Bacterial Virulence and Prevention for Human Spaceflight.

With the advancement in reusable rocket propulsion technology, space tourist trips into outer space are now becoming a possibility at a cost-effective rate. As such, astronauts will face a host of health-related challenges, particularly on long-duration space missions where maintaining a balanced healthy microbiome is going to be vital for human survival in space exploration as well as mission success. The human microbiome involves a whole list of micro-organisms that reside in and on the human host, and plays an integral role in keeping the human host healthy. However, imbalances in the microbiome have been directly linked to many human diseases. Research findings have clearly shown that the outer space environment can directly affect the normal microbiome of astronauts when the astronaut is exposed to the microgravity environment. In this study, we show that the simulation of microgravity on earth can mimic the outer space microgravity environment. Staphylococus aureus (S. aureus) was chosen for this study as it is an opportunistic pathogen, which is part of the normal human skin microflora and the nasal passages. This study's results show that S. aureus proliferation was significantly increased under a microgravity environment compared to Earth's gravity conditions, which complements previous work performed on bacteria in the outer space environment in the International Space Station (ISS). This demonstrates that this technology can be utilised here on Earth to mimic the outer space environment and to study challenging health-related questions. This in return saves us the cost on conducting experiments in the ISS and can help advance knowledge at a faster rate and produce countermeasures to mitigate the negative side effects of the hostile outer space environment on humans.

In vitro testing and efficacy of poly-lactic acid coating incorporating antibiotic loaded coralline bioceramic on Ti6Al4V implant against Staphylococcus aureus.

Biofilm formation on an implant surface is most commonly caused by the human pathogenic bacteria Staphylococcus aureus, which can lead to implant related infections and failure. It is a major problem for both implantable orthopedic and maxillofacial devices. The current antibiotic treatments are typically delivered orally or in an injectable form. They are not highly effective in preventing or removing biofilms, and they increase the risk of antibiotic resistance of bacteria and have a dose-dependent negative biological effect on human cells. Our aim was to improve current treatments via a localized and controlled antibiotic delivery-based implant coating system to deliver the antibiotic, gentamicin (Gm). The coating contains coral skeleton derived hydroxyapatite powders (HAp) that act as antibiotic carrier particles and have a biodegradable poly-lactic acid (PLA) thin film matrix. The system is designed to prevent implant related infections while avoiding the deleterious effects of high concentration antibiotics in implants on local cells including primary human adipose derived stem cells (ADSCs). Testing undertaken in this study measured the rate of S. aureus biofilm formation and determined the growth rate and proliferation of ADSCs. After 24 h, S. aureus biofilm formation and the percentage of live cells found on the surfaces of all 5%-30% (w/w) PLA-Gm-(HAp-Gm) coated Ti6Al4V implants was lower than the control samples. Furthermore, Ti6Al4V implants coated with up to 10% (w/w) PLA-Gm-(HAp-Gm) did not have noticeable Gm related adverse effect on ADSCs, as assessed by morphological and surface attachment analyses. These results support the use and application of the antibacterial PLA-Gm-(HAp-Gm) thin film coating design for implants, as an antibiotic release control mechanism to prevent implant-related infections.

Bio-Activation of HA/ß-TCP Porous Scaffolds by High-Pressure CO2 Surface Remodeling: A Novel "Coating-from" Approach.

Biphasic macroporous Hydroxyapatite/ß-Tricalcium Phosphate (HA/ß-TCP) scaffolds (BCPs) are widely used for bone repair. However, the high-temperature HA and ß-TCP phases exhibit limited bioactivity (low solubility of HA, restricted surface area, low ion release). Strategies were developed to coat such BCPs with biomimetic apatite to enhance bioactivity. However, this can be associated with poor adhesion, and metastable solutions may prove difficult to handle at the industrial scale. Alternative strategies are thus desirable to generate a highly bioactive surface on commercial BCPs. In this work, we developed an innovative "coating from" approach for BCP surface remodeling via hydrothermal treatment under supercritical CO2, used as a reversible pH modifier and with industrial scalability. Based on a set of complementary tools including FEG-SEM, solid state NMR and ion exchange tests, we demonstrate the remodeling of macroporous BCP surface with the occurrence of dissolution-reprecipitation phenomena involving biomimetic CaP phases. The newly precipitated compounds are identified as bone-like nanocrystalline apatite and octacalcium phosphate (OCP), both known for their high bioactivity character, favoring bone healing. We also explored the effects of key process parameters, and showed the possibility to dope the remodeled BCPs with antibacterial Cu2+ ions to convey additional functionality to the scaffolds, which was confirmed by in vitro tests. This new process could enhance the bioactivity of commercial BCP scaffolds via a simple and biocompatible approach.

