated. In order to analyze these systematic deviations and their physical relations, we apply a rigorous simulation model considering both the transfer characteristics of the measurement instrument as well as the geometry and material of different measurement objects. Simulation results are compared to measurement results for different polarizations, wavelengths and interferometer types, considering surface structures including edges, slopes and different materials as the main reasons for those deviations. Compared to former publications, a full three-dimensional (3D) modeling of the image formation with regard to two-dimensional (2D) surface structures is provided. The advantages of 3D modeling in contrast to a time efficient 2D approach are discussed. Further, an extract of an atomic force microscope (AFM) measurement result is used as the basis for the FEM simulation in one example in order to achieve most realistic simulation results.

Microsphere-assisted interferometry with high numerical apertures for 3D topography measurements.

Improving the lateral resolution is a key focus of the research on optical measuring systems to expand the fields of application for optical metrology. By means of microspheres put on an object in a microscope, and therefore used as a near-field support, it has already been shown that a superresolution of structures below Abbe's diffraction limit is possible. The following investigations give more detailed theoretical and experimental insight into the physical mechanisms responsible for the transition of near-field information to the far field. In particular, the effects of microspheres as near-field support on the behavior of phase-evaluating interference microscopes close to the optical resolution limit are studied experimentally as well as with numerical simulations. Special attention is drawn to measured data taken with a Linnik microscope of high numerical aperture. Finally, the measurement results of grating structures with a period below Abbe's diffraction limit are presented.

Quadrature-based interferometry using pulsed RGB illumination.

This contribution introduces a novel image recording approach for phase retrieval in a RGB-interferometer setup with pulsed LED illumination and an oscillating reference mirror. The effective acquisition time of the interference images is below 100 µs with a repetition rate of 10 frames per second. The pulsed illumination is synchronized with the exposure gap of a Bayer-Pattern CMOS RGB camera to enable the recording of two π/2 phase shifted images with a short delay compared to the camera exposure time. The proposed quadrature method enables surface phase retrieval with a standard deviation of ≈ [3 nm, · · ·, 5 nm], depending on phase noise and actuator precision. The applicability of the reconstructed phase data to unambiguity range extension algorithms based on the exact fraction method is considered. Experimental results demonstrate the feasibility of the setup to measure the topography of samples in motion or oscillating by mechanical vibrations.

Temporal high-resolution evaluation algorithm for sinusoidally phase modulated interference signals.

In this paper, we present a practical approach for phase analysis of sinusoidally phase shifted interference signals, which are generally used to detect optical path length changes in one arm of the interferometer based on an algorithm introduced by de Groot. We describe the original algorithm from our point of view and try to emphasize the limitations and some details that need to be known for practical implementation. We introduce methods for how to overcome these limitations, and in addition, we provide an extension of the algorithm to a temporal high-resolution mode, which provides a possibility to calculate a phase value for each sampled point of an interference signal and opens new applications for the existing measurement devices without any hardware changes. Simulated and experimental results verify our extensions.

Adaptive high-resolution Linnik interferometry for 3D measurement of microparticles.

Tailored 3D microparticles and nanostructures lead to increasing possibilities in semiconductor industry or biomedical applications. In an interdisciplinary study we investigate the parallel production of such particles by using nanoimprint lithography in combination with their characterization based on interference microscopy. In this Letter we report on a metrological inspection, which tends to a universal measurement solution comparing the sample optically to a master object produced in the same way as the sample.

Coherence scanning and phase imaging optical interference microscopy at the lateral resolution limit.

To get physical insight into the 3D transfer characteristics of interference microscopy at high numerical apertures we study reflecting rectangular grating structures. In general, the height obtained from phase information seems to be reduced, whereas height values resulting from coherence scanning sometimes seem to be systematically overestimated. Increasing the numerical aperture of an interference microscope broadens the spectra of the resulting interference signals, thus offering a broad variety of wavelength contributions to be analyzed. If phase analysis of a measured far-field interference wavefront is performed at very short wavelengths the periodical profiles obtained from coherence scanning and phase shifting analysis differ only by the measured amplitude. However, at longer wavelength there is a 180° phase shift of the measured profiles obtained from phase analysis compared to coherence peak analysis. Increasing the evaluation wavelength improves the lateral resolution since the long wavelength contributions are related to electromagnetic waves of high angles of incidence. This behavior is to the best of our knowledge not documented in literature so far. It was first observed experimentally and could be confirmed by simulation results obtained from either Kirchhoff diffraction theory or an extended Richards-Wolf model developed in our group. Compared to original input profiles used for the simulation the profiles obtained from phase evaluation correspond quite well at longer wavelength, whereas the results obtained from coherence peak analysis are typically inverted with respect to height.

