Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease.

Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual's well-being. This cumulative impact of DED on an individual's activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.

Biodegradation of Nitrile Gloves as Sole Carbon Source of Pseudomonas aeruginosa in Liquid Culture.

Nitrile gloves have become a significant environmental pollutant after the COVID-19 pandemic due to their single-use design. This study examines the capability of P. aeruginosa to use nitrile gloves as its sole carbon energy source. Biodegradation was determined by P. aeruginosa adapting to increasing nitrile glove concentrations at 1%, 3%, and 5% (w/v). The growth kinetics of P. aeruginosa were evaluated, as well as the polymer weight loss. Topographic changes on the glove surfaces were examined using SEM, and FT-IR was used to evaluate the biodegradation products of the nitrile gloves. Following the establishment of a biofilm on the glove surface, the nitrile toxicity was minimized via biodegradation. The result of the average weight loss of nitrile gloves was 2.25%. FT-IR analysis revealed the presence of aldehydes and aliphatic amines associated with biodegradation. SEM showed P. aeruginosa immersed in the EPS matrix, causing the formation of cracks, scales, protrusions, and the presence of semi-spherical particles. We conclude that P. aeruginosa has the capability to use nitrile gloves as its sole carbon source, even up to 5%, through biofilm formation, demonstrating the potential of P. aeruginosa for the degradation of nitrile gloves.

Colombian Ocular Diseases Epidemiology Study (CODES): Prevalence and Sociodemographic Characterization of Refractive Errors in Colombian Eye Care Consultations.

PURPOSE: To estimate the prevalence and demographic characteristics of uncorrected refractive errors (URE) in people who attended eye care consultations in Colombia between 2015 and 2019, using the National Health Registry data. METHODS: We identified ICD codes for myopia (H-52.1), degenerative myopia (H-44.2), hyperopia (H-52.0), and astigmatism (H-52.2) from the Integrated Social Protection Information System. Crude prevalence rates by age and sex were calculated for the population attending eye care services during these years. Additionally, we developed a standardized morbidity map across county departments. RESULTS: In Colombia, the prevalence of URE among eye care consultations was 30.26%, increasing from 30.39% in 2015 to 35.14% in 2019. Of the 1,579,778 cases analyzed, 60.9% were females. Astigmatism emerged as the most prevalent URE, predominantly seen in individuals under 40 years old. Myopia showed the highest prevalence in the 10-30 age group, whereas hyperopia was most prevalent in the first decade of life. Geographically, the Andean region recorded most of URE cases, while more remote areas have seen a rising morbidity risk in recent years. CONCLUSIONS: The rising trend of URE in Colombia and its demographic and geographical variations underscores the urgent need for health professionals and government authorities to acknowledge and address this issue. This study provides crucial insights into the refractive error landscape across the country, highlighting the necessity for prevention programs specifically designed to cater to the country's unique needs.

Knowledge gaps in heart and lung donation after the circulatory determination of death: Report of a workshop of the National Heart, Lung, and Blood Institute.

In a workshop sponsored by the U.S. National Heart, Lung, and Blood Institute, experts identified current knowledge gaps and research opportunities in the scientific, conceptual, and ethical understanding of organ donation after the circulatory determination of death and its technologies. To minimize organ injury from warm ischemia and produce better recipient outcomes, innovative techniques to perfuse and oxygenate organs postmortem in situ, such as thoracoabdominal normothermic regional perfusion, are being implemented in several medical centers in the US and elsewhere. These technologies have improved organ outcomes but have raised ethical and legal questions. Re-establishing donor circulation postmortem can be viewed as invalidating the condition of permanent cessation of circulation on which the earlier death determination was made and clamping arch vessels to exclude brain circulation can be viewed as inducing brain death. Alternatively, TA-NRP can be viewed as localized in-situ organ perfusion, not whole-body resuscitation, that does not invalidate death determination. Further scientific, conceptual, and ethical studies, such as those identified in this workshop, can inform and help resolve controversies raised by this practice.

