The Development of Principles for Patient and Public Involvement (PPI) in Preclinical Spinal Cord Research: A Modified Delphi Study.

INTRODUCTION: There is currently limited guidance for researchers on Patient and Public Involvement (PPI) for preclinical spinal cord research, leading to uncertainty about design and implementation. This study aimed to develop evidence-informed principles to support preclinical spinal cord researchers to incorporate PPI into their research. METHODS: This study used a modified Delphi method with the aim of establishing consensus on a set of principles for PPI in spinal cord research. Thirty-eight stakeholders including researchers, clinicians and people living with spinal cord injury took part in the expert panel. Participants were asked to rate their agreement with a series of statements relating to PPI in preclinical spinal cord research over two rounds. As part of Round 2, they were also asked to rate statements as essential or desirable. RESULTS: Thirty-eight statements were included in Round 1, after which five statements were amended and two additional statements were added. After Round 2, consensus (> 75% agreement) was reached for a total of 27 principles, with 13 rated as essential and 14 rated as desirable. The principles with highest agreement related to diversity in representation among PPI contributors, clarity of the purpose of PPI and effective communication. CONCLUSION: This research developed a previously unavailable set of evidence-informed principles to inform PPI in preclinical spinal cord research. These principles provide guidance for researchers seeking to conduct PPI in preclinical spinal cord research and may also inform PPI in other preclinical disciplines. PATIENT AND PUBLIC INVOLVEMENT STATEMENT: This study was conducted as part of a project aiming to develop PPI in preclinical spinal cord injury research associated with an ongoing research collaboration funded by the Irish Rugby Football Union Charitable Trust (IRFU CT) and the Science Foundation Ireland Centre for Advanced Materials and BioEngineering Research (SFI AMBER), with research conducted by the Tissue Engineering Research Group (TERG) at the RCSI University of Medicine and Health Sciences. The project aims to develop an advanced biomaterials platform for spinal cord repair and includes a PPI Advisory Panel comprising researchers, clinicians and seriously injured rugby players to oversee the work of the project. PPI is included in this study through the involvement of members of the PPI Advisory Panel in the conceptualisation of this research, review of findings, identification of key points for discussion and preparation of the study manuscript as co-authors.

A Retrospective Database Analysis to Investigate if Electrolytes in Venous Blood are Equivalent to the Levels in Arterial Blood.

Background: In a critically ill patient, when an arterial blood sample is processed on an arterial blood gas (ABG) analyzer, it also measures electrolytes apart from analyzing the blood gases. The turnaround time for ABG analysis is way too less compared to the conventional electrolyte analysis with a serum sample. Objective: This study intends to investigate whether values of electrolytes estimated in arterial blood can substitute the routinely practiced method. Materials and methods: This is a retrospective cross-sectional study. The source of data is patients' reports of serum electrolytes and ABG analysis from the Clinical Biochemistry laboratory, CIMS Teaching Hospital, Chamarajanagar between January and June 2021. The electrolytes report of 200 patients from whom both arterial and venous blood samples were sent to the Clinical Biochemistry laboratory on the same day and at the same time for analysis were selected. The data was compiled, compared, and correlated using a suitable statistical tool. Results: The mean and standard deviation of sodium (135.62 ± 5.20 in venous vs 134.08 ± 8.49 in arterial blood), potassium (4.20 ± 0.64 vs 3.80 ± 0.75), and chloride (102.28 ± 4.99 vs 96.33 ± 8.11) were observed. However, when the concordance correlation coefficient and Bland-Altman plot analysis were made there was no agreement between electrolytes analyzed on serum in an autoanalyzer with that of ABG analyzer. Conclusion: We conclude that the electrolytes measured by a conventional autoanalyzer on a serum sample cannot be replaced by values analyzed on a blood gas analyzer. How to cite this article: Devaki RN, Kasargod P, Roopa Urs AN, Chandrika N. A Retrospective Database Analysis to Investigate if Electrolytes in Venous Blood are Equivalent to the Levels in Arterial Blood. Indian J Crit Care Med 2024;28(5):442-446.

ABG Analyzer for Electrolyte Measurement in ICU Patients: To Do or Not to Do.

