DR.BEAT: Initial Functional Testing of a BCG Wearable Prototype for Recording Ballistocardiographic Signals.

DR.BEAT ("Digital Research on Ballistocardiography for Extraterrestrial And Terrestrial use") develops a miniaturized sensor system with signal processing to interpret ballistocardiographic signals and implements an application oriented user interface. Presented is a breadboard prototype's functional tests with regard to data completeness and plausibility. The analysis confirmed a reliability of 99.99995% over the tests and the signals displayed the expected heart-specific characteristics. These results support the ethical justifiability of an initial study.

DR.BEAT: First Insights into a Study to Collect Baseline BCG Data with a Sensor-Based Wearable Prototype in Heart-Healthy Adults.

The DR.BEAT project aims at the further development of a measurement system for recording ballistocardiographic signals into a body-worn sensor system combined with extensive signal processing, data evaluation and visualization. With a first breadboard prototype, an explorative feasibility study for acquiring initial signals of healthy cardiac activity in adults was performed. This paper briefly presents the DR.BEAT project, the breadboard prototype, the study conducted, and initial insights into the study results. The signals obtained in the study exhibit the seismocardiographic characteristics as reported in the literature and form the basis for further development of the hardware as well as the pre-processing and automated analysis algorithms in the DR.BEAT project.Clinical Relevance- The characteristics of ballisto- and seismocardiographic signals allow to infer about the mechanical work of the heart. The development of a body-worn sensor system to record ballisto- and seismocardiographic signals, compact enough for everyday wear, enables the acquisition of heart-specific parameters in terrestrial as well as extraterrestrial application scenarios. Combined with extensive signal analysis and visualization, it holds the potential to monitor heart health in a variety of contexts and support its maintenance and improvement.

Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents.

Across biological scales, gene-regulatory networks employ autorepression (negative feedback) to maintain homeostasis and minimize failure from aberrant expression. Here, we present a proof of concept that disrupting transcriptional negative feedback dysregulates viral gene expression to therapeutically inhibit replication and confers a high evolutionary barrier to resistance. We find that nucleic-acid decoys mimicking cis-regulatory sites act as "feedback disruptors," break homeostasis, and increase viral transcription factors to cytotoxic levels (termed "open-loop lethality"). Feedback disruptors against herpesviruses reduced viral replication >2-logs without activating innate immunity, showed sub-nM IC50, synergized with standard-of-care antivirals, and inhibited virus replication in mice. In contrast to approved antivirals where resistance rapidly emerged, no feedback-disruptor escape mutants evolved in long-term cultures. For SARS-CoV-2, disruption of a putative feedback circuit also generated open-loop lethality, reducing viral titers by >1-log. These results demonstrate that generating open-loop lethality, via negative-feedback disruption, may yield a class of antimicrobials with a high genetic barrier to resistance.

Characterization of Recruited Mononuclear Phagocytes following Corneal Chemical Injury.

Mononuclear phagocytes (MP) have central importance in innate immunity, inflammation, and fibrosis. Recruited MPs, such as macrophages, are plastic cells and can switch from an inflammatory to a restorative phenotype during the healing process. However, the role of the MPs in corneal wound healing is not completely understood. The purpose of this study is to characterize the kinetics of recruited MPs and evaluate the role of macrophage metalloelastase (MMP12) in the healing process, using an in vivo corneal chemical injury model. Unwounded and wounded corneas of wild-type (WT) and Mmp12-/- mice were collected at 1, 3, and 6 days after chemical injury and processed for flow cytometry analysis. Corneal MP phenotype significantly changed over time with recruited Ly6Chigh (proinflammatory) cells being most abundant at 1 day post-injury. Ly6Cint cells were highly expressed at 3 days post-injury and Ly6Cneg (patrolling) cells became the predominant cell type at 6 days post-injury. CD11c+ dendritic cells were abundant in corneas from Mmp12-/- mice at 6 days post-injury. These findings show the temporal phenotypic plasticity of recruited MPs and provide valuable insight into the role of the MPs in the corneal repair response, which may help guide the future development of MP-targeted therapies.

Development and nationwide implementation of a postdischarge responsive parenting intervention program for very preterm born children: The TOP program.

