First Application of a Mixed Porcine-Human Repopulated Bioengineered Liver in a Preclinical Model of Post-Resection Liver Failure.

In this study, a mixed porcine-human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research.

'It's like being in a tunnel': Understanding the patient journey from tooth loss to life with removable dentures.

INTRODUCTION: The aim of this study was to conceptualise the key stages of the patient journey in the provision of a new denture and examine the factors leading to successful patient-related outcomes. METHODS: Two partially dentate patient samples were included: (i) Denture wearers - patients who had a denture fitted within the previous five years and (ii) New dentures - patients receiving treatment for a new or replacement denture. The methods involved direct targeted participant observations of the denture fitting process, debriefing interviews and a follow-up focus group exploring the patient journey. Data were analysed through the use of phenomenology and grounded theory. RESULTS: Interviews were completed with twenty participants of the denture-wearing sample (11 males and nine females, age range 22 to 86 years). Thirteen participants were included in the treatment journey sample in two primary care settings (six males and seven females, age range 55 to 101 years). Tooth loss and recovery was described as being in an 'emotional tunnel' resulting from 'bodyphonic processes' associated with tooth loss. 'Bodyphonia' subsequently became the context for 'taking control' and 'managing disclosure' when living with a removable denture. Different courses through this process can be readily observed, moderated by different variables (i.e., previous experience, working knowledge, a good fit, the treatment alliance, negotiated compromises and bounded responsibility). CONCLUSIONS: An'integrating framework' that seeks to describe the patient journey from the experience of tooth loss to recovery with a denture is proposed. This framework could be used to aid development of a clinical pathway to guide treatment options. CLINICAL SIGNIFICANCE: This paper conceptualises the patient journey. It stresses the importance of understanding the stages patients go through and highlights that for the dental team, the try-in stage is perhaps the best stage to give information about the denture and plans for continued care.

Monitoring of species' genetic diversity in Europe varies greatly and overlooks potential climate change impacts.

Genetic monitoring of populations currently attracts interest in the context of the Convention on Biological Diversity but needs long-term planning and investments. However, genetic diversity has been largely neglected in biodiversity monitoring, and when addressed, it is treated separately, detached from other conservation issues, such as habitat alteration due to climate change. We report an accounting of efforts to monitor population genetic diversity in Europe (genetic monitoring effort, GME), the evaluation of which can help guide future capacity building and collaboration towards areas most in need of expanded monitoring. Overlaying GME with areas where the ranges of selected species of conservation interest approach current and future climate niche limits helps identify whether GME coincides with anticipated climate change effects on biodiversity. Our analysis suggests that country area, financial resources and conservation policy influence GME, high values of which only partially match species' joint patterns of limits to suitable climatic conditions. Populations at trailing climatic niche margins probably hold genetic diversity that is important for adaptation to changing climate. Our results illuminate the need in Europe for expanded investment in genetic monitoring across climate gradients occupied by focal species, a need arguably greatest in southeastern European countries. This need could be met in part by expanding the European Union's Birds and Habitats Directives to fully address the conservation and monitoring of genetic diversity.

Manufacturing and Functional Characterization of Bioengineered Liver Grafts for Extracorporeal Liver Assistance in Acute Liver Failure.

Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs). Decellularized scaffolds seeded entirely with human cells were shown to adhere to stringent sterility and safety guidelines and demonstrated increased functionality when compared to grafts seeded with primary porcine liver cells (PPLCs). BELs with PHLCs were able to clear more ammonia than PPLCs and demonstrated lower perfusion pressures during patency testing. Additionally, to determine the full therapeutic potential of BELs seeded with PHLCs, longer culture periods were assessed to address the logistical constraints associated with manufacturing and transporting a product to a patient. The fully humanized BELs were able to retain their function after cold storage simulating a product transport period. Therefore, this study demonstrates the manufacture of bioengineered liver grafts and their potential in the clinical setting as a treatment for ALF.

The belief that masculinity has a negative influence on one's behavior is related to reduced mental well-being.

