Terminal Organ Research Articles

Toxicity study of Stachybotrys chartarum (CASRN 67892-26-6) administered by inhalation to B6C3F1/N mice.

Stachybotrys chartarum, also known as "black mold," is a cellulolytic saprophyte with a worldwide distribution. Public concern for potential illnesses associated with water-damaged indoor environments has been heightened since the report of pediatric acute idiopathic pulmonary hemorrhage/hemosiderosis cases in the United States and following recent natural disasters. Although mycotoxicosis and pulmonary immunological endpoints have been previously examined, the systemic toxicity following subchronic inhalation of viable S. chartarum remains undercharacterized. To evaluate the toxicological responses to S. chartarum, B6C3F1/N mice were exposed to viable S. chartarum conidia (spores) twice a week for 3 months. All in-life procedures, including inhalation exposure, test article preparation, and hematology analysis, were completed by the National Institute for Occupational Safety and Health (NIOSH, Morgantown, WV). Battelle (Columbus, OH) conducted terminal necropsies, measured terminal body and organ weights, and evaluated gross lesions onsite at the NIOSH facility. Tissue processing and histopathology were completed at Battelle. Genetic toxicology studies on mouse peripheral blood erythrocytes were conducted by Integrated Laboratory Systems, LLC (Research Triangle Park, NC). (Abstract Abridged).

Perspectives on donor‐derived infections from Germany

AbstractAimOften, organ transplantation is the only option to improve the life expectancy and quality of life of patients with terminal organ failure. Despite improved donor and organ assessment, a residual risk remains for transmitting infection, tumor, or other disease from the donor to recipients. Analysis, reporting, and managing of donor‐derived diseases through a vigilance and surveillance system (V&S) is mandatory in many countries. We report on suspected and proven/probable donor‐derived infections (DDI) in Germany over a period of 8 years (2016–2023).MethodsAll incoming serious‐adverse‐event and serious‐adverse‐reaction (SAE/SAR) reports from 01.01.2016 to 31.12.2023 were evaluated for suspected DDI. Analysis of imputability followed the definition of the US Disease Transmission Advisory Committee (DTAC). Only probable and proven cases according to DTAC classification were defined as DDI.ResultsDuring the study period, 9771 donors in Germany donated post‐mortem organs to 27 919 recipients. In that period 612 SAE/SAR cases were reported, 377 (62%) involved infections. 41 cases were proven/probable DDI affecting 58 recipients (seven recipients died, 12%). Suspected infections were bacterial (182/377, 48%), fungal (135/377, 36%), viral (55/377, 15%), and parasitic (5/377, 1%). In case of bacterial DDI, no recipient died, but organ loss occurred in six recipients. In case of fungal or viral DDI, 19% (3/16) and 21% (3/14) of the recipients died, respectively.ConclusionsDDI are rare in solid organ transplantation (58/27 919, 0.21%), but when they occur, they are associated with high morbidity and mortality in affected recipients. Careful and detailed donor evaluation and a reliable V&S help improve recipient safety. image

Mechanisms of Tolerance Induction in Liver Transplantation: Lessons Learned from Fetomaternal Tolerance, Autoimmunity and Tumor Immunity.

Since the first published report of experimental kidney transplantation in dogs in 1902, there were many experimental and clinical trials of organ transplantation, with many sacrifices. After the establishment of the surgical technique and the discovery of immunosuppressive drugs, transplantation became the definitive treatment strategy for patients with terminal organ failure. However, this is not a common therapy method due to the difficulty of solving the fundamental issues behind organ transplantation, including the shortage of donor graft, potential risks of transplant surgery and economic capability. The pre- and post-transplant management of recipients is another critical issue that may affect transplant outcome. Most liver transplant recipients experience post-transplant complications, including infection, acute/chronic rejection, metabolic syndrome and the recurrence of hepatocellular carcinoma. Therefore, the early prediction and diagnosis of these complications may improve overall and disease-free survival. Furthermore, how to induce operational tolerance is the key to achieving the ultimate goal of transplantation. In this review, we focus on liver transplantation, which is known to achieve operational tolerance in some circumstances, and the mechanical similarities and differences between liver transplant immunology and fetomaternal tolerance, autoimmunity or tumor immunity are discussed.

