Non-pharmacological interventions for improving language and communication in people with primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) accounts for approximately 43% of frontotemporal dementias and is mainly characterised by a progressive impairment of speech and communication abilities. Three clinical variants have been identified: (a) non-fluent/agrammatic, (b) semantic, and (c) logopenic/phonological PPA variants. There is currently no curative treatment for PPA, and the disease progresses inexorably over time, with devastating effects on speech and communication ability, functional status, and quality of life. Several non-pharmacological interventions that may improve symptoms (e.g. different forms of language training and non-invasive brain stimulation) have been investigated in people with PPA. OBJECTIVES: To assess the effects of non-pharmacological interventions for people with PPA on word retrieval (our primary outcome), global language functions, cognition, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's trial register, MEDLINE (Ovid SP), Embase (Ovid SP), four other databases and two other trial registers. The latest searches were run on 26 January 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of non-pharmacological interventions in people with PPA. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: There were insufficient data available to conduct the network meta-analyses that we had originally planned (due to trial data being insufficiently reported or not reported at all, as well as the heterogeneous content of the included interventions). Therefore, we provide a descriptive summary of the included studies and results. We included 10 studies, with a total of 132 participants, evaluating non-pharmacological interventions. These were: transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) as stand-alone treatments (used by two and one studies, respectively); tDCS combined with semantic and phonological word-retrieval training (five studies); tDCS combined with semantic word-retrieval training (one study); and tDCS combined with phonological word-retrieval training (one study). Results for our primary outcome of word retrieval were mixed. For the two studies that investigated the effects of tDCS as stand-alone treatment compared to placebo ("sham") tDCS, we rated the results as having very low-certainty evidence. One study found a significant beneficial effect on word retrieval after active tDCS; one study did not report any significant effects in favour of the active tDCS group. Five studies investigated tDCS administered to the dorsolateral prefrontal cortex, inferior frontal cortex, left frontotemporal region, or the temporoparietal cortex, combined with semantic and phonological word-retrieval training. The most consistent finding was enhancement of word-retrieval ability for trained items immediately after the intervention, when behavioural training was combined with active tDCS compared to behavioural training plus sham tDCS. We found mixed effects for untrained items and maintenance of treatment effects during follow-up assessments. We rated the certainty of the evidence as very low in all studies. One study investigated tDCS combined with semantic word-retrieval training. Training was provided across 15 sessions with a frequency of three to five sessions per week, depending on the personal preferences of the participants. tDCS targeted the left frontotemporal region. The study included three participants: two received 1 mA stimulation and one received 2 mA stimulation. The study showed mixed results. We rated it as very low-certainty evidence. One study investigated tDCS combined with phonological word-retrieval training. Training was again provided across 15 sessions over a period of three weeks. tDCS targeted the left inferior frontal gyrus. This study showed a significantly more pronounced improvement for trained and untrained words in favour of the group that had received active tDCS, but we rated the certainty of the evidence as very low. One study compared active rTMS applied to an individually determined target site to active rTMS applied to a control site (vertex) for effects on participants' word retrieval. This study demonstrated better word retrieval for active rTMS administered to individually determined target brain regions than in the control intervention, but we rated the results as having a very low certainty of evidence. Four studies assessed overall language ability, three studies assessed cognition, five studies assessed potential adverse effects of brain stimulation, and one study investigated quality of life. AUTHORS' CONCLUSIONS: There is currently no high-certainty evidence to inform clinical decision-making regarding non-pharmacological treatment selection for people with PPA. Preliminary evidence suggests that the combination of active tDCS with specific language therapy may improve impaired word retrieval for specifically trained items beyond the effects of behavioural treatment alone. However, more research is needed, including high-quality RCTs with detailed descriptions of participants and methods, and consideration of outcomes such as quality of life, depressive symptoms, and overall cognitive functioning. Moreover, studies assessing optimal treatments (i.e. behavioural interventions, brain stimulation interventions, and their combinations) for individual patients and PPA subtypes are needed. We were not able to conduct the planned (network) meta-analyses due to missing data that could not be obtained from most of the authors, a general lack of RCTs in the field, and heterogeneous interventions in eligible trials. Journals should implement a mandatory data-sharing requirement to assure transparency and accessibility of data from clinical trials.

Single shot three-dimensional imaging using an engineered point spread function.

A system approach to acquire a three-dimensional object distribution is presented using a compact and cost efficient camera system with an engineered point spread function. The corresponding monocular setup incorporates a phase-only computer-generated hologram in combination with a conventional imaging objective in order to optically encode the axial information within a single two-dimensional image. The object's depth map is calculated using a novel approach based on the power cepstrum of the image. The in-plane RGB image information is restored with an extended depth of focus by applying an adapted Wiener filter. The presented approach is tested experimentally by estimating the three-dimensional distribution of an extended passively illuminated scene.