Objectives: Masculinity is sometimes presumed to be a cause of mental health problems and antisocial behavior in men. This study sought to identify the predictors of men's mental well-being, including their attitudes to masculinity. Methods: 4,025 men from the UK and Germany (GDR) were asked about their core values, which areas of their life they felt were important, and their opinions about masculinity., Their mental well-being was measured using the Positive Mindset Index (PMI). Multiple linear regression assessed the degree to which their answers were linked to their mental well-being. Results: The results in both countries were similar. The main predictors of higher PMI scores were Personal Growth Satisfaction (UK ß = 0.211; t = 6.146; P < 0.0000005; GDR ß = 0.160; t = 5.023; P < 0.000001), Age (being older) (UK ß = 0.150; t = 4.725; P < 0.00001; GDR ß =0.125; t = 4.075; P < 0.00005), not taking a Negative view of Masculinity (UK ß = 0.101; t = -3.458; P < 0.001; GDR ß = -0.118; t = -4.014; P < 0.0001), and Health Satisfaction (UK ß = 0.124; t = 3.785; P < 0.0001; GDR ß = 0.118; t = 3.897; P < 0.0001). In addition, in the UK, Education Satisfaction was the fourth strongest predictor of PMI (ß = 0.105; t = 3.578; P < 0.0005), and in Germany, Having a Positive View of Masculinity was the fifth strongest predictor of PMI (ß = 0.097; t = 3.647; P < 0.0005). Conclusions: These findings are discussed in relation to whether the negative view of masculinity often cited in the media and elsewhere is having a negative impact on men's mental health.

Transfusion-related cost comparison of trauma patients receiving whole blood versus component therapy.

INTRODUCTION: With the emergence of whole blood (WB) in trauma resuscitation, cost-related comparisons are of significant importance to providers, blood banks, and hospital systems throughout the country. The objective of this study was to determine if there is a transfusion-related cost difference between trauma patients who received low titer O+ whole blood (LTO+WB) and component therapy (CT). METHODS: A retrospective review of adult and pediatric trauma patients who received either LTO+WB or CT from time of injury to within 4 hours of arrival was performed. Annual mean cost per unit of blood product was obtained from the regional blood bank supplier. Pediatric and adult patients were analyzed separately and were compared on a cost per patient (cost/patient) and cost per patient per milliliter (cost/patient/mL) basis. Subgroup analysis was performed on severely injured adult patients (Injury Severity Score, >15) and patients who underwent massive transfusion. RESULTS: Prehospital LTO+WB transfusion began at this institution in January 2018. After the initiation of the WB transfusion, the mean annual cost decreased 17.3% for all blood products, and the average net difference in cost related to component blood products and LTO+WB was more than $927,000. In adults, LTO+WB was associated with a significantly lower cost/patient and cost/patient/mL compared with CT at 4 hours ( p < 0.001), at 24 hours ( p < 0.001), and overall ( p < 0.001). In the severely injured subgroup (Injury Severity Score, >15), WB was associated with a lower cost/patient and cost/patient/mL at 4 hours ( p < 0.001), 24 hours ( p < 0.001), and overall ( p < 0.001), with no difference in the prehospital setting. Similar findings were true in patients meeting massive transfusion criteria, although differences in injury severity may account for this finding. CONCLUSION: With increased use of LTO+WB for resuscitation, cost comparison is of significant importance to all stakeholders. Low titer O+ WB was associated with reduced cost in severely injured patients. Ongoing analyses may improve resource utilization and benefit overall healthcare cost. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Mood and Anxiety Disorders and Suicidality in Patients With Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity.

BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models.

This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1(Fig. 1).

Use of whole blood deployment programs for mass casualty incidents: South Texas experience in regional response and preparedness.