How to cite this article: Tyagi N. ABG Analyzer for Electrolyte Measurement in ICU Patients: To Do or Not to Do. Indian J Crit Care Med 2024;28(5):416-418.

Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models.

The development of targeted cancer therapies based on monoclonal antibodies against tumor-associated antigens has progressed markedly over recent decades. This approach is dependent on the identification of tumor-specific, normal tissue-sparing antigenic targets. The transmembrane protein claudin-18 splice variant 2 (CLDN18.2) is frequently and preferentially displayed on the surface of primary gastric adenocarcinomas, making it a promising monoclonal antibody target. Phase 3 studies of zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody targeting CLDN18.2, combined with 5-fluorouracil/leucovorin plus oxaliplatin (modified FOLFOX6) or capecitabine plus oxaliplatin (CAPOX) in advanced or metastatic first-line gastric or gastroesophageal junction (G/GEJ) adenocarcinoma have demonstrated favorable clinical results with zolbetuximab. In studies using xenograft or syngeneic models with gastric cancer cell lines, zolbetuximab mediated death of CLDN18.2-positive human cancer cell lines via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro and demonstrated anti-tumor efficacy as monotherapy and combined with chemotherapy in vivo. Mice treated with zolbetuximab plus chemotherapy displayed a significantly higher frequency of tumor-infiltrating CD8+ T cells versus vehicle/isotype control-treated mice. Furthermore, zolbetuximab combined with an anti-mouse programmed cell death-1 antibody more potently inhibited tumor growth compared with either agent alone. These results support the potential of zolbetuximab as a novel treatment option for G/GEJ adenocarcinoma.

Experimental laboratory models as tools for understanding modifiable dementia risk.

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research.

BACKGROUND: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. METHODS: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. DISCUSSION: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.

Engaging patients as partners or collaborators in clinical research is becoming more common, but it is still new in preclinical research. Preclinical researchers work in laboratories on cell and animal experiments. They traditionally don't have frequent interactions with patients compared to their clinical research colleagues. Integrating patient engagement in preclinical laboratory research may help ensure that patient perspectives and values are considered. To help preclinical laboratory research align with patient-centred priorities we propose the development of a practical framework. This framework will facilitate patient engagement in preclinical laboratory research. To achieve this, we will first hold in-depth discussions with patient partners, researchers, and other collaborators to understand views on patient engagement in preclinical laboratory research. Together, we will identify key considerations to draft a framework, including motivations for patient engagement in preclinical laboratory research, and defining the roles of those who need to be involved. We will refine the framework through an international survey where we will collect feedback from researchers, patient partners, and other collaborators to make further improvements. The framework will then be tested and refined by preclinical laboratory teams inclusive of patient partners. The finalized framework and other resources to facilitate patient engagement in preclinical laboratory research will be hosted in a 'one-stop-shop' of online resources. Ultimately, this framework will enable partnerships between patients and researchers and provide a roadmap for patient engagement in preclinical laboratory research. This presents an exciting new opportunity for patients and researchers to collaborate and potentially improve translation of laboratory-based research.

Fibrotic progression from acute cellular rejection is dependent on secondary lymphoid organs in a mouse model of chronic lung allograft dysfunction.

Chronic lung allograft dysfunction (CLAD) remains one of the major limitations to long-term survival after lung transplantation. We modified a murine model of CLAD and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 which, by day 30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis, reminiscent of changes observed in restrictive allograft syndrome. Lung transplantation into splenectomized B6 alymphoplastic (aly/aly) or splenectomized B6 lymphotoxin-ß receptor-deficient mice demonstrated that recipient secondary lymphoid organs, such as spleen and lymph nodes, are necessary for progression from acute cellular rejection to allograft fibrosis in this model. Our work uncovered a critical role for recipient secondary lymphoid organs in the development of CLAD after pulmonary transplantation and may provide mechanistic insights into the pathogenesis of this complication.

E-learning and research experience exchange in the online setting of student peer mentor network during COVID-19 pandemic and beyond: A laboratory case study.

