Associations between brain morphology, inflammatory markers and symptoms of fatigue, depression or anxiety in active and remitted Crohn's disease.

BACKGROUND: Fatigue and psychosocial impairments are highly prevalent in IBD, especially during active disease. Disturbed brain-gut-interactions may contribute to these symptoms. This study examined associations between brain structure, faecal calprotectin and symptoms of fatigue, depression and anxiety in persons with Crohn's Disease (CD) in different disease states. METHODS: In this prospective observational study, n=109 participants (n=67 persons with CD, n=42 healthy controls) underwent cranial magnetic resonance imaging, provided stool samples for analysis of faecal calprotectin and completed questionnaires to assess symptoms of fatigue, depression and anxiety. We analysed differences in grey matter volume (GMV) between patients and controls and associations between regional GMV alterations, neuropsychiatric symptoms and faecal calprotectin. RESULTS: Symptoms of fatigue, depression and anxiety were increased in patients with CD compared to controls, with highest scores in active CD. Patients exhibited regionally reduced GMV in cortical and subcortical sensorimotor regions, occipitotemporal and medial frontal areas. Regional GMV differences showed a significant negative association with fatigue, but not with depression or anxiety. Subgroup analyses revealed symptom-GMV-associations for fatigue in remitted, but not in active CD, while fatigue was positively associated with faecal calprotectin in active, but not remitted disease. CONCLUSION: Our findings support disturbed brain-gut-interactions in CD which may be particularly relevant for fatigue during remitted disease. Reduced GMV in the precentral gyrus and other sensorimotor areas could reflect key contributions to fatigue pathophysiology in CD. A sensorimotor model of fatigue in CD could also pave the way for novel treatment approaches.

Deformation versus Sphericity in the Ground States of the Lightest Gold Isotopes.

The changes in mean-squared charge radii of neutron-deficient gold nuclei have been determined using the in-source, resonance-ionization laser spectroscopy technique, at the ISOLDE facility (CERN). From these new data, nuclear deformations are inferred, revealing a competition between deformed and spherical configurations. The isotopes ^{180,181,182}Au are observed to possess well-deformed ground states and, when moving to lighter masses, a sudden transition to near-spherical shapes is seen in the extremely neutron-deficient nuclides, ^{176,177,179}Au. A case of shape coexistence and shape staggering is identified in ^{178}Au which has a ground and isomeric state with different deformations. These new data reveal a pattern in ground-state deformation unique to the gold isotopes, whereby, when moving from the heavy to light masses, a plateau of well-deformed isotopes exists around the neutron midshell, flanked by near-spherical shapes in the heavier and lighter isotopes-a trend hitherto unseen elsewhere in the nuclear chart. The experimental charge radii are compared to those from Hartree-Fock-Bogoliubov calculations using the D1M Gogny interaction and configuration mixing between states of different deformation. The calculations are constrained by the known spins, parities, and magnetic moments of the ground states in gold nuclei and show a good agreement with the experimental results.

Infrasound detection of approaching lahars.

Infrasound may be used to detect the approach of hazardous volcanic mudflows, known as lahars, tens of minutes before their flow fronts arrive. We have analyzed signals from more than 20 secondary lahars caused by precipitation events at Fuego Volcano during Guatemala's rainy season in May through October of 2022. We are able to quantify the capabilities of infrasound monitoring through comparison with seismic data, time lapse camera imagery, and high-resolution video of a well-recorded event on August 17. We determine that infrasound sensors, deployed adjacent to the lahar path and in small-aperture (10 s of meters) arrays, are particularly sensitive to remote detection of lahars, including small-sized events, at distances of at least 5 km. At Fuego Volcano these detections could be used to provide timely alerts of up to 30 min before lahars arrive at a downstream monitoring site, such as in the frequently impacted Ceniza drainage. We propose that continuous infrasound monitoring, from locations adjacent to a drainage, may complement seismic monitoring and serve as a valuable tool to help identify approaching hazards. On the other hand, infrasound arrays located a kilometer or more from the lahar path can be effectively used to track a lahar's progression.

[Late-life depression and frailty-Epidemiological, clinical and neurobiological associations]. / Depression im Alter und Frailty ­ epidemiologische, klinische und neurobiologische Zusammenhänge.