Association of Disease Trajectory and Place of Care with End-of-Life Burdensome Transitions: A Retrospective Cohort Study

ObjectivesEnd-of-life (EOL) transitions to hospital can be burdensome for older adults and may contribute to poor outcomes. We investigated the association of disease trajectory and place of care with EOL burdensome transitions. DesignRetrospective cohort study using administrative data. Setting/ParticipantsOntarians aged ≥65 years who died between 2015 and 2018 and received long-term care (LTC) or home care 6 months before death. MethodsDisease trajectories were defined based on EOL functional decline: terminal illness, organ failure, frailty, sudden death, and other. Places of care included LTC, EOL home care, and non-EOL home care. Burdensome transitions were defined as early (≥3 hospitalizations for any reason or ≥2 hospitalizations due to pneumonia, urinary tract infection, sepsis, or dehydration in the last 90 days of life) or late (≥1 hospitalizations for any reason in the last 3 days of life). Multinomial logistic regression tested for effect modification between disease trajectory and places of care on burdensome transitions. ResultsOf 110,776 decedents, 40.7% had organ failure, 37.5% had frailty, and 12.8% had a terminal illness, with the remainder in sudden death or other categories. Most were in LTC (62.5%), and 37.5% received home care, with 6.8% receiving designated EOL home care and 30.7% non-EOL home care. There was a significant interaction (P < .001) between disease trajectory and care settings. Compared with terminal illness, organ failure was associated with increased odds of early transitions across all care settings [odds ratios (ORs) ranging 1.14-1.21]. Frailty was associated with increased odds of early transitions solely for non-EOL home care recipients (OR 1.17, 95% CI 1.06-1.28). Organ failure and frailty were associated with increased odds of late transitions across all settings, with organ failure having greater odds in LTC (organ failure OR 2.29, 95% CI 2.02-2.60, vs frailty OR 1.79, 95% CI 1.58-2.04). Conclusions and ImplicationsDisparities exist in burdensome transitions, notably for noncancer decedents with organ failure in LTC. Enhancing palliative care may help reduce burdensome transitions and improve patient outcomes.

Dwarf males of the seven-arm octopus, Haliphron atlanticus: morphology and adaptations

ABSTRACT The Argonautoidea is a monophyletic superfamily of pelagic incirrate octopods primarily distinguished by an unusual means of copulation where a sexually modified arm, or hectocotylus, is detached and transferred from dwarf males to the female. Males of the seven-arm octopus Haliphron atlanticus are scarcely observed and little is known about their reproductive strategy. A detailed description of H. atlanticus digestive system, hectocotylus morphology, histology and functioning was carried out with fresh and preserved material from two males captured in the Bay of Biscay (North Atlantic). It is the first time that a hydrostatic sac/swimbladder in the anterior region of the intestine is described in an argonautoid male. Investing in reproductive rather than somatic growth is evident in the dwarf males of H. atlanticus, which lack the Needham sac and the terminal organ. Functionally, these organs have been replaced by two external modifications at the distal end of the detachable hectocotylus: a spermatophore reservoir with a single long spermatophore and a muscular penis, both essential to ensure fertilization once the hectocotylus is detached from the dwarf males. Haliphron has been considered a monospecific genus, with a single species distributed around the world. However, mitochondrial genetic analysis (cytochrome c oxidase subunit I and 16S ribosomal RNA) supports the existence of at least two species of Haliphron, one in the northern Atlantic and another in the southern Atlantic/Pacific. Further genetic and morphological studies are needed to unravel the diversity of this oceanic octopod family.

Organ Donation: A Necessary Social Obligation?