For close to 2 years, we have witnessed the impacts of the SARS-CoV-2 pandemic on research at several different levels. Among the list, limited access to laboratory-based training for undergraduate students prevented this cohort from gaining exposure to the realities of a research laboratory at a critical time in training when they may have found motivation in this area as a career. COVID exposed a weakness in our training pipeline; an extreme dependency on face-to-face training that threatened to create a void in the research talent needed to replenish the scientific community every year. In the classroom, we witnessed a revolution of e-learning based approaches that could be rapidly implemented based on existing footprints. Out of necessity, our laboratory developed and implemented an e-learning model of an undergraduate peer mentor network that provides a knowledge and experience exchange platform between students with different levels of research experience. Implementation of the platform was to aid students with gaining knowledge in multiple aspects of scientific research and hands-on work in a research laboratory. The collaboration between the students of the network was aimed at not only advancing the theoretical and practical research experience, but also at developing feedback implementation and practicing "soft skills" critical for teamwork and leadership. Herein, we present an overview of the model along with survey responses of the students participating in the peer mentor network. We have found that peer delivery of practical benchwork both via scientific presentations and visualized experiments, reduced the time of training and the amount of staff assistance needed when students returned to the bench. Furthermore, this model accelerated student independence in laboratory work and increased research interest overall. In summary, the model of a peer mentor network has the potential to serve as a training platform and as a customized tool, supplementing research laboratory training at the undergraduate level beyond the pandemic.

Comparative Evaluation of Nano Inorganic Metal Oxides as Intracanal Medicaments for Cytotoxicity and Antimicrobial Activity in the Root Canal System.

Aim and objective: To evaluate and compare the cytotoxicity and antimicrobial activity of various inorganic metal oxide nanoparticles along with vehicles when used as intracanal medicaments in the root canal system. Materials and methods: The study included triplicates (n = 36 times) that were subjected to n calcium oxide (CaO), n zinc oxide (ZnO), n magnesium oxide (MgO), and metapaste as intracanal medicaments. The efficacy of novel intracanal medicaments was evaluated for biocompatibility assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reagent following antimicrobial efficacy against Enterococcus faecalis (E. faecalis) was evaluated using zone of inhibition (ZOI) and minimum inhibitory concentration (MIC). The statistical analysis Kruskal-Wallis test, student t-test, and analysis of variance (ANOVA) using Statistical Package for the Social Sciences (SPSS) software (v.20.0). Results: The order of proliferative activity of experimental groups on L929 mouse fibroblast cells using MTT assay was: metapaste > nCaO > nMgO > nZnO). After evaluation of antimicrobial efficacy, group I: nCaO showed maximum ZOI and MIC against E. faecalis, which showed high statistically significant differences between all four groups after ANOVA (p < 0.0001*). Conclusion: n calcium oxide (CaO) mixed with propylene glycol (PPG) 400 has a potential role as an intracanal medicament with minimum cytotoxic effect and maximum antimicrobial activity against endodontic pathogens. Clinical significance: Nanoparticles-based intracanal medicament can provide a promising future in reducing endodontic flareups when used as intracanal medicament. How to cite this article: Barge P, Gugawad S, Devendrappa SN, et al. Comparative Evaluation of Nano Inorganic Metal Oxides as Intracanal Medicaments for Cytotoxicity and Antimicrobial Activity in the Root Canal System. Int J Clin Pediatr Dent 2023;16(S-2):S168-S175.

In vitro laboratory infection research in orthopaedics: Why, when, and how.

The musculoskeletal system involves multiple tissues which are constantly exposed to being exposed to various biological and mechanical stimuli. As such, isolating and studying a particular system from a complex human clinical environment is not always a realistic expectation. On top of that, recruitment limitations, in addition to the nature of orthopaedic interventions and their associated cost, sometimes preclude consideration of human trials to answer a clinical question. Therefore, in this mini review, we sought to rationalize the rapid evolution of biomedical research at a basic scientific level and explain why the perception of orthopaedic conditions has fundamentally changed over the last decades. In more detail, we highlight that the number of orthopaedic in vitro publications has soared since 1990. Last but not least, we elaborated on the minimum requirements for conducting a scientifically sound infection-related laboratory experiment to offer valuable information to clinical practitioners. We also explained the rationale behind implementing molecular biology techniques, ex vivo experiments, and artificial intelligence in this type of laboratory research.

Future developments in sociology in the age of the metaverse.