Fabrication of microoptical freeform arrays on wafer level for imaging applications.

Miniaturized imaging systems combining an ultra-compact form factor in combination with the ability of refocusing and depth imaging have gained much interest in the field of mobile imaging. Therefore, artificial compound eye cameras are an extremely promising approach for the realization of compact monolithic camera modules on wafer level. Up to now, their imaging performance was limited to low resolution in the range of VGA format according to fabrication constrains given by the established microoptical fabrication methods, namely the reflow of photoresist. In order to overcome these classical limitations, the use of refractive freeform arrays (RFFA) instead of conventional microlens arrays is inevitable. To enable high volume and cost efficient mass production of artificial compound eye cameras for mass markets like the consumer electronics industry, their fabrication on wafer level is essential, but has not been published up to now. We present a wafer level based process chain enabling the fabrication of these elements for the first time.

The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy.

BACKGROUND: Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant. METHODS AND RESULTS: This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and (99m)Tc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by (99m)Tc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade (n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0-108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%. CONCLUSIONS: This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long-term survival rates.

Laser lithographic approach to micro-optical freeform elements with extremely large sag heights.

Artificial compound eye cameras are an attractive approach to generate imaging systems of maximum miniaturization. Their thickness can be reduced by a factor of two in comparison to miniaturized single aperture cameras with the same pixel size and resolution. The imaging performance of these systems can be improved significantly by the use of micro-optical refractive freeform arrays (RFFA). Due to the complexity of these non-symmetric surface profiles with sag heights larger than 50 µm in combination with extreme profile accuracies better than λ/14 (rms), there is no dedicated fabrication technology currently available. In the presented research, significant improvements in the fabrication of these elements with laser lithography were reached. Therefore, a laser lithographic process based on several coating steps in combination with a multiple exposure strategy was developed that is suitable for the fabrication of arbitrary freeform structures with sag heights up to 60 µm. In order to minimize surface deviations caused by unavoidable process nonlinearities, a compensation strategy based on an empirical process model is used. The achievable accuracy of the proposed method and its limitations were investigated by fabricating a spherical micro lens array for demonstration. The fabricated elements possess a shape deviation of less than 1.3 µm (rms) and can be used as master structures for a subsequent replication process in order to realize a cost efficient mass production of artificial compound eye optics on wafer level.

Ultraslim fixed pattern projectors with inherent homogenization of illumination.

For a given illumination source brightness, the transmitted flux of common single-aperture projection optics scales with all three system dimensions, thus preventing the realization of slim devices along with a high lumen output. In this article we introduce a multichannel approach, called "array projector," which breaks this constraint, thus enabling the realization of ultraslim but high flux systems with inherent homogenization for still image content. The concept is based on regular two-dimensional arrangements of absorbing object structures and projective microlenses superposing their individual images on the screen. After deriving first-order scaling laws for the multichannel projector in contrast to common single-aperture optics, specification of system parameters is shown considering aberrations of a single-channel and collective effects of the array. The technological realization of a sample system is shown and characterized in terms of modulation transfer, homogeneity, depth of focus and flux.

Optical Cluster Eye fabricated on wafer-level.

Wafer-level optics is considered as a cost-effective approach to miniaturized cameras, because fabrication and assembly are carried out for thousands of lenses in parallel. However, in most cases the micro-optical fabrication process is not mature enough to reach the required accuracy of the optical elements, which may have complex profiles and sags in the mm-scale. Contrary, the creation of microlens arrays is well controllable so that we propose a multi aperture system called "Optical Cluster Eye" which is based on conventional micro-optical fabrication techniques. The proposed multi aperture camera consists of many optical channels each transmitting a segment of the whole field of view. The design of the system provides the stitching of the partial images, so that a seamless image is formed and a commercially available image sensor can be used. The system can be fabricated on wafer-level with high yield due to small aperture diameters and low sags. The realized optics has a lateral size of 2.2 × 2.9 mm2, a total track length of 1.86 mm, and captures images at VGA video resolution.

Vocal cord paralysis and rapid progressive motor neuron disease by the I113F mutation in SOD1 gene.

Familial cases of amyotrophic lateral sclerosis are most frequently caused by mutation in the superoxide dismutase-1 (SOD1) gene. We report a heterozygous I113F mutation in a patient with familial ALS characterized by early and predominant bilateral vocal cord paralysis followed by descending spinal cord paresis. Modelling of the mutant SOD1 showed an alteration of the protein secondary structure leading to impaired strength of the dimer interface. This may result in a failure of the protein folding and subsequently generation of toxic intracellular aggregates, suggesting a pathogenic role for the mutation.

Endogenous vasoactive peptides and the human vagina--a molecular biology and functional study.