BACKGROUND: Depression is the most common mental disorder in older adults and is influenced by age-related processes. Frailty is a well-established clinical expression of ageing that implies a state of increased vulnerability to stressor events as well as increased risks of disability, hospitalization and death. Neurobiological findings will disentangle the comorbidity of frailty and depression and may inform future management of depression in old age. OBJECTIVE: This narrative review provides an overview of the comorbidity of late-life depression and frailty, with a focus on neuroscientific findings that are organized within the research domain criteria (RDoC) framework. RESULTS: More than one third of old people with depression are affected by frailty, which results in more chronic depression and in poorer efficacy and tolerability of antidepressant medication. Depression and frailty share motivational and psychomotor characteristics, particularly apathy, decreased physical activity and fatigue. In patients with frailty, altered activity of the supplementary motor cortex is associated with motor performance deficits. Patients with late-life depression and apathy are characterized by abnormal structure and altered functional connectivity of the reward network and the salience network, along with altered functional connectivity of these networks with premotor brain areas. CONCLUSION: Identifying frailty in older adults with depression is relevant for prognostic assessment and treatment. A better understanding of the neuronal mechanisms of comorbidity will provide potential targets for future personalized therapeutic interventions.

Paratonia, Gegenhalten and psychomotor hypertonia Back to the roots.

In the first half of the 20th century, well before the antipsychotic era, paratonia, Gegenhalten and psychomotor hypertonia were described as new forms of hypertonia intrinsic to particular psychoses and catatonic disorders. A series of astute clinical observations and experiments supported their independence from rigidity seen in Parkinson's disease. After World War II, motor disorders went out of fashion in psychiatry, with drug-induced parkinsonism becoming the prevailing explanation for all involuntary resistance to passive motion. With the 'forgetting' of paratonia and Gegenhalten, parkinsonism became the prevailing reading grid, such that the rediscovery of hypertonia in antipsychotic-naive patients at the turn of the 21st century is currently referred to as "spontaneous parkinsonism", implicitly suggesting intrinsic and drug-induced forms to be the same. Classical descriptive psychopathology gives a more nuanced view in suggesting two non-parkinsonian hypertonias: (i) locomotor hypertonia corresponds to Ernest Dupré's paratonia and Karl Kleist's reactive Gegenhalten; it is a dys-relaxation phenomenon that often needs to be activated. (ii) Psychomotor hypertonia is experienced as an admixture of assistance and resistance that partially overlaps with Kleist's spontaneous Gegenhalten, but was convincingly isolated by Henri Claude and Henri Baruk thanks to electromyogram recordings; psychomotor hypertonia is underpinned by "anticipatory contractions" of cortical origin, occurrence of which in phase or antiphase with the movement accounted for facilitation or opposition to passive motions. This century-old knowledge is not only of historical interest. Some results have recently been replicated in dementia and as now known to involve specific premotor systems.

Adequate funding of comprehensive community-based programs for key populations needed now more than ever to reach and sustain HIV targets.

INTRODUCTION: Globally, over half of the estimated new HIV infections now occur among key populations, including men who have sex with men, sex workers, people who inject drugs, transgender individuals, and people in prisons and other closed settings, and their sexual partners. Reaching epidemic control will, for many countries, increasingly require intensified programming and targeted resource allocation to meet the needs of key populations and their sexual partners. However, insufficient funding, both in terms of overall amounts and the way the funding is spent, contributes to the systematic marginalization of key populations from needed HIV services. DISCUSSION: The Joint United Nations Programme on HIV/AIDS (UNAIDS) has recently highlighted the urgent need to take action to end inequalities, including those faced by key populations, which have only been exacerbated by the COVID-19 pandemic. To address these inequalities and improve health outcomes, key population programs must expand the use of a trusted access platform, scale up differentiated service delivery models tailored to the needs of key populations, rollout structural interventions and ensure service integration. These critical program elements are often considered "extras," not necessities, and consequently costing studies of key population programs systematically underestimate the total and unitary costs of services for key populations. Findings from a recent costing study from the LINKAGES project suggest that adequate funding for these four program elements can yield benefits in program performance. Despite this and other evidence, the lack of data on the true costs of these elements and the costs of failing to provide them prevents sufficient investment in these critical elements. CONCLUSIONS: As nations strive to reach the 2030 UNAIDS goals, donors, governments and implementers should reconsider the true, but often hidden costs in future healthcare dollars and in lives if they fail to invest in the community-based and community-driven key population programs that address structural inequities. Supporting these efforts contributes to closing the remaining gaps in the 95-95-95 goals. The financial and opportunity cost of perpetuating inequities and missing those who must be reached in the last mile of HIV epidemic control must be considered.

ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors.

In the past year, four antibody-drug conjugates (ADC) were approved, nearly doubling the marketed ADCs in oncology. Among other attributes, successful ADCs optimize targeting antibody, conjugation chemistry, and payload mechanism of action. Here, we describe the development of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC for the treatment of small cell lung cancer (SCLC). We engineered a calicheamicin conjugate that lacks the acid-labile hydrazine linker that leads to systemic release of a toxic catabolite. We then screened a patient-derived xenograft library to identify SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs. Using RNA sequencing (RNA-seq) data from primary and xenograft SCLC samples, we identified seizure-related homolog 6 (SEZ6) as a surface-expressed SCLC target with broad expression in SCLC and minimal normal tissue expression by both RNA-seq and IHC. We developed an antibody targeting SEZ6 that is rapidly internalized upon receptor binding and, when conjugated to the calicheamicin linker drug, drives potent tumor regression in vitro and in vivo. These preclinical data suggest that ABBV-011 may provide a novel treatment for patients with SCLC and a rationale for ongoing phase I studies (NCT03639194).

A versatile setup for studying size and charge-state selected polyanionic nanoparticles.

Using the example of metal clusters, an experimental setup and procedure is presented, which allows for the generation of size and charge-state selected polyanions from monoanions in a molecular beam. As a characteristic feature of this modular setup, the further charging process via sequential electron attachment within a three-state digital trap takes place after mass-selection. In contrast to other approaches, the rf-based concept permits access to heavy particles. The procedure is highly flexible with respect to the preparation process and potentially suitable for a wide variety of anionic species. By adjusting the storage conditions, i.e., the radio frequency, to the change in the mass-to-charge ratio, we succeeded in producing clusters in highly negative charge states, i.e., Ag800 7-. The capabilities of the setup are demonstrated by experiments extracting electronic and optical properties of polyanionic metal clusters by analyzing the corresponding photoelectron spectra.

Sources for constellation errors in modulated dispersion interferometers.

Dispersion interferometry (DI) is being employed on an increasing number of fusion experiments to measure the plasma density with a minimal sensitivity to vibrations. DIs employed in high-density experiments use phase modulation techniques up to several hundred kilohertz to enable quadrature detection and to be unaffected by variations of the signal amplitude. However, the evaluation of the temporal interferogram can be a significant source for phase errors and does not have an established processing method. There are two non-approximation-based methods currently in use: one using the ratio of amplitudes in the signal's Fourier spectrum and the other using its sectioned integration. Previously, the methods could not be used simultaneously since they differ in their respective calibration point. In this paper, we present a technique to use both phase evaluation methods simultaneously using quadrature correction methods. A comparison of their strengths and weaknesses is presented based on identical measurements indicating one to be more reliable in a more static measurement scenario, while the other excels in highly dynamic ones. Several comparative experiments are presented, which identify a significant error source in the phase measurement induced by polarization rotation. Since the same effect may be induced by Faraday rotation, the results may have direct consequence on the design of the ITER dispersion interferometer/polarimeter as well as the European DEMO's interferometer concept.

The polysemous concepts of psychomotricity and catatonia: A European multi-consensus perspective.