The intent of this article is to shed light on the future challenges that sociology, in concert with other disciplines, will have to face from now on, starting with one of the possible hypotheses of research methodology. Indeed, as much as some of these issues in the last two decades have become the preserve of neuroscience, their origins, namely the conceptualizations of the classics of sociology, should not be forgotten. In this regard, it will be the task of researchers and sociology to investigate, through applied research attempts, phenomena such as empathy and emotions from innovative methodologies and research different from the current ones, capable of highlighting how emotions are modified by cultural context and spaces of interaction, moving away from a depersonalizing structuralism we were used to, refuting, for example, what neuroscientists have pointed out, according to which empathy and emotions belong to biological universalisms. Therefore, within this brief and informative article we intend to present a possibility of investigation, without any claim to truth or the only way to be able to do research in this field, moved only by the desire to open a fruitful discourse that can lead to the methodological approach toward applied sociology or laboratory research. The idea is to move beyond online netnography, not because the latter cannot provide satisfactory results, but because it will be necessary to broaden the range of choices, such as analysis in the metaverse, generating a viable alternative where this type of analysis cannot be pursued.

Effectiveness of Two Intensity Levels of Diode Laser in Debonding Metallic Brackets Regarding Enamel Surface Integrity and Pulpal Temperature: An Ex-Vivo Study.

INTRODUCTION: The traditional methods of deboning metal brackets exert excessive force, resulting in enamel scratches, fractures, and patient discomfort. The objective of this study was to evaluate the effectiveness of using two intensity levels of a diode laser for debonding metallic orthodontic brackets as an alternative to the conventional debonding method. MATERIALS AND METHODS: Sixty intact, extracted human premolar teeth were used in this study, and metal orthodontic brackets were bonded to the buccal surface of these teeth. The teeth were divided into three groups for the experiment: (1) the control group, where conventional bracket debonding was performed using a debonding plier, (2) the first experimental group, where a diode laser (2.5W, 980nm) was utilized for laser debonding, and (3) the second experimental group, where a diode laser (5W, 980nm) was used for laser debonding. The laser was applied using a sweeping movement for 5 seconds. After debonding, the adhesive remnant index (ARI), the lengths, and the frequency of enamel cracks were compared among the groups. Additionally, an increase in intra-pulpal temperature was measured. RESULTS: In all groups, there were no instances of enamel fractures. Laser debonding resulted in a significant reduction in both the frequency and length of newly formed enamel cracks compared to the conventional debonding method. The laser debonding group exhibited increases in intra-pulpal temperature of 2.37°C and 3.60°C in the second and third groups, respectively. These temperature increases were significantly lower than the threshold of 5.5°C. There were no significant differences observed in the ARI scores among the groups. CONCLUSION: With all debonding methods, an increase in the length and frequency of enamel cracks should be anticipated. However, laser-assisted debonding of metal brackets offers the advantage of reducing the risk of enamel damage while avoiding thermal damage to the pulp.

Endothelial phosphoinositide 3-kinase-ß inactivation confers protection from immune-mediated vascular injury.

Heart transplant and recipient survival are limited by immune cell-mediated injury of the graft vasculature. We examined the role of the phosphoinositide 3-kinase-ß (PI3Kß) isoform in endothelial cells (EC) during coronary vascular immune injury and repair in mice. In minor histocompatibility-antigen mismatched allogeneic heart grafts, a robust immune response was mounted to each wild-type, PI3Kß inhibitor-treated, or endothelial-selective PI3Kß knockout (ECßKO) graft transplanted to wild-type recipients. However, microvascular EC loss and progressive occlusive vasculopathy only developed in control, but not PI3Kß-inactivated hearts. We observed a delay in inflammatory cell infiltration of the ECßKO grafts, particularly in the coronary arteries. Surprisingly, this was accompanied by an impaired display of proinflammatory chemokine and adhesion molecules by the ECßKO ECs. In vitro, tumor necrosis factor α-stimulated endothelial ICAM1 and VCAM1 expression was blocked by PI3Kß inhibition or RNA interference. Selective PI3Kß inhibition also blocked tumor necrosis factor α-stimulated degradation of inhibitor of nuclear factor kappa Bα and nuclear translocation of nuclear factor kappa B p65 in EC. These data identify PI3Kß as a therapeutic target to reduce vascular inflammation and injury.