Revisión sistemática de las aplicaciones y límites de la impresión 3D en la cirugía de raquis / Systematic review of the utility and limits of 3D printing in spine surgery

Objetivo: El objetivo principal de este estudio ha sido demostrar por qué la impresión aditiva permite hacer más visibles y entendibles los procesos patológicos quirúrgicos complejos que afectan al raquis, aumentando la precisión, la seguridad y la fiabilidad del procedimiento quirúrgico.MetodologíaSe realizó una revisión sistemática de los trabajos publicados en los últimos 10 años, sobre la cirugía de raquis asistida por impresión 3D, de acuerdo con la declaración PRISMA 2020. Con las palabras clave «printing 3D» y «spine surgery» se hicieron búsquedas en las bases de datos Pubmed, Embase, Cochrane Database of Systematic Reviews, Google Scholar y Opengrey, que se completó con la búsqueda manual a través de la lista de referencias bibliográficas de los artículos que fueron seleccionados siguiendo los criterios de inclusión y exclusión definidos.ResultadosDel análisis de los 38 estudios seleccionados resultó que la impresión 3D es útil en la planificación quirúrgica, en la enseñanza médica, en la relación médico-paciente, así como en el diseño de plantillas de navegación e implantes de raquis y, en investigación, ofreciendo un magnífico apoyo al proceder quirúrgico.ConclusionesEl uso de biomodelos impresos de forma tridimensional permite: hacer más visibles y entendibles los procesos patológicos quirúrgicos complejos que afectan al raquis; aumentar la exactitud, precisión y seguridad del procedimiento quirúrgico; y abrir la posibilidad de poner en práctica tratamientos personalizados, fundamentalmente en la cirugía tumoral. (AU)

Objective: The main objective of this study has been to demonstrate why additive printing allows to make complex surgical pathological processes that affect the spine more visible and understandable, increasing precision, safety and reliability of the surgical procedure.MethodsA systematic review of the articles published in the last 10 years on 3D printing-assisted spinal surgery was carried out, in accordance with PRISMA 2020 declaration. Keywords «3D printing» and «spine surgery» were searched in Pubmed, Embase, Cochrane Database of Systematic Reviews, Google Scholar and Opengrey databases, which was completed with a manual search through the list of bibliographic references of the articles that were selected following the defined inclusion and exclusion criteria.ResultsFrom the analysis of the 38 selected studies, it results that 3D printing is useful in surgical planning, medical teaching, doctor–patient relationship, design of navigation templates and spinal implants, and research, optimizing the surgical process by focusing on the patient, offering magnificent support during the surgical procedure.ConclusionsThe use of three-dimensional printing biomodels allows: making complex surgical pathological processes that affect the spine more visible and understandable; increase the accuracy, precision and safety of the surgical procedure, and open up the possibility of implementing personalized treatments, mainly in tumor surgery. (AU)

Friction forces determine cytoplasmic reorganization and shape changes of ascidian oocytes upon fertilization.

Contraction and flow of the actin cell cortex have emerged as a common principle by which cells reorganize their cytoplasm and take shape. However, how these cortical flows interact with adjacent cytoplasmic components, changing their form and localization, and how this affects cytoplasmic organization and cell shape remains unclear. Here we show that in ascidian oocytes, the cooperative activities of cortical actomyosin flows and deformation of the adjacent mitochondria-rich myoplasm drive oocyte cytoplasmic reorganization and shape changes following fertilization. We show that vegetal-directed cortical actomyosin flows, established upon oocyte fertilization, lead to both the accumulation of cortical actin at the vegetal pole of the zygote and compression and local buckling of the adjacent elastic solid-like myoplasm layer due to friction forces generated at their interface. Once cortical flows have ceased, the multiple myoplasm buckles resolve into one larger buckle, which again drives the formation of the contraction pole-a protuberance of the zygote's vegetal pole where maternal mRNAs accumulate. Thus, our findings reveal a mechanism where cortical actomyosin network flows determine cytoplasmic reorganization and cell shape by deforming adjacent cytoplasmic components through friction forces.

Systematic review of the utility and limits of 3D printing in spine surgery.