Current classification systems use the terms "catatonia" and "psychomotor phenomena" as mere a-theoretical descriptors, forgetting about their theoretical embedment. This was the source of misunderstandings among clinicians and researchers of the European collaboration on movement and sensorimotor/psychomotor functioning in schizophrenia and other psychoses or ECSP. Here, we review the different perspectives, their historical roots and highlight discrepancies. In 1844, Wilhelm Griesinger coined the term "psychic-motor" to name the physiological process accounting for volition. While deriving from this idea, the term "psychomotor" actually refers to systems that receive miscellaneous intrapsychic inputs, convert them into coherent behavioral outputs send to the motor systems. More recently, the sensorimotor approach has drawn on neuroscience to redefine the motor signs and symptoms observed in psychoses. In 1874, Karl Kahlbaum conceived catatonia as a brain disease emphasizing its somatic - particularly motor - features. In conceptualizing dementia praecox Emil Kraepelin rephrased catatonic phenomena in purely mental terms, putting aside motor signs which could not be explained in this way. Conversely, the Wernicke-Kleist-Leonhard school pursued Kahlbaum's neuropsychiatric approach and described many new psychomotor signs, e.g. parakinesias, Gegenhalten. They distinguished 8 psychomotor phenotypes of which only 7 are catatonias. These barely overlap with consensus classifications, raising the risk of misunderstanding. Although coming from different traditions, the authors agreed that their differences could be a source of mutual enrichment, but that an important effort of conceptual clarification remained to be made. This narrative review is a first step in this direction.

Cancer stem cells: advances in biology and clinical translation-a Keystone Symposia report.

The test for the cancer stem cell (CSC) hypothesis is to find a target expressed on all, and only CSCs in a patient tumor, then eliminate all cells with that target that eliminates the cancer. That test has not yet been achieved, but CSC diagnostics and targets found on CSCs and some other cells have resulted in a few clinically relevant therapies. However, it has become apparent that eliminating the subset of tumor cells characterized by self-renewal properties is essential for long-term tumor control. CSCs are able to regenerate and initiate tumor growth, recapitulating the heterogeneity present in the tumor before treatment. As great progress has been made in identifying and elucidating the biology of CSCs as well as their interactions with the tumor microenvironment, the time seems ripe for novel therapeutic strategies that target CSCs to find clinical applicability. On May 19-21, 2021, researchers in cancer stem cells met virtually for the Keystone eSymposium "Cancer Stem Cells: Advances in Biology and Clinical Translation" to discuss recent advances in the understanding of CSCs as well as clinical efforts to target these populations.

Impact of Magnetic Field Configuration on Heat Transport in Stellarators and Heliotrons.

We assess the magnetic field configuration in modern fusion devices by comparing experiments with the same heating power, between a stellarator and a heliotron. The key role of turbulence is evident in the optimized stellarator, while neoclassical processes largely determine the transport in the heliotron device. Gyrokinetic simulations elucidate the underlying mechanisms promoting stronger ion scale turbulence in the stellarator. Similar plasma performances in these experiments suggests that neoclassical and turbulent transport should both be optimized in next step reactor designs.

Predicting sensitivity of repeated environmental sampling for Mycobacterium avium subsp. paratuberculosis in dairy herds using a Bayesian latent class model.

Between-herd transmission of Mycobacterium avium subsp. paratuberculosis (MAP) by subclinically infected cattle is an important risk which can hamper effective control of paratuberculosis. Knowledge of herd status would substantially reduce this risk; MAP positive farms can be detected with environmental sampling. The objective of this study was to compare cumulative sensitivities of annual environmental sampling with two or four samples per sampling event without knowledge of true herd status and to calculate the number of sampling events to achieve a cumulative sensitivity of at least 0.9. Data from three repeated sampling events in two study populations, one with 55 herds (two samples/event) and another with 30 herds (four samples/event) including test results, herd and sample characteristics and prior prevalence estimates, were derived from the Alberta Johne's Disease Initiative (Alberta, Canada). A recursive Bayesian latent class model was used to predict the cumulative sensitivity of repeated environmental sampling events. A sampling scheme with four samples per sampling event had a higher cumulative sensitivity than an alternative scheme with two samples. To achieve a cumulative sensitivity of at least 0.9 with 95% probability, eight sampling events with two environmental samples per set, or four sampling events with four samples per set were required. Further model assessment demonstrated that these results can only be generalized to cattle populations with a similar within-herd prevalence to those studied here (approximately 0.08). Nonetheless, these results could help predict herd-level prevalence in cattle populations after environmental testing and provide information regarding the uncertainty behind status estimates for herds repeatedly tested using environmental samples.