Normalization of lipid oxidation defects arising from hypoxia early posthepatectomy prevents liver failure in mouse.

Surgical liver failure (SLF) develops when a marginal amount of hepatic mass is left after surgery, such as following excessive resection. SLF is the commonest cause of death due to liver surgery; however, its etiology remains obscure. Using mouse models of standard hepatectomy (sHx) (68%, resulting in full regeneration) or extended hepatectomy (eHx) (86%/91%, causing SLF), we explored the causes of early SLF related to portal hyperafflux. Assessing the levels of HIF2A with or without oxygenating agent inositol trispyrophosphate (ITPP) indicated hypoxia early after eHx. Subsequently, lipid oxidation (PPARA/PGC1α) was downregulated and associated with persisting steatosis. Mild oxidation with low-dose ITPP reduced the levels of HIF2A, restored downstream PPARA/PGC1α expression along with lipid oxidation activities (LOAs), and normalized steatosis and other metabolic or regenerative SLF deficiencies. Promotion of LOA with L-carnitine likewise normalized the SLF phenotype, and both ITPP and L-carnitine markedly raised survival in lethal SLF. In patients who underwent hepatectomy, pronounced increases in serum carnitine levels (reflecting LOA) were associated with better recovery. Lipid oxidation thus provides a link between the hyperafflux of O2-poor portal blood, the metabolic/regenerative deficits, and the increased mortality typifying SLF. Stimulation of lipid oxidation-the prime regenerative energy source-particularly through L-carnitine may offer a safe and feasible way to reduce SLF risks in the clinic.

Oral administration of the commensal Alistipes onderdonkii prolongs allograft survival.

Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously correlated longer survival of minor mismatched skin grafts in mice with the presence of an intestinal commensal bacterium, Alistipes onderdonkii. In this study, we investigated its sufficiency and mechanism of action. Oral administration of A onderdonkii strain DSM19147 but not DSM108265 was sufficient to prolong minor mismatched skin graft survival through inhibition of tumor necrosis factor production. Through metabolomic and metagenomic comparisons between DSM19147 and DSM108265, we identified candidate gene products associated with the anti-inflammatory effect of DSM19147. A onderdonkii DSM19147 can lower inflammation both at a steady state and after transplantation and may serve as an anti-inflammatory probiotic beneficial for transplant recipients.

Renin-angiotensin-aldosterone system function in the pig-to-baboon kidney xenotransplantation model.

After pig-to-baboon kidney transplantation, episodes of hypovolemia and hypotension from an unexplained mechanism have been reported. This study evaluated the renin-angiotensin-aldosterone system post-kidney xenotransplantation. Kidneys from genetically-engineered pigs were transplanted into 5 immunosuppressed baboons after the excision of the native kidneys. Immunosuppressive therapy was based on the blockade of the CD40/CD154 costimulation pathway. Plasma renin, angiotensinogen (AGT), angiotensin II (Ang II), aldosterone levels, and urine osmolality and electrolytes were measured in healthy pigs, healthy nonimmunosuppressed baboons, and immunosuppressed baboons with life-supporting pig kidney grafts. After pig kidney transplantation, plasma renin and Ang II levels were not significantly different, although Ang II trended lower, even though plasma AGT and potassium were increased. Plasma aldosterone levels were unchanged. Urine osmolality and sodium concentration were decreased. Even in the presence of increasing AGT and potassium levels, lower plasma Ang II concentrations may be because of reduced, albeit not absent, the reactivity of pig renin to cleave baboon AGT, suggesting an impaired response of the renin-angiotensin-aldosterone system to hypovolemic and hypotensive episodes. The maintenance of aldosterone may be protective. The reduced urine osmolality and sodium concentration reflect the decreased ability of the pig kidney to concentrate urine. These considerations should not prohibit successful clinical pig kidney xenotransplantation.

TIGIT agonism alleviates costimulation blockade-resistant rejection in a regulatory T cell-dependent manner.