INTRODUCTION: Endogenous peptides, such as vasoactive intestinal polypeptide (VIP), C-type natriuretic peptide (CNP), and bradykinin (BK), have been proposed to play a role in the female sexual arousal response by exerting relaxation of clitoral, labial, and vaginal smooth muscle. While the effects of endogenous peptides on the human male erectile tissue have already been described, only very few studies have been conducted to investigate the peptidergic control of female genital tissues, including the vagina. AIMS: To elucidate the expression of mRNA specifically encoding for peptide receptors in the human vagina and the effects of VIP, CNP, and BK on the tension induced by endothelin-1 (ET-1) of isolated human vaginal wall smooth muscle. The production of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in response to exposure of the tissue to the peptides was also measured. METHODS: The expression of mRNA encoding for receptor proteins specific for VIP, CNP, and BK were investigated by means of molecular biology (reverse transcriptase polymerase chain reaction [RT-PCR] analysis). Using the organ bath technique, the effects of VIP, CNP, and BK (0.1 nM to 1 µM) on the tension induced by 0.1 µM ET-1 of human vaginal strips were investigated. The tissue was also exposed to three different concentrations of VIP, CNP, and BK (0.01 µM, 0.1 µM, 1 µM) and the production of cAMP and cGMP determined by means of radioimmunoassays. MAIN OUTCOME MEASURES: Characterize the expression of peptide receptors in the human vagina and measure the relaxation exerted by BK, CNP, and VIP on the contraction induced by ET-1 of isolated human vaginal tissue. In addition, the effects of the peptides on the production of cAMP and cGMP were also elucidated. RESULTS: RT-PCR analysis revealed the expression of mRNA transcripts encoding for the VIP receptors VIP1R/vasoactive intestinal polypeptide receptor type 1 (VPAC1) and VIP2R/VPAC2, CNP receptors natriuretic peptide receptor type A (NPRA), natriuretic peptide receptor type B (NPRB) and natriuretic peptide receptor type C (NPRC), and BK receptor B2R. The tension induced by ET-1 was reversed by the peptides with the following rank order of efficacy: BK (21.7%) > VIP (20.9%) > CNP (13.3%). The relaxing effects of VIP and BK were paralleled by a 4.8-fold and fivefold increase in cAMP, while the production of cGMP was stimulated 38-fold and 119-fold in the presence of CNP or BK, respectively. CONCLUSION: Our results are in support of the hypothesis that endogenous peptides may contribute to the control of human vaginal smooth muscle tone through the involvement of the cyclic nucleotide-dependent pathways.

Thin wafer-level camera lenses inspired by insect compound eyes.

We propose a microoptical approach to ultra-compact optics for real-time vision systems that are inspired by the compound eyes of insects. The demonstrated module achieves approx. VGA resolution with a total track length of 1.4 mm which is about two times shorter than comparable single-aperture optics on images sensors of the same pixel pitch. The partial images that are separately recorded in different optical channels are stitched together to form a final image of the whole field of view by means of image processing. A software correction is applied to each partial image so that the final image is made free of distortion. The microlens arrays are realized by state of the art microoptical fabrication techniques on wafer-level which are suitable for a potential application in high volume e.g. for consumer electronic products.

The Gabor superlens as an alternative wafer-level camera approach inspired by superposition compound eyes of nocturnal insects.

We present the microoptical adaption of the natural superposition compound eye, which is termed "Gabor superlens". Enabled by state-of-the-art microoptics technology, this well known principle has been adapted for ultra-compact imaging systems for the first time. By numerical ray tracing optimization, and by adding diaphragm layers and a field lens array, the optical performance of the Gabor superlens is potentially comparable to miniaturized conventional lens modules, such as currently integrated in mobile phones. However, in contrast to those, the Gabor superlens is fabricated using a standard microlens array technology with low sag heights and small diameter microlenses. Hence, there is no need for complex diamond turning for the generation of the master structures. This results in a simple and well controllable lens manufacturing process with the potential to high yield.

Dispersion-model-free determination of optical constants: application to materials for organic thin film devices.

We describe a method to determine the refractive index and extinction coefficient of thin film materials without prior knowledge of the film thickness and without the assumption of a dispersion model. A straightforward back calculation to the optical parameters can be performed starting from simple measurements of reflection and transmission spectra of a 100-250 nm thick supported film. The exact film thickness is found simultaneously by fulfilling the intrinsic demand of continuity of the refractive index as a function of wavelength. If both the layer and the substrate are homogeneous and isotropic media with plane and parallel interfaces, effects like surface roughness, scattering, or thickness inhomogeneities can be neglected. Then, the accuracy of the measurement is approximately 10(-2) and 10(-3) for the refractive index and the extinction coefficient, respectively. The error of the thin film thickness determination is well below 1 nm. Thus this technique is well suited to determine the input parameters for optical simulations of organic thin film devices, such as organic light-emitting diodes (OLEDs) or organic photovoltaic (OPV) cells. We apply the method to the electroluminescent polymer poly(2,5-dioctyl-p-phenylene vinylene) (PDO-PPV) and show its applicability by comparing the measured and calculated reflection and transmission spectra of OLED stacks with up to five layers.