Group refractive index quantification using a Fourier domain short coherence Sagnac interferometer.

The group refractive index is important in length calibration of Fourier domain interferometers by transparent transfer standards. We demonstrate accurate group refractive index quantification using a Fourier domain short coherence Sagnac interferometer. Because of a justified linear length calibration function, the calibration constants cancel out in the evaluation of the group refractive index, which is then obtained accurately from two uncalibrated lengths. Measurements of two standard thickness coverslips revealed group indices of 1.5426±0.0042 and 1.5434±0.0046, with accuracies quoted at the 95% confidence level. This agreed with the dispersion data of the coverslip manufacturer and therefore validates our method. Our method provides a sample specific and accurate group refractive index quantification using the same Fourier domain interferometer that is to be calibrated for the length. This reduces significantly the requirements of the calibration transfer standard.

System spectrum conversion from white light interferogram.

Capability to simulate the coherence function is important when tuning an interference microscope in an effort to reduce sidelobes in interference signals. The coherence function cannot directly be derived from the light source spectrum since the microscope's effective spectrum is affected by e.g. spatial coherence effects. We show this by comparing the true system spectrum measured using a spectrometer against the effective system spectrum obtained by Fourier analysis of the interference data. The results show that a modulation function that describes the scattering-induced spatial coherence dampening in the system is needed to correct the observed difference between these two spectra. The validity of this modulation function is further verified by quantifying the arithmetic mean roughness of two specified roughness standards. By providing a spectral transfer function for scattering, our method can simulate a sample specific coherence function, and thus shows promise to increase the quality of interference microscope images.

Signal modeling in low coherence interference microscopy on example of rectangular grating.

Besides the illumination wavelength also the numerical aperture (NA) of a microscope objective affects the fringe spacing in interference microscopy. Therefore, at high NA values an effective wavelength should be obtained by calibration. At step height structures both, the effective wavelength and the batwing effect strongly depend on the height-to-wavelength-ratio (HWR). Therefore, changes of the effective wavelength considering temporal and spatial coherence enable us to estimate the batwing effect in measurement results. For high NA systems and broadband illumination two different theoretical approaches for signal modeling are introduced to study the influence of the center wavelength, the temporal, and the spatial coherence of the illuminating light on measurement results of a rectangular grating. In both models diffraction is considered. While the first simulation model (Kirchhoff) is mostly analytical the second one (Richards-Wolf) is primarily numerical. Simulation results of both models show a good agreement with experimental measurement results.

Passive vibration compensation in scanning white-light interferometry.

We present a passive vibration compensation approach in scanning white-light interferometry (SWLI). A pointwise distance measuring interferometer (DMI) obtains fast temporal distance changes during the white-light depth-scan of an aerial-measuring Michelson white-light interferometer for topography measurement. Both interferometers share a part of the optical path so that the measurement spot of the DMI is within the field of view of SWLI. With the real positions of the interferometer with respect to the measuring object during the depth scan known from DMI measurements, we can compensate for the influence of unintentional distance changes caused by environmental vibrations or scanner nonlinearities. By reordering of the captured image frames and improved correlogram interpolation, we are able to reconstruct correct signals from completely distorted (and unusable) SWLI signals. Although the basic idea of the system already has been published, we improved the signal reconstruction technique so that the specimen's topography measurement can be obtained with the same accuracy as without any vibrations or scan distortions influence. In addition, we demonstrate the feasibility of the approach by different practical measurements with and without vibrations.

Effects of stomata clustering on leaf gas exchange.

A general theoretical framework for quantifying the stomatal clustering effects on leaf gaseous diffusive conductance was developed and tested. The theory accounts for stomatal spacing and interactions among 'gaseous concentration shells'. The theory was tested using the unique measurements of Dow et al. (2014) that have shown lower leaf diffusive conductance for a genotype of Arabidopsis thaliana with clustered stomata relative to uniformly distributed stomata of similar size and density. The model accounts for gaseous diffusion: through stomatal pores; via concentration shells forming at pore apertures that vary with stomata spacing and are thus altered by clustering; and across the adjacent air boundary layer. Analytical approximations were derived and validated using a numerical model for 3D diffusion equation. Stomata clustering increases the interactions among concentration shells resulting in larger diffusive resistance that may reduce fluxes by 5-15%. A similar reduction in conductance was found for clusters formed by networks of veins. The study resolves ambiguities found in the literature concerning stomata end-corrections and stomatal shape, and provides a new stomata density threshold for diffusive interactions of overlapping vapor shells. The predicted reduction in gaseous exchange due to clustering, suggests that guard cell function is impaired, limiting stomatal aperture opening.