OBJECTIVE: The main objective of this study has been to demonstrate why additive printing allows to make complex surgical pathological processes that affect the spine more visible and understandable, increasing precision, safety and reliability of the surgical procedure. METHODS: A systematic review of the articles published in the last 10 years on 3D printing-assisted spinal surgery was carried out, in accordance with PRISMA 2020 declaration. Keywords "3D printing" and "spine surgery" were searched in Pubmed, Embase, Cochrane Database of Systematic Reviews, Google Scholar and Opengrey databases, which was completed with a manual search through the list of bibliographic references of the articles that were selected following the defined inclusion and exclusion criteria. RESULTS: From the analysis of the 38 selected studies, it results that 3D printing is useful in surgical planning, medical teaching, doctor-patient relationship, design of navigation templates and spinal implants, and research, optimizing the surgical process by focusing on the patient, offering magnificent support during the surgical procedure. CONCLUSIONS: The use of three-dimensional printing biomodels allows: making complex surgical pathological processes that affect the spine more visible and understandable; increase the accuracy, precision and safety of the surgical procedure, and open up the possibility of implementing personalized treatments, mainly in tumor surgery.

An Orphan VrgG Auxiliary Module Related to the Type VI Secretion Systems from Pseudomonas ogarae F113 Mediates Bacterial Killing.

The model rhizobacterium Pseudomonas ogarae F113, a relevant plant growth-promoting bacterium, encodes three different Type VI secretion systems (T6SS) in its genome. In silico analysis of its genome revealed the presence of a genetic auxiliary module containing a gene encoding an orphan VgrG protein (VgrG5a) that is not genetically linked to any T6SS structural cluster, but is associated with genes encoding putative T6SS-related proteins: a possible adaptor Tap protein, followed by a putative effector, Tfe8, and its putative cognate immunity protein, Tfi8. The bioinformatic analysis of the VgrG5a auxiliary module has revealed that this cluster is only present in several subgroups of the P. fluorescens complex of species. An analysis of the mutants affecting the vgrG5a and tfe8 genes has shown that the module is involved in bacterial killing. To test whether Tfe8/Tfi8 constitute an effector-immunity pair, the genes encoding Tfe8 and Tfi8 were cloned and expressed in E. coli, showing that the ectopic expression of tfe8 affected growth. The growth defect was suppressed by tfi8 ectopic expression. These results indicate that Tfe8 is a bacterial killing effector, while Tfi8 is its cognate immunity protein. The Tfe8 protein sequence presents homology to the proteins of the MATE family involved in drug extrusion. The Tfe8 effector is a membrane protein with 10 to 12 transmembrane domains that could destabilize the membranes of target cells by the formation of pores, revealing the importance of these effectors for bacterial interaction. Tfe8 represents a novel type of a T6SS effector present in pseudomonads.

Public Preferences for Digital Health Data Sharing: Discrete Choice Experiment Study in 12 European Countries.

BACKGROUND: With new technologies, health data can be collected in a variety of different clinical, research, and public health contexts, and then can be used for a range of new purposes. Establishing the public's views about digital health data sharing is essential for policy makers to develop effective harmonization initiatives for digital health data governance at the European level. OBJECTIVE: This study investigated public preferences for digital health data sharing. METHODS: A discrete choice experiment survey was administered to a sample of European residents in 12 European countries (Austria, Denmark, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom) from August 2020 to August 2021. Respondents answered whether hypothetical situations of data sharing were acceptable for them. Each hypothetical scenario was defined by 5 attributes ("data collector," "data user," "reason for data use," "information on data sharing and consent," and "availability of review process"), which had 3 to 4 attribute levels each. A latent class model was run across the whole data set and separately for different European regions (Northern, Central, and Southern Europe). Attribute relative importance was calculated for each latent class's pooled and regional data sets. RESULTS: A total of 5015 completed surveys were analyzed. In general, the most important attribute for respondents was the availability of information and consent during health data sharing. In the latent class model, 4 classes of preference patterns were identified. While respondents in 2 classes strongly expressed their preferences for data sharing with opposing positions, respondents in the other 2 classes preferred not to share their data, but attribute levels of the situation could have had an impact on their preferences. Respondents generally found the following to be the most acceptable: a national authority or academic research project as the data user; being informed and asked to consent; and a review process for data transfer and use, or transfer only. On the other hand, collection of their data by a technological company and data use for commercial communication were the least acceptable. There was preference heterogeneity across Europe and within European regions. CONCLUSIONS: This study showed the importance of transparency in data use and oversight of health-related data sharing for European respondents. Regional and intraregional preference heterogeneity for "data collector," "data user," "reason," "type of consent," and "review" calls for governance solutions that would grant data subjects the ability to control their digital health data being shared within different contexts. These results suggest that the use of data without consent will demand weighty and exceptional reasons. An interactive and dynamic informed consent model combined with oversight mechanisms may be a solution for policy initiatives aiming to harmonize health data use across Europe.