Demonstration of reduced neoclassical energy transport in Wendelstein 7-X.

Research on magnetic confinement of high-temperature plasmas has the ultimate goal of harnessing nuclear fusion for the production of electricity. Although the tokamak1 is the leading toroidal magnetic-confinement concept, it is not without shortcomings and the fusion community has therefore also pursued alternative concepts such as the stellarator. Unlike axisymmetric tokamaks, stellarators possess a three-dimensional (3D) magnetic field geometry. The availability of this additional dimension opens up an extensive configuration space for computational optimization of both the field geometry itself and the current-carrying coils that produce it. Such an optimization was undertaken in designing Wendelstein 7-X (W7-X)2, a large helical-axis advanced stellarator (HELIAS), which began operation in 2015 at Greifswald, Germany. A major drawback of 3D magnetic field geometry, however, is that it introduces a strong temperature dependence into the stellarator's non-turbulent 'neoclassical' energy transport. Indeed, such energy losses will become prohibitive in high-temperature reactor plasmas unless a strong reduction of the geometrical factor associated with this transport can be achieved; such a reduction was therefore a principal goal of the design of W7-X. In spite of the modest heating power currently available, W7-X has already been able to achieve high-temperature plasma conditions during its 2017 and 2018 experimental campaigns, producing record values of the fusion triple product for such stellarator plasmas3,4. The triple product of plasma density, ion temperature and energy confinement time is used in fusion research as a figure of merit, as it must attain a certain threshold value before net-energy-producing operation of a reactor becomes possible1,5. Here we demonstrate that such record values provide evidence for reduced neoclassical energy transport in W7-X, as the plasma profiles that produced these results could not have been obtained in stellarators lacking a comparably high level of neoclassical optimization.

Neural network surrogates of Bayesian diagnostic models for fast inference of plasma parameters.

We present a framework for training artificial neural networks (ANNs) as surrogate Bayesian models for the inference of plasma parameters from diagnostic data collected at nuclear fusion experiments, with the purpose of providing a fast approximation of conventional Bayesian inference. Because of the complexity of the models involved, conventional Bayesian inference can require tens of minutes for analyzing one single measurement, while hundreds of thousands can be collected during a single plasma discharge. The ANN surrogates can reduce the analysis time down to tens/hundreds of microseconds per single measurement. The core idea is to generate the training data by sampling them from the joint probability distribution of the parameters and observations of the original Bayesian model. The network can be trained to learn the reconstruction of plasma parameters from observations and the model joint probability distribution from plasma parameters and observations. Previous work has validated the application of such a framework to the former case at the Wendelstein 7-X and Joint European Torus experiments. Here, we first give a description of the general methodological principles allowing us to generate the training data, and then we show an example application of the reconstruction of the joint probability distribution of an effective ion charge Zeff-bremsstrahlung model from data collected at the latest W7-X experimental campaign. One key feature of such an approach is that the network is trained exclusively on data generated with the Bayesian model, requiring no experimental data. This allows us to replicate the training scheme and generate fast, surrogate ANNs for any validated Bayesian diagnostic model.

Laser Spectroscopy of Neutron-Rich

The mean-square charge radii of ^{207,208}Hg (Z=80, N=127, 128) have been studied for the first time and those of ^{202,203,206}Hg (N=122, 123, 126) remeasured by the application of in-source resonance-ionization laser spectroscopy at ISOLDE (CERN). The characteristic kink in the charge radii at the N=126 neutron shell closure has been revealed, providing the first information on its behavior below the Z=82 proton shell closure. A theoretical analysis has been performed within relativistic Hartree-Bogoliubov and nonrelativistic Hartree-Fock-Bogoliubov approaches, considering both the new mercury results and existing lead data. Contrary to previous interpretations, it is demonstrated that both the kink at N=126 and the odd-even staggering (OES) in its vicinity can be described predominately at the mean-field level and that pairing does not need to play a crucial role in their origin. A new OES mechanism is suggested, related to the staggering in the occupation of the different neutron orbitals in odd- and even-A nuclei, facilitated by particle-vibration coupling for odd-A nuclei.