INTRODUCTION: Firearm-related deaths have become the leading cause of death in adolescents and children. Since the Sutherland Springs, TX mass casualty incident (MCI), the Southwest Texas Regional Advisory Council for trauma instituted a prehospital whole blood (WB) program and blood deployment program for MCIs. METHODS: The program was adopted statewide by the Texas Emergency Medical Task Force, of which Southwest Texas Regional Advisory Council is the lead for Emergency Medical Task Force 8. The recent active shooter MCI in Uvalde, TX was the first time the MCI blood deployment program had been used. To our knowledge, no other similar programs exist in this or any other country. RESULTS: On May 24, 2022, 19 children and 2 adults were killed at an MCI in Uvalde, TX. The MCI WB deployment protocol was initiated, and South Texas Blood and Tissue Center prepared 15 U of low-titer O-positive whole blood and 10 U of leukoreduced O packed cells. The deployed blood arrived at Uvalde Memorial Hospital within 67 minutes. One of the pediatric patients sustained multiple gunshots to the chest and extremities. The child was hypotensive and received 2 U of leukoreduced O packed cells, one at the initial hospital and another during transport. On arrival, the patient required 2 U of low-titer O-positive whole blood and underwent a successful hemorrhage control operation. The remaining blood was returned to South Texas Blood and Tissue Center for distribution. CONCLUSION: Multiple studies have shown the association of early blood product resuscitation and improved mortality, with WB being the ideal resuscitative product for many. The ongoing efforts in South Texas serve as a model for development of similar programs throughout the country to reduce preventable deaths. This event represents the first ever successful deployment of WB to the site of an MCI related to a school shooting in the modern era. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level V.

Botulinum toxin promotes orofacial antinociception by modulating TRPV1 and NMDA receptors in adult zebrafish.

The aim of the study was to evaluate the possible involvement of transient receptor potential (TRP) channels, Acid-sensing ion channels (ASIC) and N-Methyl-D-aspartate receptor (NMDAR) in the orofacial antinociceptive behaviour effect of botulinum toxin type A (BoNT/A) in adult zebrafish. Initially, the open field test was performed to evaluate the effect of BoNT/A on the locomotor activity of zebrafish. Subsequently, the animals were pretreated with BoNT/A (0.05U, 0.1U or 0.5U/masseter) and acute orofacial nociception was induced by cinnamaldehyde, capsaicin, menthol, acid saline or glutamate applied to the lip or masseter muscle. In another group of experiments, animals were pre-treated with capsazepine (TRPV1 antagonist) or ketamine (NMDAR antagonist) to investigate the mechanism of antinociception. The possible involvement of central C-fibre afferents was also investigated using capsaicin desensitized animals. A molecular docking study was performed to observe the in silico interaction of BoNT/A with TRPV1 and NMDA channels. Pretreatment with BoNT/A reduced the nociceptive behaviour induced by capsaicin and glutamate. Antinociception was effectively inhibited by capsazepine and ketamine, as well as by capsaicin-induced desensitization. Consistent with these in vivo findings, the molecular docking study indicated that BoNT/A can interact with TRPV1 and NMDAR. The results indicate the involvement of TRP and NMDAR mechanisms in the orofacial antinociceptive behaviour effect of BoNT/A. The results also confirm the pharmacological relevance of BoNT/A as an inhibitor of orofacial nociception behaviour.

Mapping emergent public engagement in societal transitions: a scoping review.

