The hierarchy of coupled sleep oscillations reverses with aging in humans.

A well-orchestrated coupling hierarchy of slow waves and spindles during slow wave sleep supports memory consolidation. In old age, duration of slow wave sleep and number of coupling events decreases. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N=340, 237 female, 103 male) spanning most of the human lifespan (ages 15-83). We find that, instead of changing abruptly, spindles gradually shift from being driven by-, to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow wave frequency, and starts around midlife (∼age 40-48), with an established reversed hierarchy at age 56-83. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using phase slope index (PSI) and number of coupling events, is associated with blood plasma glial fibrillary acidic protein (GFAP) levels, a marker for astrocyte activation. Data-driven models suggest decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a back-shift of the coupling hierarchy (PSI) towards a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.Significance StatementEvidence accumulates that sleep disturbances and cognitive decline are bi-directionally and causally linked forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human lifespan and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human lifespan

When increasing vegetable production may worsen food availability gaps: A simulation model in India

Translating agricultural productivity into food availability depends on food supply chains. Agricultural policy and research efforts promote increased horticultural crop production and yields, but the ability of low-resource food supply chains to handle increased volumes of perishable crops is not well understood. This study developed and used a discrete event simulation model to assess the impact of increased production of potato, onion, tomato, brinjal (eggplant), and cabbage on vegetable supply chains in Odisha, India. Odisha serves as an exemplar of vegetable supply chain challenges in many low-resource settings

HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation

The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based nextgeneration sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5 mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLAmatched subgroup. The worse outcome was mainly driven by a significantly higher nonrelapse mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future

The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided

Machine learning based prediction of COVID-19 mortality suggests repositioning of anticancer drug for treating severe cases

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center ‘Lean European Open Survey on SARS-CoV-2-infected patients’ (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19

The European Insomnia Guideline : An update on the diagnosis and treatment of insomnia 2023

Publisher Copyright: © 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).Peer reviewe

Detection of explosive threats by using embedded wireless sensor based networks

This thesis focuses on the development of novel schemes for the detection of unintended electromagnetic emissions (UEE) from passive radio frequency (RF) receivers and chemical and biological (CB) agents for the purpose of locating explosive threats (ET) to improve survivability for equipment and personnel in the surrounding environment. The methods and architectures used in this work were developed for use with wireless sensor networks (WSNs). While previous work has shown that highly sensitive equipment is capable of long-range detection of UEE the intention of this work is to develop a network of small, low cost smart sensor nodes (SSNs) capable of short-range detection. Also, the use of zeolite sensors for the detection of CB agents was developed in a similar manner with efforts spent on the integration of the sensor, the routing protocol, and multiple layers of the stackable SSN design. The combination of electromagnetic (EM) and CB detection systems lead to a strategic duet of technologies for the detection of ET through the use of small, low cost WSNs. Experimental results indicate that UEE are detectable from passive circuitry and CB agents can be identified using zeolite sensors --Abstract, page iii

Nonverbal Channel Use in Communication of Emotion: How May Depend on Why

This study investigated the hypothesis that different emotions are most effectively conveyed through specific, nonverbal channels of communication: body, face, and touch. Experiment 1 assessed the production of emotion displays. Participants generated nonverbal displays of 11 emotions, with and without channel restrictions. For both actual production and stated preferences, participants favored the body for embarrassment, guilt, pride, and shame; the face for anger, disgust, fear, happiness, and sadness; and touch for love and sympathy. When restricted to a single channel, participants were most confident about their communication when production was limited to the emotion\u27s preferred channel. Experiment 2 examined the reception or identification of emotion displays. Participants viewed videos of emotions communicated in unrestricted and restricted conditions and identified the communicated emotions. Emotion identification in restricted conditions was most accurate when participants viewed emotions displayed via the emotion\u27s preferred channel. This study provides converging evidence that some emotions are communicated predominantly through different nonverbal channels. Further analysis of these channel-emotion correspondences suggests that the social function of an emotion predicts its primary channel: The body channel promotes social-status emotions, the face channel supports survival emotions, and touch supports intimate emotions

Become your own sleepexpert: development and evaluation of a web application to support a pragmatic behavioral treatment program for insomnia in inpatient psychiatric care

Introduction: Mental disorders are among the leading causes for reduced quality of life due to illness worldwide. The majority of patients with mental disorders suffer from insomnia, associated with adverse health outcomes. However, the first-line treatment, cognitive behavioral therapy for insomnia (CBT-I), is often too complex for patients with acute mental disorders and is not systematically implemented in inpatient psychiatric care. Rather, insomnia often remains untreated or treated with hypnotics, related to the risk of adverse effects and dependency. Become your own SLEEPexpert aims to empower patients with acute mental disorders to take care of their own sleep health based on a pragmatic behavioral treatment program. Methods: SLEEPexpert was developed in collaboration with inpatients and health care providers and centers on the sleep/circadian scienceand evidence-based treatment components bedtime restriction and circadian adaptation in three phases: therapist-guided treatment initiation, self-management with nurse support, and self-management. We further developed and tested the usability of a web application based on questionnaires and systematic interviews with qualitativequantitative text analyses in 15 inpatients across diagnostic entities (8F, 4M, 26.7 ± 7.8) and 12 health care providers on psychiatric wards. Results: Evaluative pre-post assessments demonstrated feasibility of the web application in an acute psychiatry setting in the hospital (average System Usability Scale value 84.7, range 67.5; 97.5, indicative of “ok” to “best imaginable”). Data show heightened interest from patients and health care providers and a willingness to use a webbased form of the SLEEPexpert program. Conclusions: We present a novel sleep-centered intervention (SLEEPexpert) that has the potential to be implemented and disseminated in routine clinical care for patients with severe mental disorders and comorbid insomnia. A current randomized controlled trial aims to further test for efficacy. Given the substantive burden of insomnia and mental disorders, the proposed developments are expected to improve the care for patients with comorbid insomnia