One success of medicine has been to change the death of a human being for the life of a patient with terminal organ failure when organs such as the liver or lung are donated. These results of organ surgery and treatments, nevertheless, are accompanied by the maintenance of patients waiting lists, and deaths. Educational programs have made advances in popular knowledge. However, the data shows that society’s undefined attitude toward donation impacts the “organ shortage”. For example, the value of the slogan that qualifies donating as a gift is controversial today. Organ shortage requires an analysis of its persistence, as well as suggestions for its solution.

(068) Perfluorooctane Sulfonate (pfos) And Perfluorooctanic Acid (pfoa) Sub-chronic Exposure has Minimal Impact on Erectile Function in Sprague-dawley Ratsa

Abstract Introduction Per and polyfluoroalkyl substances (PFAS) are commonly used in industrial and consumer products and are environmental and health contaminants. The most common PFAS chemicals, perfluorooctane sulfonate (PFOS) and perfluorooctanic acid (PFOA), are used in firefighting foam, nonstick bakeware, water-resistant fabrics, grease-resistant paper and fire-resistant materials. PFAS is a known endocrine disruptor and can reduce testosterone and lower semen quality. The impact of PFAS exposure on erectile physiology is unknown. Objective Our study will assess the effect of PFOS and PFOA on erectile function in Sprague-Dawley rats. We hypothesize that PFOS and PFOA will decrease erectile function. Methods Adult male Sprague-Dawley rats were divided into three groups (n=10/group): 1) Control; 2) PFOS (10mg/kg/day); and 3) PFOA (10mg/kg/day). PFOS/PFOA was dissolved in 0.05% Tween 20 and administered in drinking water for 28 days. Controls received 0.05% Tween 20 in drinking water. The study was carried out in two different cohorts of rats (n=4 and n=6/group). Following 28 days of PFOS/PFOA exposure, rats were placed on regular drinking water for 2 weeks. Body weights were collected weekly and terminal organ weights of liver, testes, spleen, heart, lungs, brain, seminal vesicles, kidneys, bladder, and thymus were recorded. Erectile function was assessed prior to PFAS exposure and every 2 weeks thereafter via apomorphine-induced behavioral erections and yawns. Nerve-stimulated intracavernosal pressure and mean arterial pressure (ICP/MAP) was measured 2 weeks after exposure stopped. Results Four weeks of PFOS exposure significantly decreased body weight while PFOA exposure did not impact body weight (Con: 588±63.5g; PFOS: 453±16.3g; PFOA: 535±29.9g, p&amp;lt;0.01). The PFOS dose in the second cohort was overtly toxic with 5/6 rats dying following 3-4 weeks of exposure. Two weeks following PFOS/PFOA exposure, livers were markedly enlarged (Con: 19.4±2.85g; PFOS: 25.4±0.16g; PFOA: 20.2±3.77g, p&amp;lt;0.01), spleens were smaller (Con: 0.93±0.12g; PFOS: 0.65±0.03g; PFOA: 0.88±0.12g, p&amp;lt;0.05), and testes were larger in PFOS rats (Con: 1.8±0.07g; PFOS: 2.0±0.06g; PFOA: 1.8±0.07). No other organ weights were different across exposure groups. PFOS/PFOA exposed animals had similar numbers of apomorphine-induced erections throughout the 6 week period. Two weeks post-exposure, ICP/MAP was unchanged between all groups (n=5-10/group). Ongoing studies will assess testosterone levels. Conclusions A sub-chronic PFOS exposure markedly decreased body weight, increased liver size, decreased spleen weight, and increased testes weight. PFOA exposure did not impact body or organ weights. Following PFOS or PFOA exposure, there was no change in apomorphine-induced behavioral erections or ICP/MAP. Additionally, the dose of PFOS assessed was quite toxic to the second cohort of animals. Future studies will assess if a more chronic exposure will impact erectile function. Disclosure No.