Artificial compound eye zoom camera.

We demonstrate a highly compact image capturing system with variable field of view but without any mechanically moving parts. The camera combines an ultra-thin artificial apposition compound eye with one variable focal length liquid lens. The change of optical power of the liquid lens when applying a voltage results in a change of the magnification of the microlens array imaging system. However, its effect on focusing of the individual microlenses can be neglected due to their small focal length.

Analytic modeling of the angular sensitivity function and modulation transfer function of ultrathin multichannel imaging systems.

We propose what we believe to be a novel, refined model of the angular sensitivity function of artificial apposition compound eyes. Compared with the formerly used Gaussian approximation that was derived for natural compound eyes, our model is better suited to describe the resolution capacity of artificial compound eyes accounting for the cylindrical sensitivity function of technical receptors. It is shown that this analytic model is valid over a broad range of parameters of the optical system, which was not fulfilled by one of the previous models. Finally, an analytic approach is used to derive the modulation transfer function of these multichannel imaging systems.

Beam homogenizers based on chirped microlens arrays.

Lens array arrangements are commonly used for the homogenization of highly coherent laser beams. These fly's eye condenser configurations can be used to shape almost arbitrary input intensity distributions into a top hat. Due to the periodic structure of regular arrays the output intensity distribution is modulated by equidistant sharp intensity peaks which are disturbing the homogeneity. As a new approach we apply chirped microlens arrays to the beam shaping system. These are non-regular arrays consisting of individually shaped lenses defined by a parametric description which can be derived completely from analytical functions. The advantages of the new concept and design rules are presented.

Artificial neural superposition eye.

We propose an ultra-thin imaging system which is based on the neural superposition compound eye of insects. Multiple light sensitive pixels in the footprint of each lenslet of this multi-channel configuration enable the parallel imaging of the individual object points. Together with the digital superposition of related signals this multiple sampling enables advanced functionalities for artificial compound eyes. Using this technique, color imaging and a circumvention for the trade-off between resolution and sensitivity of ultra-compact camera devices have been demonstrated in this article. The optical design and layout of such a system is discussed in detail. Experimental results are shown which indicate the attractiveness of microoptical artificial compound eyes for applications in the field of machine vision, surveillance or automotive imaging.

Micro-optically assisted high-index waveguide coupling.

Adapting the concept of solid immersion lenses, we numerically study a micro-optical scheme for conventional high-index and photonic-crystal waveguide coupling by using a combination of different numerical methods such as ray tracing, angular-spectrum propagation, finite-difference time-domain simulations, and finite-element-method simulations. The numerical findings are discussed by means of impedance, group- or energy-velocity, spot-size, and phase-matching criteria. When fabrication constraints for high-index immersion lenses made of silicon are taken into account, a coupling efficiency of -80% can be reached for monomode silicon-on-insulator waveguides with a quadratic cross section of the core and rectangular cross sections of moderate aspect ratio. Similar coupling efficiencies of -80% can be obtained for silicon-on-insulator photonic-crystal waveguides. Tolerances that are due to misalignments and variations of the substrate thickness of the silicon lens are discussed.

Visual observation of Zener tunneling.

We experimentally investigate photonic Zener tunneling between the bands of a waveguide array by directly monitoring the propagating light inside this structure. For strong transverse index gradients we observe Zener breakdown as regular outbursts of radiation escaping from the Bloch oscillations. Tunneling to higher order photonic bands and Bloch oscillations in different bands have been detected.

Artificial compound eye applying hyperacuity.

Inspired by the natural phenomenon of hyperacuity, redundant sampling in combination with the knowledge about the impulse response of the imaging system is used to extract highly accurate information using a low resolving artificial apposition compound eye. Thus the implementation of a precise position detection for simple objects like point sources and edges is described.

Thin compound-eye camera.

An artificial compound-eye objective fabricated by micro-optics technology is adapted and attached to a CMOS sensor array. The novel optical sensor system with an optics thickness of only 0.2 mm is examined with respect to resolution and sensitivity. An optical resolution of 60 x 60 pixels is determined from captured images. The scaling behavior of artificial compound-eye imaging systems is analyzed. Cross talk between channels fabricated by different technologies is evaluated, and the influence on an extension of the field of view by addition of a (Fresnel) diverging lens is discussed. The lithographic generation of opaque walls between channels for optical isolation is experimentally demonstrated.