BACKGROUND: Transition discourses are gaining prominence in efforts to imagine a future that adequately addresses the urgent need to establish low carbon and climate resilient pathways. Within these discourses the 'public' is seen as central to the creation and implementation of appropriate interventions. The role of public engagement in societal transformation while essential, is also complex and often poorly understood. The purpose of this paper is to enhance our understanding regarding public engagement and to address the often superficial and shallow policy discourse on this topic. MAIN TEXT: The paper offers a review of evolving literature to map emergent public engagement in processes of transition and change. We adopt a pragmatic approach towards literature retrieval and analysis which enables a cross-disciplinary and cross-sectoral review. We use a scoping review process and the three spheres of transformation framework (designated as the practical, political and personal spheres) to explore trends within this complex research field. The review draws from literature from the last two decades in the Irish context and looks at emergence and evolving spaces of public engagement within various systems of change including energy, food, coastal management and flood adaptation, among others. CONCLUSIONS: The results highlight the siloed and fragmented way in which public engagement in transitions is carried and we propose a more cross-sectoral and cross-disciplinary approach which depends on bringing into dialogue often contrasting theories and perspectives. The paper also illustrates some shifting engagement approaches. For instance, nexus articles between the practical and political spheres suggest deeper forms of public engagement beyond aggregated consumer behaviour to align technological delivery with institutional and societal contexts. While most articles in the practical sphere draw largely on techno-economic insights this influence and cross-disciplinarity is likely to draw in further innovations. Nexus articles between the political and personal sphere are also drawing on shifting ideas of public engagement and largely stress the need to disrupt reductive notions of engagement and agency within our institutions. Many of these articles call attention to problems with top-down public engagement structures and in various ways show how they often undermine and marginalise different groups.

GroundsWell: Community-engaged and data-informed systems transformation of Urban Green and Blue Space for population health - a new initiative.

Natural environments, such as parks, woodlands and lakes, have positive impacts on health and wellbeing. Urban Green and Blue Spaces (UGBS), and the activities that take place in them, can significantly influence the health outcomes of all communities, and reduce health inequalities. Improving access and quality of UGBS needs understanding of the range of systems (e.g. planning, transport, environment, community) in which UGBS are located. UGBS offers an ideal exemplar for testing systems innovations as it reflects place-based and whole society processes , with potential to reduce non-communicable disease (NCD) risk and associated social inequalities in health. UGBS can impact multiple behavioural and environmental aetiological pathways. However, the systems which desire, design, develop, and deliver UGBS are fragmented and siloed, with ineffective mechanisms for data generation, knowledge exchange and mobilisation. Further, UGBS need to be co-designed with and by those whose health could benefit most from them, so they are appropriate, accessible, valued and used well. This paper describes a major new prevention research programme and partnership, GroundsWell, which aims to transform UGBS-related systems by improving how we plan, design, evaluate and manage UGBS so that it benefits all communities, especially those who are in poorest health. We use a broad definition of health to include physical, mental, social wellbeing and quality of life. Our objectives are to transform systems so that UGBS are planned, developed, implemented, maintained and evaluated with our communities and data systems to enhance health and reduce inequalities. GroundsWell will use interdisciplinary, problem-solving approaches to accelerate and optimise community collaborations among citizens, users, implementers, policymakers and researchers to impact research, policy, practice and active citizenship. GroundsWell will be shaped and developed in three pioneer cities (Belfast, Edinburgh, Liverpool) and their regional contexts, with embedded translational mechanisms to ensure that outputs and impact have UK-wide and international application.

The Postnatal Growth and Retinopathy of Prematurity Model: A Multi-institutional Validation Study.

PURPOSE: The G-ROP model was proposed to improve the retinopathy of prematurity (ROP) screening efficiency. It is based on gestational age, birth weight and postnatal weight gain. The current study aimed to validate the G-ROP model's ability to predict ROP in cohorts of premature infants from Egypt and the United Kingdom (UK). METHODS: We retrospectively reviewed the records of preterm infants born between 1st of January and 30th of June 2018 with a known outcome for ROP screening and regular weight measurements until day 39 after birth. We applied the G-ROP model to the study group and calculated the sensitivity of the model for detecting Early Treatment of ROP (ETROP) study type 1 ROP and for any ROP and calculated the reduction of the number of infants requiring ROP screening by the model application. RESULTS: We applied the G-ROP model on 605 infants (504 from Egypt and 101 from the UK). The model successfully predicted all type 1 ROP cases (100% sensitivity) in both cohorts (95% confidence interval [CI], 91.1-100% in the Egyptian cohort and 65.5-100% in the UK cohort). The model reduced the number of infants requiring screening by 14.1% in the Egyptian cohort and 21.8% in the UK cohort. CONCLUSIONS: The G-ROP model was successfully validated for detecting type 1 ROP and in both cohorts from Egypt and the UK.