Uncontrolled organ donation after out-of-hospital cardiac arrest. Literature review

Organ transplantation is the best therapy for terminal and irreversible organ failure. The global development of organ transplantation as a type of medical care is inextricably linked to the establishment of neurological criteria for declaring human death (brain death). In the early evolutionary period of transplantation, organs were used, mainly kidneys, obtained from donors whose death was ascertained in accordance with the generally accepted criteria of cessation of blood circulation and respiration. As this type of organ donation developed, numerous terms were used in the world literature to designate it, such as ‘asystolic donors’, ‘non-heart beating donors’, ‘donors after cardiac death’, etc. In Russia, there is an established practice of dealing with donors after cardiac death (DCD), but the active development of Russian transplantology in the last 20 years is primarily associated with brain-dead organ donation. However, countries with the most active and advanced organ donation practices have in recent years been successfully dealing with donors who have suffered sudden out-of-hospital cardiac arrest (OHCA). Previously, this type of donation was considered inaccessible due to the unacceptable warm ischemia time and consequently severe damage to donor organs. Due to the development of new technologies in emergency medical care, it became possible to transport a patient with clinical death that occurred in an outof-hospital setting, to the hospital, while providing cardiopulmonary resuscitation by means of automatic chest compression and artificial ventilation. The article presents historical aspects of donation after cardiac death, and the most actualized definitions and practices of dealing with such donors.

TLR4 signalling in ischemia/reperfusion injury: a promising target for linking inflammation, oxidative stress and programmed cell death to improve organ transplantation outcomes.

Transplantations represent the principal therapeutic interventions for terminal organ failure, a procedure that has salvaged myriad lives annually. Ischemia/reperfusion injury (IRI) is frequently correlated with an unfavourable prognosis and is relevant for early graft dysfunction and graft survival. IRI constitutes a complex pathological state influenced by a series of factors such as oxidative stress, metabolic stress, leukocytic infiltration, programmed cell death pathways, and inflammatory immune responses. Reducing ischemia/reperfusion injury is one of the main directions of transplantation research. Toll-like receptors (TLRs) are important pattern-recognition receptors expressed on various organs that orchestrate the immune responses upon recognising PAMPs and DAMPs. Targeting the TLR4 signalling has recently been suggested as a promising approach for alleviating IRI by affecting inflammation, oxidative stress and programmed cell death (PCD). In this minireview, we summarise the role of TLR4 signalling in regulating inflammation, oxidative stress and PCD in organ transplantation and discuss their interactions during IRI. A detailed understanding of the multiple functions of TLR4 in IRI provides novel insights into developing therapies to improve organ transplantation outcomes.

Evaluation of mixtures of flavor chemicals in a 90-day nose-only exposures in sprague-dawley rats.

One of the challenges to using some flavor chemicals in aerosol products is the lack of route of administration specific toxicology data. Flavor chemicals (88) were divided into four different flavor mixtures based upon chemical compatibility and evaluated in 2-week dose-range-finding and subsequent 90-day nose-only rodent inhalation studies (OECD 413 and GLP compliant). Sprague-Dawley rats were exposed to vehicle control or one of three increasing concentrations of each flavor mixture. In the dose-range-range-finding studies, exposure to flavor mixture four resulted in adverse nasal histopathology in female rats at the high dose, resulting in this flavor mixture not being evaluated in a 90-day study. In the 90-day studies daily exposures to the three flavor mixtures did not induce biologically meaningful adverse effects (food consumption, body weights, respiratory physiology, serum chemistry, hematology, coagulation, urinalysis, bronchoalveolar lavage fluid analysis and terminal organ weights). All histopathology findings were observed in both vehicle control and flavor mixture exposed animals, with similar incidences and/or severities, and therefore were not considered flavor mixture related. Based on the absence of adverse effects, the no-observed-adverse-effect concentration for each 90-day inhalation study was the highest dose tested, 2.5mg/L of the aerosolized high dose of the three flavor mixtures.