Continuous measurement of optical surfaces using a line-scan interferometer with sinusoidal path length modulation.

We present a fast approach to the continuous measurement of rotational symmetric optical surfaces. This approach is based on a line scanning interferometer with sinusoidal modulation of the optical path length. The specimen is positioned with respect to the sensor and both are moved during measurement by use of a five axes system comprising a high precision rotational table. The calibration of both the line sensor as well as the scanning and positioning system is discussed. As proof of principle of the measurement and stitching concept results of a scan of a rotational symmetric sinusoidal structure and a spherical lens with a moderate slope are shown.

The greenbeard gene tgrB1 regulates altruism and cheating in Dictyostelium discoideum.

Greenbeard genetic elements encode rare perceptible signals, signal recognition ability, and altruism towards others that display the same signal. Putative greenbeards have been described in various organisms but direct evidence for all the properties in one system is scarce. The tgrB1-tgrC1 allorecognition system of Dictyostelium discoideum encodes two polymorphic membrane proteins which protect cells from chimerism-associated perils. During development, TgrC1 functions as a ligand-signal and TgrB1 as its receptor, but evidence for altruism has been indirect. Here, we show that mixing wild-type and activated tgrB1 cells increases wild-type spore production and relegates the mutants to the altruistic stalk, whereas mixing wild-type and tgrB1-null cells increases mutant spore production and wild-type stalk production. The tgrB1-null cells cheat only on partners that carry the same tgrC1-allotype. Therefore, TgrB1 activation confers altruism whereas TgrB1 inactivation causes allotype-specific cheating, supporting the greenbeard concept and providing insight into the relationship between allorecognition, altruism, and exploitation.

Casimir Effect in MEMS: Materials, Geometries, and Metrologies-A Review.

Casimir force densities, i.e., force per area, become very large if two solid material surfaces come closer together to each other than 10 nm. In most cases, the forces are attractive. In some cases, they can be repulsive depending on the solid materials and the fluid medium in between. This review provides an overview of experimental and theoretical studies that have been performed and focuses on four main aspects: (i) the combinations of different materials, (ii) the considered geometries, (iii) the applied experimental measurement methodologies and (iv) a novel self-assembly methodology based on Casimir forces. Briefly reviewed is also the influence of additional parameters such as temperature, conductivity, and surface roughness. The Casimir effect opens many application possibilities in microelectromechanical systems (MEMS) and nanoelectromechanical systems (NEMS), where an overview is also provided. The knowledge generation in this fascinating field requires interdisciplinary approaches to generate synergetic effects between technological fabrication metrology, theoretical simulations, the establishment of adequate models, artificial intelligence, and machine learning. Finally, multiple applications are addressed as a research roadmap.

Adverse childhood experiences, gender, and suicidality among Florida high school students: Examining intervening mechanisms.

BACKGROUND: Adverse childhood experiences (ACEs) represent a key risk factor for suicidal thoughts and behaviors among adolescents. However, the intervening mechanisms linking ACEs and suicidality, and whether such processes vary by gender, remain underexplored. OBJECTIVE: The present study examines whether the relationships between ACEs and the likelihood of experiencing suicidal thoughts and attempting suicide are indirect through depressive symptoms and low self-control. This study also investigates whether these direct and indirect paths might be moderated by gender. PARTICIPANTS AND SETTING: The analyses make use of data on a statewide representative sample of students enrolled in public high schools in Florida (N = 23,078) from the 2022 Florida Youth Substance Abuse Survey (FYSAS). METHODS: Generalized structural equation modeling (GSEM) was used to estimate the direct and indirect effects of ACEs on the likelihood of suicidal thoughts and attempting suicide. The indirect effects were assessed using bootstrapping, and between-gender differences in the coefficients were tested. RESULTS: ACEs has direct associations with depressive symptoms, low self-control, and both suicidality outcomes. The effects of ACEs on suicidal thoughts are indirect through both depressive symptoms and low self-control, and the effects of ACEs on suicide attempts are indirect through depressive symptoms. Limited gender differences in these pathways emerge. CONCLUSIONS: For male and female youth, ACEs are associated with heightened depression symptoms and reduced self-control, and both of these factors partially explain the previously established relationship between ACEs and suicidality.