A previous randomized controlled trial has suggested the effectiveness of a Dutch postdischarge responsive parenting program for very preterm (VPT) infants, indicating that nationwide implementation was justified. This paper describes the development and nationwide implementation of the intervention, known as the TOP program, which consisted of three phases. In the preparation phase (2006-2010), a theory of change and the structure of the TOP program were developed, and funding for phase two, based on a positive Business Case, was obtained. In the pilot implementation phase (2010-2014), intervention strategies were developed for a real-world setting, capacity and adoption were increased, systematic evaluations were incorporated, and sustained funding was obtained. In the full-implementation phase (2014-2019), all Dutch Healthcare Insurers reimbursed the TOP program, enabling VPT infants to participate in the program without charge. By 2018, the number of interventionists that provided the TOP program had increased from 37 to 91, and all level III hospitals and 65% of regional hospitals in the Netherlands referred VPT infants. Currently, the program reaches 70% of the Dutch target population and parental satisfaction with the TOP program is high. After a 12-year implementation period, the TOP program forms part of routine care in the Netherlands.

Un previo ensayo controlado al azar ha sugerido la eficacia de un programa holandés sobre la crianza sensible para infantes muy prematuros (VPT) posterior al momento en que se les dio de alta, indicando que la implementación a lo largo de toda la nación era justificada. Este artículo describe el desarrollo y la implementación a nivel de toda la nación de la intervención, conocida como el programa ToP, el cual consistía de tres fases. En la fase de preparación (2006-2010), se desarrollaron una teoría de cambio y la estructura del programa ToP, y se obtuvieron los fondos para la fase dos, con base en un Caso de Negocios (BC) positivo. En la fase piloto de implementación (2010-2014), se desarrollaron estrategias de intervención para un escenario del mundo real, se aumentaron la capacidad y la adopción, se incorporaron evaluaciones sistemáticas y se obtuvieron fondos para mantener el programa. En la fase de implementación completa (2014-2019), todas las Aseguradoras Holandesas del Sector Salud reembolsaron el costo del programa ToP, permitiéndoles a los infantes VPT participar en el programa sin costo alguno. Para 2018, el número de practicantes de la intervención que prestaban el servicio del programa ToP había aumentado de 37 a 91, y todos los hospitales del nivel III y 65% de los hospitales regionales en Holanda refirieron los infantes VPT al programa. Actualmente, el programa llega a 70% de la población holandesa para la cual está destinado y la satisfacción de los padres con el programa ToP es alta. Después de un período de implementación de 12 años, el programa ToP forma parte del cuidado de salud rutinario en Holanda.

Un essai contrôlé randomisé précédent a suggéré l'efficacité d'un programme hollandais de sensibilité de parentage après la sortie de l'hôpital pour les nourrissons grands prématurés (GP ici en français), indiquant qu'une mise en œuvre au niveau national était justifiée. Cet article décrit le développement et la mise en œuvre au niveau national de l'intervention, connue en tant que ToP program, qui a consisté en trois phases. Dans la phase de préparation (2006-2010), une théorie du changement et la structure du programme ToP a été développée, et le financement pour la phase deux, basée sur une Etude de Cas positive, a été sécurisé. Dans la phase pilote d'implémentation (2010-2014) des stratégies d'intervention ont été développées pour un contexte réel, la capacité et l'adoption ont été augmentées, les évaluations systématiques ont été incorporées, et un financement durable a été sécurisé. Dans la pleine phase de mise en œuvre (2014-1029), tous les Assurances Santé Hollandaises ont remboursé le programme ToP, permettant aux nourrissons GP de participer au programme sans coût. En 2018 le nombre de prestataires qui offraient le programme ToP a augmenté de 37 à 91, et tous les hôpitaux de niveau III ainsi que 65% des hôpitaux régionaux aux Pays Bas ont envoyé les nourrissons GP au programme. En ce moment le programme atteint 70% de la population cible hollandaise et la satisfaction parentale avec le programme ToP est élevée. Après une période de mise en œuvre de 12 ans le programme ToP fait partie des soins de routine aux Pays Bas.

A molecular mechanism for probabilistic bet hedging and its role in viral latency.

Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein-the major viral transactivator protein-exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.

Development of a Presentation Interface for Seismo- and Ballistocardiographic Data.