Testing 3D printed biological platform for advancing simulated microgravity and space mechanobiology research.

The advancement of microgravity simulators is helping many researchers better understanding the impact of the mechanically unloaded space environment on cellular function and disfunction. However, performing microgravity experiments on Earth, using simulators such as the Random Positioning Machine, introduces some unique practical challenges, including air bubble formation and leakage of growth medium from tissue culture flask and plates, all of which limit research progress. Here, we developed an easy-to-use hybrid biological platform designed with the precision of 3D printing technologies combined with PDMS microfluidic fabrication processes to facilitate reliable and reproducible microgravity cellular experiments. The system has been characterized for applications in the contest of brain cancer research by exposing glioblastoma and endothelial cells to 24 h of simulated microgravity condition to investigate the triggered mechanosensing pathways involved in cellular adaptation to the new environment. The platform demonstrated compatibility with different biological assays, i.e., proliferation, viability, morphology, protein expression and imaging of molecular structures, showing advantages over the conventional usage of culture flask. Our results indicated that both cell types are susceptible when the gravitational vector is disrupted, confirming the impact that microgravity has on both cancer and healthy cells functionality. In particular, we observed deactivation of Yap-1 molecule in glioblastoma cells and the remodeling of VE-Cadherin junctional protein in endothelial cells. The study provides support for the application of the proposed biological platform for advancing space mechanobiology research, also highlighting perspectives and strategies for developing next generation of brain cancer molecular therapies, including targeted drug delivery strategies.

Microgravity × Radiation: A Space Mechanobiology Approach Toward Cardiovascular Function and Disease.

In recent years, there has been an increasing interest in space exploration, supported by the accelerated technological advancements in the field. This has led to a new potential environment that humans could be exposed to in the very near future, and therefore an increasing request to evaluate the impact this may have on our body, including health risks associated with this endeavor. A critical component in regulating the human pathophysiology is represented by the cardiovascular system, which may be heavily affected in these extreme environments of microgravity and radiation. This mini review aims to identify the impact of microgravity and radiation on the cardiovascular system. Being able to understand the effect that comes with deep space explorations, including that of microgravity and space radiation, may also allow us to get a deeper understanding of the heart and ultimately our own basic physiological processes. This information may unlock new factors to consider with space exploration whilst simultaneously increasing our knowledge of the cardiovascular system and potentially associated diseases.

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research.

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.

Real versus simulated galactic cosmic radiation for investigating cancer risk in the hematopoietic system - are we comparing apples to apples?

Deep space exploration missions need strategies to mitigate the potentially harmful exposure to galactic cosmic radiation. This form of radiation can cause significant damage to biological systems and organisms, which include radiation-induced carcinogenesis in the hematopoietic system. Ongoing studies investigate these effects using cell- and animal-based studies in low earth orbit. The logistic challenges and costs involved with sending biological specimens to space have prompted the development of surrogate ground-based radiation experiments to study the mechanisms of biological injury and cancer risk. However, simulating galactic cosmic radiation has proven difficult and current studies are only partially succeeding at replicating the complexity of this radiation and its downstream injury pathways. Accurate simulation of chronic, low dose galactic radiation will improve our ability to test mitigation strategies such as drug development and improved shielding materials that could be crucial and essential for successful space exploration.

Background-free fibre optic Brillouin probe for remote mapping of micromechanics.

Brillouin imaging (BI) has become a valuable tool for micromechanical material characterisation, thanks to extensive progress in instrumentation in the last few decades. This powerful technique is contactless and label-free, thus making it especially suitable for biomedical applications. Nonetheless, to fully harness the non-contact and non-destructive nature of BI, transformational changes in instrumentation are still needed to extend the technology's utility into the domain of in vivo and in situ operation, which we foresee to be particularly crucial for wide spread usage of BI, e.g. in medical diagnostics and pathology screening. This work addresses this challenge by presenting the first demonstration of a fibre-optic Brillouin probe, capable of mapping the micromechanical properties of a tissue-mimicking phantom. This is achieved through combination of miniaturised optical design, advanced hollow-core fibre fabrication and high-resolution 3D printing. Our prototype probe is compact, background-free and possesses the highest collection efficiency to date, thus providing the foundation of a fibre-based Brillouin device for remote, in situ measurements in challenging and otherwise difficult-to-reach environments in biomedical, material science and industrial applications.