Mapping trust relationships in organ donation and transplantation: a conceptual model.

The organ donation and transplantation (ODT) system heavily relies on the willingness of individuals to donate their organs. While it is widely believed that public trust plays a crucial role in shaping donation rates, the empirical support for this assumption remains limited. In order to bridge this knowledge gap, this article takes a foundational approach by elucidating the concept of trust within the context of ODT. By examining the stakeholders involved, identifying influential factors, and mapping the intricate trust relationships among trustors, trustees, and objects of trust, we aim to provide a comprehensive understanding of trust dynamics in ODT. We employ maps and graphs to illustrate the functioning of these trust relationships, enabling a visual representation of the complex interactions within the ODT system. Through this conceptual groundwork, we pave the way for future empirical research to investigate the link between trust and organ donation rates, informed by a clarified understanding of trust in ODT. This study can also provide valuable insights to inform interventions and policies aimed at enhancing organ donation rates.

Biostimulant activity of Galaxaura rugosa seaweed extracts against water deficit stress in tomato seedlings involves activation of ABA signaling.

Water scarcity is a serious constraint for agriculture, and global warming and climate change can exacerbate it in many areas. Therefore, sustainable approaches must be implemented to deal with current and future water scarcity scenarios. Genetic and chemical approaches are being applied to manage this limitation and maintain crop yields. In particular, biostimulants obtained from natural sources such as marine algae are promising aids for coping with water deficit stress in agriculture. Here we present a bioprospection study of extracts of the macroalgae Bonnemaisonia hamifera, Galaxaura rugosa, Dasycladus vermicularis, Ulva clathrata, Cystoseira foeniculacea, Cystoseira humilis, Lobophora dagamae, Colpomenia sinuosa and Halopteris scoparia from the north coast of Tenerife, in the Canary Islands. The aqueous extracts of Bonnemaisonia hamifera, Galaxaura rugosa, Dasycladus vermicularis and Cystoseira humilis show biostimulant activity against water deficit stress in tomato seedlings under controlled conditions, providing higher tolerance than the mock-treated control. The Galaxaura rugosa extract showed the highest biostimulant activity against water deficit stress. We demonstrate that this positive effect involves the activation of the abscisic acid (ABA) pathway in Arabidopsis thaliana (arabidopsis) and Solanum lycopersicum (tomato). Application of G. rugosa extract to the root system by drenching tomato seedlings subjected to water deficit leads to improved CO2 assimilation and water use efficiency (WUEp), compared to mock-treated plants. These results highlight a new potential seaweed source of substances with osmoprotectant properties, useful for biostimulant development. Future studies may provide further insight into which components of the seaweed extract induce activation of the ABA pathway.

TBS-pyrrole as an "universal" reference to quantify artemisinin and structurally-diverse natural products in plants extracts by NMR.

The commercial production of artemisinin and other valuable bioactive natural products depends on their plant sources, which may provide variable amounts of the compound depending on plant variety, the period of the year, abiotic stress and other factors. Therefore, it requires a method for large-scale, low-cost natural product quantification. The standard HPLC and UHPLC methods are accurate but the analysis are costly and require different optimization for structurally-diverse products. An alternative method using NMR with TBS-pyrrole as a novel "universal" reference affords a simple, fast method to quantify many different products. The method is shown with antimalarial artemisinin, whose yield using conventional and novel extraction procedures was determined by standard UHPLC-MS procedures and by our NMR protocol, with similar quantification results. The novel reference compound does not interfere with artemisinin or extract signals, only needs a small amount of the extract, is accurate and operationally simple, and a large volume of samples can be processed in little time. Moreover, bioactive terpenes, steroids, alkaloids, aromatic compounds, and quinones, among others, were quantified in a model vegetal extract with this "universal" reference with excellent accuracy.

Death pluralism: a proposal.