Ballistocardiography is a method to gain detailed information about body movements imparted by the ballistic forces associated with cardiac contraction. We measured using different setups and sensor positions to gain information of a reference signal of healthy adults. We used two resting state recordings and two recordings under physical stress (ergometer and treadmill) with stepwise increasing load. Data was gathered from 34 subjects, which results in 72 data sets, overall, more than 18h of signal data. With these data we have created a first database for BCG reference. We started data analysis and created a first naive data representation prototype. Using this naive attempt, we created a user interface for the intuitive representation of live data as well as retrospective data.

A Structured Measurement of Highly Synchronous Real-Time Ballistocardiography Signal Data of Heart Failure Patients.

Ballistocardiography (BCG) has gained more attention due to the fundamental goal of medical intervention in diagnostics and follow-up. BCG is particularly suitable for the study of heart failure, which a recent study has shown. The results of this working group shall be validated and reproduced with another study trial. Therefore, acceleration sensor prototypes will be placed on various parts of the patient's body and be connected to a computer unit, which allows a high data quality and high signal resolution. A temporal shift of only 20 ns ensures real-time measurement of BCG parameters. The reference measurement will be done with a 12-channel ECG. The study will include patients with heart failure. All conducted tests take place as part of the diagnostic-therapeutic routine. The only change in the procedure concerns the additional equipment with the measuring sensors. The results will be the validation of the data from the other working group, as well as the information about the choice of sensors and clock frequency, the measuring points and the needed features for early detection of heart failure in BCG signals.

Author Correction: Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy.

Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. In Fuchs endothelial corneal dystrophy (FECD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ECM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from FECD patients. We discover that miRNA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD. Taken together, these findings suggest a novel epigenetic regulatory mechanism of matrix protein production by corneal endothelial cells in which miR-199B hypermethylation leads to miR-199b-5p downregulation and thereby the increased expression of its target genes, including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to prevent or slow down the progression of FECD disease.

Wireless Sensor Network for Fall Prevention on Geriatric Wards: A Report.

With regard to the growing number of older adults, it needs smart solutions for fall prevention. Especially at geriatric institutions, the risk of falling is very high and frequently leads to injuries, resulting in serious consequences. We present the Inexpensive Node for Bed Exit Detection (INBED), a comprehensive signaling system for fall prevention. The INBED system is based on a wireless sensor network infrastructure via IEEE802.15.4 and highly-specialized open hardware in-house developed wearable. The device, which will be attached to the patients, can detect several types of movement. Occurring events are forwarded to the nursing staff immediately by using the self-organizing and scalable network including wide area network integration. The system can help to relieve the staff while the personal freedom of movement and privacy of patients is increased. With this development, the energy-efficient, simple and intuitive mechanisms of proximity communication can be combined with broadband benefits.

First Feasibility Analysis of Ballistocardiography on a Passenger Flight.

The project SCARAB2 (Scalable, Robust and Adaptive on Board Ballistocardiography) aims to use Ballistocardiography (BCG) to monitor flight passengers. In order to show that recorded BCG data from flights give evaluable information even in the noisy environment of an airplane, we monitored a heart-healthy passenger using BCG. Furthermore, we show that there can be a conclusion to heart activities from the recorded ballistocardiogram by comparing the data to a concurrently recorded electrocardiogram (ECG).

MMP12 Inhibits Corneal Neovascularization and Inflammation through Regulation of CCL2.

Following corneal injury, coordinated cellular and protein interactions occur at the wound site to restore tissue homeostasis. Regulation of this response is required to prevent the development of chronic inflammation, abnormal neovascularization, and fibrosis. The chemokine CCL2 and its primary receptor CCR2 are key regulators of the inflammatory and neovascular responses to injury. In this study, we investigated the role of macrophage-associated matrix metalloproteinase 12 (MMP12) in the regulation of CCL2 and CCR2 after corneal wounding. Using two corneal injury models, we examined the temporal and spatial expression of CCL2 and CCR2 in Mmp12-/- and wild-type (WT) mice. Our data showed that MMP12 downregulated CCL2 and CCR2 expression in a manner dependent on the timing and mechanism of injury. We also examined the effect of CCL2 on the injury response in Mmp12-/- and WT corneas. We found that macrophage infiltration and neovascularization following CCL2 blockade was significantly reduced in Mmp12-/- corneas as compared with WT corneas. These findings indicate that MMP12 inhibits corneal inflammation and neovascularization after injury through its regulation of CCL2.