Understanding the Socioeconomic and Geographical Characteristics of Beneficiaries Receiving a Comprehensive Medication Review.

BACKGROUND: Medicare Part D sponsors are required to offer medication therapy management (MTM) programs to eligible beneficiaries. Recent studies have demonstrated that there have been racial/ethnic disparities in MTM eligibility criteria. For example, compared with non-Hispanic White beneficiaries, Hispanic and non-Hispanic Black beneficiaries are less likely to be eligible for MTM. However, there is limited evidence for socioeconomic and geographical characteristics of those who are eligible and receive MTM services. OBJECTIVE: To describe the demographic, socioeconomic, and geographic characteristics of Medicare beneficiaries who received MTM services. METHODS: As part of a previous study, a national survey evaluated a convenience sample of perspectives of Medicare beneficiaries on the MTM standardized format. The survey was distributed through Medicare Part D plans to beneficiaries receiving MTM services from 2017-2018. As part of the survey, respondents could provide their ZIP codes. Geographical variables, such as the National Center for Health Statistics (NCHS) urban-rural classification scheme and economic research service (ERS) county typology codes, were then applied to respondents' ZIP codes, allowing for the classification of counties or census tracts by urbanization and economic dependence measures. Descriptive statistics are reported for demographic, geographical, and socioeconomic information. RESULTS: Of the 300 (of 434) respondents who provided their ZIP codes, 51.3% were aged 65-74 years; 50% were male; and 66.7% had at least a college education. There were 82.7% who self-identified as White, while only 8% self-identified as Hispanic or Black/African American. The majority of respondents (58.4%) lived in large metropolitan areas as defined by the NCHS urban-rural classification scheme. Respondents' counties were characterized by economic dependence with 14.0% of respondents living in federal/state government-dependent counties and 12.7% living in recreation-dependent counties. CONCLUSIONS: The majority of respondents who provided their ZIP codes identified themselves as White and lived in large metropolitan areas. Respondents who identified themselves as Hispanic or Black/African American were not well represented. This study provides geographical and socioeconomic characteristics of Medicare beneficiaries who received MTM services and highlights racial/ethnic differences. Further work is needed to confirm geographical and socioeconomic disparities among beneficiaries who received MTM services. DISCLOSURES: No outside funding supported this study. Pellegrin is a member of the AMCP MTM Advisory Group. The other authors have nothing to disclose.

Improving Medication Management by Understanding Patient and Caregiver Preferences for Medication Packaging.

OBJECTIVE: To assess older adults' perceptions and preferences when comparing multi-medication packaging products.
DESIGN: Qualitative study involving focus group interviews (FGIs) and key informant interviews (KIIs).
SETTING: Interviews were conducted in multiple cities within the United States during June-July 2019.
PATIENTS, PARTICIPANTS: FGI participants (N=36) included community dwelling adults, 65 years of age or older, who took 5+ chronic medications, or their caregivers. KII participants (N=15) included health care professionals caring for similar populations.
INTERVENTIONS: Participants were given samples of blister packs and pouches and asked about medication management and appearance and usability of medication packaging. Interviews were audio-recorded with participants' consent, then transcribed and coded using Atlas. ti. Recurrent and emergent themes were identified, and selected quotes served as examples of identified themes.
MAIN OUTCOME MEASURE: Participants' perceptions regarding medication packaging.
RESULTS: Participants' preferences varied for different multi-medication packaging systems. Similarly, most FGI participants did not communicate a strong attitude for or against their existing management systems. However, many FGI participants perceived a need for larger font size than seen on the either of the multimedication packaging samples. KII participants also preferred a larger font size on both packagings. KII participants thought the blister packs offered better visual organization and enabled caregivers to quickly assess adherence. However, KII participants expressed concern about integrating as-needed and short-term use medications and noted difficulty opening both types of packages.
CONCLUSION: Visual appearance is important to both patients and health care providers. Continued research in this area is vital for tailoring packaging types and technology to patients.

An Interdisciplinary Approach to Implementing the Age-Friendly Health System 4Ms in an Ambulatory Clinical Pathway With a Focus on Medication Safety.