Belatacept-based immunosuppression in kidney transplantation confers fewer off-target toxicities than calcineurin inhibitors but comes at a cost of increased incidence and severity of acute rejection, potentially due to its deleterious effect on both the number and function of Foxp3+ regulatory T cells (Tregs). TIGIT is a CD28 family coinhibitory receptor expressed on several subsets of immune cells including Tregs. We hypothesized that coinhibition through TIGIT signaling could function to ameliorate costimulation blockade-resistant rejection. The results demonstrate that treatment with an agonistic anti-TIGIT antibody, when combined with costimulation blockade by CTLA-4Ig, can prolong allograft survival in a murine skin graft model compared with CTLA-4Ig alone. Further, this prolongation of graft survival is accompanied by an increase in the frequency and number of graft-infiltrating Tregs and a concomitant reduction in the number of CD8+ T cells in the graft. Through the use of Treg-specific TIGIT conditional knockout animals, we demonstrated that the TIGIT-mediated reduction in the graft-infiltrating CD8+ T cell response is dependent on signaling of TIGIT on Foxp3+ Tregs. Our results highlight both the key functional role of TIGIT on Foxp3+ Tregs under conditions in which CTLA-4 is blocked and the therapeutic potential of TIGIT agonism to optimize costimulation blockade-based immunosuppression.

miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages.

Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR development. MicroRNAs play vital roles in disease regulation; however, their effects on macrophages and AR remain unclear. In this study, rat models of AR were established following LT, and macrophages and peripheral blood mononuclear cells were isolated from rats and humans, respectively. We found miR-449a expression to be significantly reduced in macrophages and peripheral blood mononuclear cells. Overexpression of miR-449a not only inhibited the M1-polarization of macrophages in vitro but also improved the AR of transplant in vivo. The mechanism involved inhibiting the noncanonical nuclear factor-kappaB (NF-κB) pathway. We identified procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 (PLOD1) as a target gene of miR-449a, which could reverse miR-449a's inhibition of macrophage M1-polarization, amelioration of AR, and inhibition of the NF-κB pathway. Overall, miR-449a inhibited the NF-κB pathway in macrophages through PLOD1 and also inhibited the M1-polarization of macrophages, thus attenuating AR after LT. In conclusion, miR-449a and PLOD1 may be new targets for the prevention and mitigation of AR.

Honoring the gift: The transformative potential of transplant-declined human organs.

For decades, transplantation has been a life-saving treatment for those fortunate enough to gain access. Nevertheless, many patients die waiting for an organ and countless more never make it onto the waitlist because of a shortage of donor organs. Concurrently, thousands of donated organs are declined for transplant each year because of concerns about poor outcomes post-transplant. The decline of any donated organ-even if medically justified-is tragic for both the donor family and potential recipients. In this Personal Viewpoint, we discuss the need for a new mindset in how we honor the gift of organ donation. We believe that the use of transplant-declined human organs in translational research has the potential to hasten breakthrough discoveries in a multitude of scientific and medical areas. More importantly, such breakthroughs will allow us to properly value every donated organ. We further discuss the many practical challenges that such research presents and offer some possible solutions based on experiences in our own research laboratories. Finally, we share our perspective on what we believe are the necessary next steps to ensure a future where every donated organ realizes its full potential to impact the lives of current and future patients.

Effective negative pressure wound therapy for open wounds: The importance of consistent pressure delivery.

Two distinct design concepts exist for single-use negative pressure wound therapy systems: Canister-based versus canisterless. The canister-based technology provides intrinsic stable delivery of the intended negative pressure, because exudate is constantly transferred from the wound into a canister, thereby preventing dressing saturation. In contrast, with a canisterless system, where delivery of the negative pressure depends on continuous evaporation of wound fluids from its dressing, loss of the intended wound-bed pressure may occur due to dressing saturation. To investigate whether these two designs differ in their mechanobiological effect with respect to magnitudes and distributions of tissue strain fields under the absorptive dressing, termed the influence zone, we integrated computational modelling with an animal study. This influence zone must be of biologically influential strain levels and extend sufficiently into the peri-wound for stimulating fibroblasts to migrate and progress the healing. We found that an effective influence zone requires continuous delivery of the intended pressure to the wound-bed. Loss of negative pressure at the wound-bed below 40 mmHg adversely lowered the peri-wound stimulation around a 120 × 70 mm sized wound to less than one-third of the baseline stimulation, and further pressure decreases to 20 mmHg or lower resulted in complete lack of peri-wound mechano-stimulation.