Role of chemokine receptors in transplant rejection and graft-versus-host disease.

Organ transplantation increases life expectancy and improves the quality of life of patients experiencing specific conditions such as terminal organ failure. Despite matching efforts between donor and recipient, immune activation can interfere with allograft survival after transplantation if immunosuppression is not used. With both innate and adaptive responses, this is a complicated immunological process. This can lead to organ rejection, or graft-versus-host disease (GVHD), depending on the origin of the immune response. Inflammatory factors, such as chemokine receptors and their ligands, are involved in a wide variety of immunological processes, including modulating transplant rejection or GVHD, therefore, chemokine biology has been a major focus of transplantation studies. These molecules attract circulating peripheral leukocytes to infiltrate into the allograft and facilitate dendritic and T cell trafficking between lymph nodes and the graft during the allogeneic response. In this chapter, we will review the most relevant chemokine receptors such as CXCR3 and CCR5, among others, and their ligands involved in the process of allograft rejection for solid organ transplantation and graft-versus-host disease in the context of hematopoietic cell transplantation.

Deoxyribonuclease I Alleviates Septic Liver Injury in a Rat Model Supported by Venoarterial Extracorporeal Membrane Oxygenation.

Sepsis is an unusual systemic reaction with high mortality and secondary septic liver injury is proposed to be the major cause of mortality. Extracorporeal membrane oxygenation (ECMO) can enhance terminal organ perfusion by elevating circulatory support which is used in severe sepsis patients. However, the interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response. Besides, inflammation and apoptosis are the main mediators in the pathophysiology of septic liver injury. Therefore, we investigated the protective effect of Deoxyribonuclease I (DNase I) against septic liver injury supported by ECMO in rats. Sepsis was induced by lipopolysaccharide (LPS) and 24 hours after the administration, the rats were treated with ECMO. Then blood samples and liver tissues were collected. DNase I significantly attenuated the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and significantly decreased hepatic levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, myeloperoxidase (MPO), downstream inflammatory factor interleukin-1β (IL-1β) and interleukin-18 (IL-18), and improved neutrophil infiltration. Additionally, DNase I significantly reduced the expression of apoptosis key protein and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-labeled apoptotic hepatocytes. In summary, our findings demonstrated that DNase I alleviates liver injury in ECMO-supported septic rats by reducing the inflammatory and apoptotic responses.

The effects of foot reflexology on symptoms of discomfort in palliative care: a feasibility study

BackgroundIn palliative care, the relief of discomfort is sought by an overall approach, combining prescribed medication and additional therapies, such as foot reflexology (FR). The main objective of this study was to assess the feasibility of FR in a population of inpatients in a palliative care unit (PCU).The precariousness of the patients led us to perform a feasibility study and not a cohort study from the outset. Its secondary objective was to assess the impact of an FR session on some symptoms of discomfort (anxiety, pain, troubled sleep, and psychological distress).MethodsThis is a feasibility study designed as a randomized controlled two-arm therapeutic trial. One arm tested FR, the other an active control, massage therapy (MT). The evaluators were blinded.ResultsFR was feasible for 14 patients out of the 15 included in the FR group (95% CI [68%; 100%]). These patients were in the palliative care phase of cancer, motor neuron disease, or terminal organ failure. Concerning the symptoms of discomfort, ESAS sleep quality score was on average 3.9 (± 2.5) before a session in the FR group. It was improved to an average of 3 (± 2.3) on the day after the session (effect-size = 0.38 [0.03; 0.73]).ConclusionThis study confirms the feasibility of an FR session for patients hospitalized in a PCU. It resulted in a slight improvement in sleep quality. For other discomfort symptoms such as anxiety, pain and distress, FR yielded a non-significant improvement. Significant results would have needed a larger cohort.

Tonsillectomy Outcomes in Children After Solid-Organ Transplantation: A 15-Year Single-Center Experience.