MedStar's Center for Successful Aging (CSA) participated in the Age-Friendly Health Systems initiative led by The John A. Hartford Foundation and the Institute for Healthcare Improvement in partnership with the American Hospital Association and the Catholic Health Association of the United States. This initiative focuses on bringing the 4Ms framework-What Matters, Medication, Mentation, and Mobility-to caring for older adults. A quality improvement project was conducted at the CSA to integrate the 4Ms framework into the CSA ambulatory clinical pathway. Our interventions found upward trends in patients receiving 4Ms care during their new patient visits. Positive preliminary feedback was also obtained from providers following the incorporation of the 4Ms framework in the high-risk rounds discussion. A focus on high-risk medications and deprescribing illustrated positive clinical outcomes. This ongoing interprofessional collaboration illustrates the importance of person-centered care and quality improvement to achieve Age-Friendly Health Systems status within an ambulatory practice. [Journal of Gerontological Nursing, 46(10), 7-11.].

The inhibition of cellular toxicity of amyloid-ß by dissociated transthyretin.

The protective effect of transthyretin (TTR) on cellular toxicity of ß-amyloid (Aß) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aß, a protein associated with Alzheimer's disease. TTR binds Aß, alters its aggregation, and inhibits its toxicity both in vitro and in vivo In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aß oligomers. These findings suggest that the Aß-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aß aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aß oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aß catalyzed by Aß fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

Optimizing Medication Management During the COVID-19 Pandemic: It Takes a Village.

Coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has particularly affected nursing homes and long-term care facilities. To support frontline health care professionals caring for older adults, the current article provides guidance on strategies to optimize medication management within nursing homes and long-term care facilities. In addition, the article reviews two medications that have been granted U.S. Food and Drug Administration emergency use authorization for treatment of COVID-19: hydroxychloroquine and remdesivir. Finally, this article highlights resources and strategies for improving communication among an interprofessional team during the ongoing pandemic, as well as education on COVID-19. Although the COVID-19 pandemic has had many negative implications, it has also brought to attention opportunities to improve the delivery of care and increase the importance of working as an interprofessional team ("village") during these challenging times. [Journal of Gerontological Nursing, 46(7), 3-8.].

Modeling the Impact of Microgravity at the Cellular Level: Implications for Human Disease.

A lack of gravity experienced during space flight has been shown to have profound effects on human physiology including muscle atrophy, reductions in bone density and immune function, and endocrine disorders. At present, these physiological changes present major obstacles to long-term space missions. What is not clear is which pathophysiological disruptions reflect changes at the cellular level versus changes that occur due to the impact of weightlessness on the entire body. This review focuses on current research investigating the impact of microgravity at the cellular level including cellular morphology, proliferation, and adhesion. As direct research in space is currently cost prohibitive, we describe here the use of microgravity simulators for studies at the cellular level. Such instruments provide valuable tools for cost-effective research to better discern the impact of weightlessness on cellular function. Despite recent advances in understanding the relationship between extracellular forces and cell behavior, very little is understood about cellular biology and mechanotransduction under microgravity conditions. This review will examine recent insights into the impact of simulated microgravity on cell biology and how this technology may provide new insight into advancing our understanding of mechanically driven biology and disease.

Identifying and Bridging the Gaps in Antimicrobial Stewardship in Post-Acute and Long-Term Care.

National organizations have developed guidelines and tools for antimicrobial stewardship (AMS) in post-acute and long-term care (PALTC), but there is a need to effectively translate these into actionable, measurable, and impactful programs. An electronic needs assessment survey was developed and distributed to health care providers and administrators involved with AMS activities in PALTC facilities in Maryland. The results of this survey were used to develop a statewide initiative to improve AMS in nursing facilities. The survey revealed that barriers to implementing AMS include limited access or poor utilization of experts in AMS and infectious disease, adverse event data collection tools, and locally developed protocols and guidelines. Strategies to improve AMS included the provision of free continuing education to a multidisciplinary audience and improved access to individuals with expertise in infectious disease and the development of an adverse drug event tool. Continuing to provide meaningful tools and resources that address the specific needs of nursing facilities should lead to improved compliance with regulations and ultimately improved resident outcomes. [Journal of Gerontological Nursing, 46(1), 8-13.].

Mechanical testing of antimicrobial biocomposite coating on metallic medical implants as drug delivery system.

Post-operative infection often occurs following orthopedic and dental implant placement requiring systemically administered antibiotics. However, this does not provide long-term protection. Over the last few decades, alternative methods involving slow drug delivery systems based on biodegradable poly-lactic acid and antibiotic loaded hydroxyapatite microspheres were developed to prevent post-operative infection. In this study, thermally anodised and untreated Ti6Al4V discs were coated with Poly-Lactic Acid (PLA) containing Gentamicin (Gm) antibiotic-loaded coralline Hydroxyapatite (HAp) are investigated. Following chemical characterization, mechanical properties of the coated samples were measured using nanoindentation and scratch tests to determine the elastic modulus, hardness and bonding adhesion between film and substrate. It was found that PLA biocomposite multilayered films were around 400nm thick and the influence and effect of the substrate were clearly observed during the nanoindentation studies with heavier loads. Scratch tests of PLA coated samples conducted at ~160nm depth showed the minimal difference in the measured friction between Gm and non Gm containing films. It is also observed that the hardness values of PLA film coated anodised samples ranged from 0.45 to 1.9GPa (dependent on the applied loads) against untreated coated samples which ranged from 0.28 to 0.8GPa.