The debate over the determination of death has been raging for more than fifty years. Since then, objections against the diagnosis of brain death from family members of those diagnosed as dead-have been increasing and are causing some countries to take novel steps to accommodate people's beliefs and preferences in the determination of death. This, coupled with criticism by some academics of the brain death criterion, raises some questions about the issues surrounding the determination of death. In this paper, we discuss some of the main approaches to death determination that have been theoretically proposed or currently put into practice and propose a new approach to death determination called "weak pluralism" as a reasonable ethical and political alternative to respect diversity in death determination.

The use of chitosan oligosaccharide to improve artemisinin yield in well-watered and drought-stressed plants.

Introduction: Artemisinin is a secondary metabolite well-known for its use in the treatment of malaria. It also displays other antimicrobial activities which further increase its interest. At present, Artemisia annua is the sole commercial source of the substance, and its production is limited, leading to a global deficit in supply. Furthermore, the cultivation of A. annua is being threatened by climate change. Specifically, drought stress is a major concern for plant development and productivity, but, on the other hand, moderate stress levels can elicit the production of secondary metabolites, with a putative synergistic interaction with elicitors such as chitosan oligosaccharides (COS). Therefore, the development of strategies to increase yield has prompted much interest. With this aim, the effects on artemisinin production under drought stress and treatment with COS, as well as physiological changes in A. annua plants are presented in this study. Methods: Plants were separated into two groups, well-watered (WW) and drought-stressed (DS) plants, and in each group, four concentrations of COS were applied (0, 50,100 and 200 mg•L-1). Afterwards, water stress was imposed by withholding irrigation for 9 days. Results: Therefore, when A. annua was well watered, COS did not improve plant growth, and the upregulation of antioxidant enzymes hindered the production of artemisinin. On the other hand, during drought stress, COS treatment did not alleviate the decline in growth at any concentration tested. However, higher doses improved the water status since leaf water potential (YL) improved by 50.64% and relative water content (RWC) by 33.84% compared to DS plants without COS treatment. Moreover, the combination of COS and drought stress caused damage to the plant's antioxidant enzyme defence, particularly APX and GR, and reduced the amount of phenols and flavonoids. This resulted in increased ROS production and enhanced artemisinin content by 34.40% in DS plants treated with 200 mg•L-1 COS, compared to control plants. Conclusion: These findings underscore the critical role of ROS in artemisinin biosynthesis and suggest that COS treatment may boost artemisinin yield in crop production, even under drought conditions.

Abscisic acid mimic-fluorine derivative 4 alleviates water deficit stress by regulating ABA-responsive genes, proline accumulation, CO2 assimilation, water use efficiency and better nutrient uptake in tomato plants.

Water deficit represents a serious limitation for agriculture and both genetic and chemical approaches are being used to cope with this stress and maintain plant yield. Next-generation agrochemicals that control stomatal aperture are promising for controlling water use efficiency. For example, chemical control of abscisic acid (ABA) signaling through ABA-receptor agonists is a powerful method to activate plant adaptation to water deficit. Such agonists are molecules able to bind and activate ABA receptors and, although their development has experienced significant advances in the last decade, few translational studies have been performed in crops. Here, we describe protection by the ABA mimic-fluorine derivative 4 (AMF4) agonist of the vegetative growth in tomato plants subjected to water restriction. Photosynthesis in mock-treated plants is markedly impaired under water deficit conditions, whereas AMF4 treatment notably improves CO2 assimilation, the relative plant water content and growth. As expected for an antitranspirant molecule, AMF4 treatment diminishes stomatal conductance and transpiration in the first phase of the experiment; however, when photosynthesis declines in mock-treated plants as stress persists, higher photosynthetic and transpiration parameters are recorded in agonist-treated plants. Additionally, AMF4 increases proline levels over those achieved in mock-treated plants in response to water deficit. Thus water deficit and AMF4 cooperate to upregulate P5CS1 through both ABA-independent and ABA-dependent pathways, and therefore, higher proline levels are produced Finally, analysis of macronutrients reveals higher levels of Ca, K and Mg in AMF4- compared to mock-treated plants subjected to water deficit. Overall, these physiological analyses reveal a protective effect of AMF4 over photosynthesis under water deficit and enhanced water use efficiency after agonist treatment. In summary, AMF4 treatment is a promising approach for farmers to protect the vegetative growth of tomatoes under water deficit stress.

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.