Solid-organ transplantation (SOT) has become the standard of care for children with terminal organ failure. Long-term immunosuppression has improved survival substantially but is associated with secondary malignancies and impaired wound healing. Our goal was to review the incidence, outcomes, complications, and rate of posttransplant lymphoproliferative disorder on pathologic examination following tonsillectomy/adenotonsillectomy (T/AT) in children after SOT. A retrospective cohort study. Tertiary care children's hospital. Data were extracted from charts of children with a history of kidney, heart, or liver transplantation, who underwent T/AT between 2006 and 2021. A total of 110 patients met the inclusion criteria, including 46 hearts, 41 kidneys, 19 livers, and 4 liver-and-kidney transplants. The mean age at transplantation was 4.2 years, and the mean transplantation-to-T/AT time interval was 28.8 months. The posttransplantlymphoproliferative disorder was diagnosed in 52 (47.3%) patients, and 25% of these had no tonsillar hypertrophy. There was no difference in age at transplantation, organ received, transplantation-to-T/AT time interval, immunosuppressive medications, tonsil size, or tonsillar asymmetry between patients diagnosed with the posttransplant lymphoproliferative disorder and patients with benign tonsillar/adenotonsillar hypertrophy. Posttonsillectomy complications were similar between the groups. The incidence of posttransplant lymphoproliferative disorder undergoing tonsillectomy for any indication was 47.3%. There was no association between preoperative signs and symptoms and the histopathological diagnosis of posttransplant lymphoproliferative disorder. Stratification by organ received and immunosuppressive medications did not identify differences among the groups relative to the incidence of posttransplant lymphoproliferative disorder and other postoperative complications.

AWARENESS REGARDING ORGAN DONATION AMONG YOUNG ADULTS OF UTTARAKHAND.

Background: Organ donation is dened as giving an organ or part of an organ to be transplanted into another person. Organ transplantation is the only option to save lives in patients affected by terminal organ failure and improves their quality of life1. Objective- To asses knowledge regarding organ donation among young adults of Uttarakhand. Methods: A descriptive cross sectional study was conducted to assess knowledge regarding Organ Donation among young adults of Uttarakhand. Research was conducted among 50 young adults of Doiwala Block of Uttarakhand who were selected using systematic random sampling technique. Data was collected through self administered structured knowledge questionnaire. Results: 4% sample had good knowledge, 88% had average knowledge and 8% had poor knowledge regarding organ donation. There was signicant association between knowledge score and gender of the participants. Conclusion: There is a need for educational programs to create awareness and improve knowledge regarding organ donation among public to ll the gap between need of organ and donor

Evaluation of the toxicity of WS-5 in a 90-days nose-only exposure in sprague-dawley rats

Introduction WS-5 is a flavor ingredient that provides a cooling sensation similar to that of menthol but without the characteristic menthol flavor. In the available toxicological evaluations of WS-5 there was no data specific to inhalation exposure. Methods A 90-days nose-only inhalation study was conducted using Sprague Dawley rats exposed to Filtered air, propylene glycol/glycerin (40/60 by weight; vehicle control), or one of three WS-5 concentrations (0.2, 0.4, or 0.8% by weight) to assess the inhalation toxicity of WS-5. The study design was consistent with the Organization for Economic Development and Cooperation test guideline 413 and included a 28-day and 6-week recovery sacrifices, in addition to the 13-week assessment. Results Food consumption and body weights were unaffected by WS-5 exposure compared to vehicle control or Filtered air. No WS-5 exposure related alterations were observed in serum chemistry, hematology, coagulation, urinalysis or bronchoalveolar lavage fluid cytology and clinical chemistry. Macroscopic examinations and terminal organ weights revealed no observations associated with exposure to WS-5. Discussion Histopathology findings of alveolar hemorrhage and mixed cell infiltration at the 28-day necropsy were either not present in the WS-5 exposed groups or were present at similar frequencies in the vehicle control and/or Filtered air groups at the 13-weeks necropsy and thus, were not considered to be vehicle control or WS-5 related. Conclusion Based on the absence of adverse effects, the no-observed-adverse effect concentration was considered to be 2.5 mg/L of aerosolized 0.8 w% WS-5 that achieved a mean measured exposure concentration of approximately 18 μg WS-5/L

Postbiotics as potential new therapeutic agents for sepsis.