Supramolecular-based nanofibers.

Supramolecular-based nanofibers, which successfully combine the unique properties of supramolecular interactions with the advantages of nanofibrous structure, are widely used in a variety of biomedical applications such as controlled drug delivery. Compared with traditional polymer nanofibers, supramolecular-based nanofibers can overcome the bottleneck of sensitivity because of the non-covalent binding modes, and therefore match the requirements of rapid and reversible response to the external stimuli. In addition, supramolecular-based nanofibers can achieve extra controllable and dynamic responsive (e.g. pH, temperature) functions in different environments. In this review, we retrospected and summarized the recent development of supramolecular-based nanofibers, focusing particularly on electrospun supramolecular nanofibers, while also touching on the advances of directly self-assembled supramolecular nanofibers without the use of electrospinning. Furthermore, we discussed the potential biomedical applications of supramolecular nanofibers. Finally, this review was concluded by elaborating upon individual reflection on the current situation, forecasting the future trend of this promising material.

Findings from a National Survey of Medicare Beneficiary Perspectives on the Medicare Part D Medication Therapy Management Standardized Format.

BACKGROUND: The Medication Therapy Management (MTM) Program Standardized Format (SF) is a written summary of a comprehensive medication review (CMR) that must be provided to Medicare Part D beneficiaries. Concerns have been raised regarding the number of pages of the SF, mailing costs, the static nature of the document, and the lack of integration into beneficiaries' electronic health records. To date, limited research exists on beneficiaries' perceptions of the SF. OBJECTIVE: To evaluate the perspectives of beneficiaries regarding the utility of the SF to inform potential modifications for optimal use. METHODS: An online survey, designed based on the standard approach to measuring patient satisfaction with health service attributes and previous qualitative research, was distributed through Medicare Part D plans to beneficiaries who had received a CMR in the past year. Survey distribution began July 1, 2018, and data collection ended on October 31, 2018. Descriptive statistics are reported for demographic information; health status; perceived value and helpfulness of the SF and its 3 components (cover letter, medication action plan [MAP], personal medication list [PML]); updates to the SF; alternate formatting; and integration of the SF into health records. RESULTS: A total of 9,975 surveys were sent electronically by 4 Medicare Part D plans to beneficiaries who had received a CMR in the past year. Of the 434 unduplicated survey respondents (response rate of 4.3%), 58.5% were aged 65 to 84 years; 60% identified themselves as white; and 49.1% had at least a college education. The most commonly reported comorbidities were diabetes (50.5%) and high cholesterol (43.1%), with 10.7% of respondents rating their health as "very good" or "excellent" and 27.4% choosing "poor" or "fair." Beneficiaries rated how well the SF helped improve different aspects of their medication management (e.g., solving medication-related problems, keeping track of medications, correctly using medications, and understanding why medications are being taken), with 40.8%-44.9% choosing "very good" to "excellent" for each aspect. Helpful sections included "What we talked about" and "What I need to do"for the MAP, and medication name, strength, dosage form, and "How and why I use the medication" for the PML. Less helpful were the fill-in sections of the MAP, with 48.6% reporting that they did not write in any information. In contrast, 44.7% of the participants noted that they updated their PML. A wallet card version of the PML, if available, would be used by 54.6% of participants. About one third of Medicare beneficiaries shared the SF with their doctor, and 26% of the participants gave copies of their medication summary to their relatives. CONCLUSIONS: Fewer than half of the respondents perceived the SF as very good or excellent in helping them to manage their medications. This national survey provides Medicare beneficiary-focused evidence that more work is needed to improve the usability and portability of the SF. This can be achieved by allowing flexibility in the design of the SF, while including essential elements. DISCLOSURES: This study was funded by the Academy of Managed Care Pharmacy (AMCP), which provided a grant to the University of Maryland School of Pharmacy to conduct this study. Carden and Kumbera are AMCP employees. Brandt reports a grant from IMPAQ and consulting fees from Rand, outside of this study. Pellegrin is a member of the AMCP MTM Advisory Board. The other authors have nothing to disclose.