Overexpression of MMPs in Corneas Requiring Penetrating and Deep Anterior Lamellar Keratoplasty.

Purpose: Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases involved in wound healing processes, including neovascularization and fibrosis. We assessed MMP protein expression levels in diseased corneas of patients requiring penetrating and deep anterior lamellar keratoplasty. The purpose of this study was to test the hypothesis that upregulation of MMPs in diseased corneas is positively associated with clinical levels of corneal neovascularization and fibrosis. Methods: Protein expression levels of nine individual MMPs were quantified simultaneously in human corneal lysates by using the Bio-Plex Pro Human MMP 9-Plex Panel and the MAGPIX technology. Measurements of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, and MMP13 were performed on diseased specimens from 21 patients undergoing corneal transplantation (17 for penetrating keratoplasty and 4 for deep anterior lamellar keratoplasty) and 6 normal control corneas. Results: Luminex-based expression analysis revealed a significant overexpression of four of the nine MMPs tested (MMP2, MMP8, MMP12, and MMP13) in patient samples compared to control. Significant overexpression of MMP1, MMP2, MMP8, MMP12, and MMP13 was observed in diseased corneas with neovascularization compared with diseased corneas without neovascularization. Overexpression of MMP1, MMP2, MMP8, MMP12, and MMP13 also corresponded with the levels of corneal fibrosis. Finally, reduced expression of MMP3 was detected in keratoconus patients. Conclusions: Multiple MMPs are expressed in the corneas of patients with chronic disease requiring keratoplasty even when the pathologic process appears to be clinically inactive. In particular, the expression of several MMPs (MMP2, MMP8, MMP12, and MMP13) is positively associated with increased levels corneal fibrosis and neovascularization.

Advantages of Modular Hybrid Network Communication on Clinical Wards.

The ever-increasing flood of information, especially in the medical-clinical field, inter alia due to the increase of data-intensive mobile/wearable devices, is one of the biggest challenges of medical informatics. In this work different possibilities of the integration of wearable devices on the example of the development of a fall prevention system are presented and classified. We started with a commercial off-the-shelf one-on-one system (Shimmer/Arduino) using a Bluetooth connection, integrated via nurse call system as Human-Machine-Interface. During the evaluation of the system we mentioned several new requirements and optimization possibilities. Thus, we adjusted the hardware-software-system; the near-field communication was realized by IEEE802.15.4, we replaced commercial off-the-shelf devices with highly-specialized open hardware in-house developments and we transferred the nurse call integration by setting up our own network and integrating this into an existing (wireless) local area network. With this development, the energy-efficient, simple and intuitive mechanisms of proximity communication via IEEE802.15.4 can be combined with the benefits broadband functionalities, e.g. of Wi-Fi, with both worlds benefits and the compensation of some disadvantages.

Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers.

The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2.

Effects of MMP12 on cell motility and inflammation during corneal epithelial repair.

Corneal epithelial defects are a common cause of ocular morbidity and can result in corneal scarring if they do not heal properly. Matrix metalloproteinases (MMPs) are extracellular matrix proteinases that regulate multiple aspects of corneal repair. We have previously shown that MMP12 has a protective effect on corneal fibrosis through its regulation of neutrophil and macrophage infiltration and angiogenesis in a chemical injury model involving full thickness damage to the cornea. However, the role of MMP12 in injuries limited to the corneal epithelium is relatively unknown. This study investigates the reparative effects of MMP12 following isolated corneal epithelial injury. Using a corneal epithelial debridement injury model performed on corneas of wild-type (WT) mice, we show that Mmp12 is expressed early following corneal epithelial injury with highest expression levels at 8 h after injury and lower expression levels at 4 and 8 days after injury. We investigated whether MMP12 has an effect on the rate of epithelial repair and cell migration using in vivo and in vitro scratch assays performed on WT and Mmp12-/- mice. We found that loss of MMP12 results in a slower scratch wound repair rate both in vivo and in vitro. We also found that corneas of Mmp12-/- mice have decreased neutrophil infiltration following injury. Loss of MMP12, however, does not affect cell proliferation in the center of the wounds. These data support a role of MMP12 in promoting early repair processes following corneal epithelial injury by enhancing epithelial cell migration and neutrophil infiltration.