Sepsis is the main cause of death in critically ill patients and gut microbiota dysbiosis plays a crucial role in sepsis. On the one hand, sepsis leads to the destruction of gut microbiota and induces and aggravates terminal organ dysfunction. On the other hand, the activation of pathogenic gut flora and the reduction in beneficial microbial products increase the susceptibility of the host to sepsis. Although probiotics or fecal microbiota transplantation preserve gut barrier function on multiple levels, their efficacy in sepsis with intestinal microbiota disruptions remains uncertain. Postbiotics consist of inactivated microbial cells or cell components. They possess antimicrobial, immunomodulatory, antioxidant and antiproliferative activities. Microbiota-targeted therapy strategies, such as postbiotics, may reduce the incidence of sepsis and improve the prognosis of patients with sepsis by regulating gut microbial metabolites, improving intestinal barrier integrity and changing the composition of the gut microbiota. They offer a variety of mechanisms and might even be superior to more conventional 'biotics' such as probiotics and prebiotics. In this review, we present an overview of the concept of postbiotics and summarize what is currently known about postbiotics and their prospective utility in sepsis therapy. Overall, postbiotics show promise as a viable adjunctive therapy option for sepsis.

Merkel Cells Are Multimodal Sensory Cells: A Review of Study Methods

Merkel cells (MCs) are rare multimodal epidermal sensory cells. Due to their interactions with slowly adapting type 1 (SA1) Aβ low-threshold mechanoreceptor (Aβ-LTMRs) afferents neurons to form Merkel complexes, they are considered to be part of the main tactile terminal organ involved in the light touch sensation. This function has been explored over time by ex vivo, in vivo, in vitro, and in silico approaches. Ex vivo studies have made it possible to characterize the topography, morphology, and cellular environment of these cells. The interactions of MCs with surrounding cells continue to be studied by ex vivo but also in vitro approaches. Indeed, in vitro models have improved the understanding of communication of MCs with other cells present in the skin at the cellular and molecular levels. As for in vivo methods, the sensory role of MC complexes can be demonstrated by observing physiological or pathological behavior after genetic modification in mouse models. In silico models are emerging and aim to elucidate the sensory coding mechanisms of these complexes. The different methods to study MC complexes presented in this review may allow the investigation of their involvement in other physiological and pathophysiological mechanisms, despite the difficulties in exploring these cells, in particular due to their rarity.

COMPARATIVE ANALYSIS OF THE LEGAL REGULATION OF ORGAN DONATION IN THE RUSSIAN FEDERATION, SWITZERLAND AND THE UNITED STATES OF AMERICA

For a long time, the transplantation of organs and tissues from one person to another has remained an unsolvable medical problem. Nowadays, donor organ transplantation is a common and successful way to treat patients with terminal organ failure, which undoubtedly makes it more in demand. The largest percentage of all organ transplants involves transplants from people who have already died. In this regard, an important issue is the possibility for a person to express his or her will regarding the posthumous removal of organs for transplantation, and the mechanisms and possibilities of this expression of will as such. The article deals with the provisions of Russian, US and Swiss legislation regulating the organization and functioning of the organ transplantation system in each country; legal relations in the field of organ and tissue transplantation as well as the mechanisms of citizens' will regarding the posthumous removal of organs and tissues for transplantation purposes. Legal problems of realization of such will in the Russian Federation are covered. The ways of solving the arising problems are offered. The role of legislation, including the presumption on the removal of organs, and other factors influencing the increase in the number of transplantations carried out in the country are considered.

Terminal Complement Inhibition and Control of Hemolysis in Paroxysmal Nocturnal Hemoglobinuria Following Switching from High-Dose Eculizumab to Ravulizumab: An Interim Analysis

Background: Intravenous (IV) complement component 5 (C5) inhibitors, eculizumab and ravulizumab, are the current standards of care in patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare chronic blood disorder characterized by terminal complement activation, intravascular hemolysis (IVH), thrombotic events and organ damage. Ravulizumab is a second-generation analog of eculizumab with substitutions of four amino acids in the chemical backbone. This design enables ravulizumab to provide the same clinical benefit as eculizumab in patients with PNH at a longer dosing interval (every 8 weeks [q8w] vs every 2 weeks [q2w]). Approximately 10-15% of patients with PNH who receive the approved, fixed eculizumab dose (900 mg q2w) experience insufficient inhibition of IVH, as characterized by breakthrough hemolysis (BTH) towards the end of the dosing interval. In such patients, increasing the eculizumab dose (to > 900 mg q2w) can be effective. However, currently there are no recommendations or clinical trial data regarding the impact of switching these patients to ravulizumab. Aim: To assess the safety of switching from high-dose eculizumab to approved, weight-based ravulizumab dosing in patients with PNH. Methods: Study 401 (NCT04320602) is an ongoing, phase 4, single-arm, multicenter trial designed to investigate the impact of switching treatment from fixed, high-dose IV eculizumab (1200 mg q2w) to weight-based IV ravulizumab q8w in adult (≥ 18 years of age; N = 18) patients with PNH. Prior to (≥ 3 months) screening, patients receive high-dose IV eculizumab (1200 mg q2w); patients continue to receive this throughout the 3-month screening period before switching to weight-based IV ravulizumab. Patients receive loading and maintenance ravulizumab doses, as per the approved prescribing information (Alexion, AstraZeneca Rare Disease. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761108s000lbl.pdf). The primary endpoint is the proportion of patients who experience serum free C5-associated BTH (defined as ≥ 1 new or worsening symptom or sign of IVH [fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular events, dysphagia or erectile dysfunction] with lactate dehydrogenase [LDH] levels ≥ 2 × upper limit of normal [ULN] and free C5 concentrations ≥ 0.5 μg/mL). Other endpoints include change in free C5 concentrations and LDH levels over time, and the proportion of patients with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). This interim analysis describes data up to day 183 of follow-up. Results: Data for 10/18 enrolled patients (55.6%) were available. Baseline demographics and clinical characteristics are described in Table 1. From baseline to day 183, no instances of free C5-associated BTH were reported and free C5 concentrations remained below 0.5 μg/mL for all patients at all study timepoints (Figure 1). Similarly, from baseline to day 183, LDH levels remained ≤ 1.5 × ULN in all patients. Up to day 183, 7/10 patients (70.0%) reported TEAEs that were mild (n = 3, 30.0%) or moderate (n = 4, 40.0%) in severity. There were no instances of meningococcal infection, TESAEs and none of the documented TEAEs led to death or study withdrawal. BTH was reported in one patient (local laboratory-reported LDH level = 492.0 U/L; local normal range: 120.0-246.0 U/L), this was deemed to be vaccine-related as both coronavirus disease 2019 and influenza vaccinations were administered the day prior to the event. However, no elevated free C5 level was detected in the earliest available sample (0.11 μg/mL, collected four days after the event) and the patient continued ravulizumab treatment. Conclusions: Results of this interim analysis showed that, based on a small sample of patients with PNH (N = 10), switching treatment from high-dose IV eculizumab (1200 mg q2w) to standard, weight-based IV ravulizumab q8w was well tolerated, with minimal changes in laboratory measures associated with PNH symptoms. Up to day 183, no free C5-associated BTH was reported and the safety profile of ravulizumab was considered comparable to previously published studies, with no instances of meningococcal infection or TESAEs reported. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal