Maintaining the permanence principle of death during normothermic regional perfusion in controlled donation after the circulatory determination of death: Results of a prospective clinical study.

One concern about the use of normothermic regional perfusion (NRP) in controlled donation after the circulatory determination of death (cDCD) is that the brain may be perfused. We aimed to demonstrate that certain technical maneuvers preclude such brain perfusion. A nonrandomized trial was performed on cDCD donors. In abdominal normothermic regional perfusion (A-NRP), the thoracic aorta was blocked with an intra-aortic occlusion balloon. In thoracoabdominal normothermic regional perfusion (TA-NRP), the arch vessels were clamped and the cephalad ends vented to the atmosphere. The mean intracranial arterial blood pressure (ICBP) was invasively measured at the circle of Willis. Ten cDCD donors subject to A-NRP or TA-NRP were included. Mean ICBP and mean blood pressure at the thoracic and the abdominal aorta during the circulatory arrest were 17 (standard deviation [SD], 3), 17 (SD, 3), and 18 (SD, 4) mmHg, respectively. When A-NRP started, pressure at the abdominal aorta increased to 50 (SD, 13) mmHg, while the ICBP remained unchanged. When TA-NRP was initiated, thoracic aorta pressure increased to 71 (SD, 18) mmHg, but the ICBP remained unmodified. Recorded values of ICBP during NRP were 10 mmHg. In conclusion, appropriate technical measures applied during NRP preclude perfusion of the brain in cDCD. This study might help to expand NRP and increase the number of organs available for transplantation.

Clinical relevance of genetic variants in the von Willebrand factor according to in-silico methods.

Clinical interpretation of genetic variants in the context of the patient's phenotype is a time-consuming and costly process. In-silico analysis using in-silico prediction tools, and molecular modeling have been developed to predict the influence of genetic variants on the quality and/or quantity of the resulting translated protein, and in this way, to alert clinicians of disease likelihood in the absence of previous evidence. Our objectives were to evaluate the success rate of the in-silico analysis in predicting the disease-causing variants as pathogenic and the single-nucleotide variants as neutral, and to establish the reliability of in-silico analysis for determining pathogenicity or neutrality of von Willebrand factor gene-associated genetic variants. Using in-silico analysis, we studied pathogenicity in 31 disease-causing variants, and neutrality in 61 single-nucleotide variants from patients previously diagnosed as type 2 von Willebrand disease. Disease-causing variants and non-synonymous single-nucleotide variants were explored by in-silico tools that analyze the amino acidic sequence. Intronic and synonymous single-nucleotide variants were analyzed by in-silico methods that evaluate the nucleotidic sequence. We found a consistent agreement between predictions achieved by in-silico prediction tools and molecular modeling, both for defining the pathogenicity of disease-causing variants and the neutrality of single-nucleotide variants. Based on our results, the in-silico analysis would help to define the pathogenicity or neutrality in novel genetic variants observed in patients with clinical and laboratory phenotypes suggestive of von Willebrand disease.

Assessing Outcomes of Patients Subject to Intensive Care to Facilitate Organ Donation: A Spanish Multicenter Prospective Study.

Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC. Of the 194 patients, 144 (74.2%) patients fulfilled DNC after a median of 25 h (95% IQR: 17-44) from ICOD onset. Two patients (1%) shifted from ICOD to curative treatment, both were alive at discharge. Factors associated with progression to DNC included: age below 70 years, clinical score consistent with severe brain injury, instability, intracranial hemorrhage, midline shift ≥5 mm and certain types of brain herniation. Overall 151 (77.8%) patients progressed to organ donation. Based on these results, we conclude that ICOD is a beneficial and efficient practice that can contribute to the pool of deceased donors.

Physical Examination of Potential Deceased Organ and Tissue Donors: An Overview of the European Landscape.

Physical examination (PE) of donors is essential to identify potential risks to the safety and efficacy of donated organs and tissues and is mandatory in the EU. However, no detailed guidance is available as to how PE should be performed. Health authorities (HA) and health professionals (HP) in member states of the European Committee on Organ Transplantation of the Council of Europe (CD-P-TO) and observer countries completed surveys relating to the regulatory requirements for PE and the professional practice of PE in their countries for organ and tissue donors. The HA survey addressed regulatory aspects, and the HP survey addressed professional practices, training, and respondents' opinions on the value of PE. These surveys revealed significant inter-country variation in the regulatory approach to PE and the performance of PE by professionals. Most respondents opined that PE was important and yielded valuable information in identifying contraindications to donation. There is no consensus at a regulatory or professional level as to how PE should be performed on organ and tissue donors. There is a requirement for agreed best practice guidelines in this area.

Practice and challenges for organ donation after medical assistance in dying: A scoping review including the results of the first international roundtable in 2021.

The procedure combining medical assistance in dying (MAiD) with donations after circulatory determination of death (DCDD) is known as organ donation after euthanasia (ODE). The first international roundtable on ODE was held during the 2021 WONCA family medicine conference as part of a scoping review. It aimed to document practice and related issues to advise patients, professionals, and policymakers, aiding the development of responsible guidelines and helping to navigate the issues. This was achieved through literature searches and national and international stakeholder meetings. Up to 2021, ODE was performed 286 times in Canada, the Netherlands, Spain, and Belgium, including eight cases of ODE from home (ODEH). MAiD was provided 17,217 times (2020) in the eight countries where ODE is permitted. As of 2021, 837 patients (up to 14% of recipients of DCDD donors) had received organs from ODE. ODE raises some important ethical concerns involving patient autonomy, the link between the request for MAiD and the request to donate organs and the increased burden placed on seriously ill MAiD patients.

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms.

Type 2A and 2M von Willebrand disease (VWD) broadly show similar phenotypic parameters, but involve different pathophysiological mechanisms. This report presents the clinical and laboratory profiles of type 2A and type 2M patients genotypically diagnosed at one large center. Higher bleeding score values and a higher incidence of major bleeding episodes were observed in type 2A compared with type 2M, potentially reflective of the absence of large and intermediate von Willebrand factor (VWF) multimers in 2A. In type 2A, most of disease-causing variants (DCVs) appeared to be responsible for increased VWF clearance and DCV clustered in the VWF-A1 domain resulted in more severe clinical profiles. In type 2M, DCV in the VWF-A1 domain showed different laboratory patterns, related to either reduced synthesis or shortened VWF survival, and DCV in the VWF-A2 domain showed patterns related mainly to shortened survival. VWF-type 1 collagen binding/Ag (C1B/Ag) showed different patterns according to DCV location: in type 2A VWD, C1B/Ag was much lower when DCVs were located in the VWF-A2 domain. In type 2M with DCV in the VWF-A1domain, C1B/Ag was normal, but with DCV in the VWF-A2 domain, C1B/Ag was low. The higher frequency of major bleeding in VWD 2M patients with DCV in the VWF-A2 domain than that with DCV in the VWF-A1 domain could be a summative effect of abnormal C1B/Ag, on top of the reduced VWF-GPIb binding. In silico modeling suggests that DCV impairing the VWF-A2 domain somehow modulates collagen binding to the VWF-A3 domain. Concomitant normal FVIII:C/Ag and VWFpp/Ag, mainly in type 2M VWD, suggest that other nonidentified pathophysiological mechanisms, neither related to synthesis/retention nor survival of VWF, would be responsible for the presenting phenotype.

Access of non-residents to transplantation of deceased donor organs: practices and strategies in the European setting.

The access of non-resident patients to the deceased donor waiting list (DDWL) poses different challenges. The European Committee on Organ Transplantation of the Council of Europe (CD-P-TO) has studied this phenomenon in the European setting. A questionnaire was circulated among the Council of Europe member states to inquire about the criteria applied for non-residents to access their DDWL. Information was compiled from 28 countries. Less than 1% of recipients of deceased donor organs were non-residents. Two countries never allow non-residents to access the DDWL, four allow access without restrictions and 22 only under specific conditions. Of those, most give access to non-resident patients already in their jurisdictions who are in a situation of vulnerability (urgent life-threatening conditions). In addition, patients may be given access: (i) after assessment by a specific committee (four countries); (ii) within the framework of official cooperation agreements (15 countries); and (iii) after patients have officially lived in the country for a minimum length of time (eight countries). The ethical and legal implications of these policies are discussed. Countries should collect accurate information about residency status of waitlisted patients. Transparent criteria for the access of non-residents to DDWL should be clearly defined at national level.

Behavioral economics-A framework for donor organ decision-making in pediatric heart transplantation.

The high discard rate of pediatric donor hearts presents a major challenge for children awaiting heart transplantation. Recent literature identifies several factors that contribute to the disparities in pediatric donor heart usage, including regulatory oversight, the absence of guidelines on pediatric donor heart acceptance, and variation among transplant programs. However, a likely additional contributor to this issue are the behavioral factors influencing transplant team decisions in donor offer scenarios, a topic that has not yet been studied in detail. Behavioral economics and decision psychology provide an excellent foundation for investigating decision-making in the pediatric transplant setting, offering key insights into the behavior of transplant professionals. We conducted a systematic review of published literature in pediatric heart transplant related to behavioral economics and the psychology of decision-making. In this review, we draw on paradigms from these two domains in order to examine how existing aspects of the transplant environment, including regulatory oversight, programmatic variation, and allocation systems, may precipitate potential biases surrounding donor offer decisions. Recognizing how human decision behavior influences donor acceptance is a first step toward improving utilization of potentially viable pediatric donor hearts.

A Genome-Wide Association Study of Resistance to Puccinia striiformis f. sp. hordei and P. graminis f. sp. tritici in Barley and Development of Resistant Germplasm.

Stripe rust (incited by Puccinia striiformis f. sp. hordei) and stem rust (incited by P. graminis f. sp. tritici) are two of the most important diseases affecting barley. Building on prior work involving the introgression of the resistance genes rpg4/Rpg5 into diverse genetic backgrounds and the discovery of additional quantitative trait locus (QTLs) for stem rust resistance, we generated an array of germplasm in which we mapped resistance to stripe rust and stem rust. Stem rust races TTKSK and QCCJB were used for resistance mapping at the seedling and adult plant stages, respectively. Resistance to stripe rust, at the adult plant stage, was determined by QTLs on chromosomes 1H, 4H, and 5H that were previously reported in the literature. The rpg4/Rpg5 complex was validated as a source of resistance to stem rust at the seedling stage. Some parental germplasm, selected as potentially resistant to stem rust or susceptible but having other positive attributes, showed resistance at the seedling stage, which appears to be allelic to rpg4/Rpg5. The rpg4/Rpg5 complex, and this new allele, were not sufficient for adult plant resistance to stem rust in one environment. A QTL on 5H, distinct from Rpg5 and a previously reported resistance QTL, was required for resistance at the adult plant stage in all environments. This QTL is coincident with the QTL for stripe rust resistance. Germplasm with mapped genes/QTLs conferring resistance to stripe and stem rust was identified and is available as a resource to the research and breeding communities.

Summary of Spanish recommendations on intensive care to facilitate organ donation.

With the aim of consolidating recommendations about the practice of initiating or continuing intensive care to facilitate organ donation (ICOD), an ad hoc working group was established, comprising 10 intensivists designated by the Spanish Society of Intensive Care and Coronary Units (SEMICYUC) and the Spanish National Transplant Organization (ONT). Consensus was reached in all recommendations through a deliberative process. After a public consultation, the final recommendations were institutionally adopted by SEMICYUC, ONT, and the Transplant Committee of the National Health-Care System. This article reports on the resulting recommendations on ICOD for patients with a devastating brain injury for whom the decision has been made not to apply any medical or surgical treatment with a curative purpose on the grounds of futility. Emphasis is made on the systematic referral of these patients to donor coordinators, the proper assessment of the likelihood of brain death and medical suitability, and on transparency in communication with the patient's family. The legal and ethical aspects of ICOD are addressed. ICOD is considered a legitimate practice that offers more patients the opportunity of donating their organs upon their death and helps to increase the availability of organs for transplantation.

Introgression of rpg4/Rpg5 Into Barley Germplasm Provides Insights Into the Genetics of Resistance to Puccinia graminis f. sp. tritici Race TTKSK and Resources for Developing Resistant Cultivars.

Stem rust (incited by Puccinia graminis f. sp. tritici) is a devastating disease of wheat and barley in many production areas. The widely virulent African P. graminis f. sp. tritici race TTKSK is of particular concern, because most cultivars are susceptible. To prepare for the possible arrival of race TTKSK in North America, we crossed a range of barley germplasm-representing different growth habits and end uses-with donors of stem rust resistance genes Rpg1 and rpg4/Rpg5. The former confers resistance to prevalent races of P. graminis f. sp. tritici in North America, and the latter confers resistance to TTKSK and other closely related races from Africa. We produced doubled haploids from these crosses and determined their allele type at the Rpg loci and haplotype at 7,864 single-nucleotide polymorphism loci. The doubled haploids were phenotyped for TTKSK resistance at the seedling stage. Integration of genotype and phenotype data revealed that (i) Rpg1 was not associated with TTKSK resistance, (ii) rpg4/Rpg5 was necessary but was not sufficient for resistance, and (iii) specific haplotypes at two quantitative trait loci were required for rpg4/Rpg5 to confer resistance to TTKSK. To confirm whether lines found resistant to TTKSK at the seedling resistance were also resistant at the adult plant stage, a subset of doubled haploids was evaluated in Kenya. Additionally, adult plant resistance to leaf rust and stripe rust (incited by Puccinia hordei and Puccinia striiformis f. sp. hordei, respectively) was also assessed on the doubled haploids in field trials at three locations in the United States over a 2-year period. Doubled haploids were identified with adult plant resistance to all three rusts, and this germplasm is available to the research and breeding communities.

Phenotypic Parameters in Genotypically Selected Type 2B von Willebrand Disease Patients: A Large, Single-Center Experience Including a New Novel Mutation.

von Willebrand disease type 2B (VWD2B) expresses gain-of-function mutations that enhance binding of an individual's von Willebrand factor (VWF) to its platelet ligand, glycoprotein Ib (GPIb), and which are usually identified by increased ristocetin-induced platelet aggregation (RIPA). We describe here the phenotypic profile of 38 genotypically selected VWD2B-affected family members (AFMs) belonging to 19 unrelated families. Major bleeding was observed in 68.4% of AFMs (previous to their diagnosis and registered by lifetime interviews), with a total of 46 episodes (1.21/patient), and was found to be highly related to the individual bleeding score and presence of thrombocytopenia, but otherwise unrelated to other laboratory parameters. Excessive muco-cutaneous bleeding symptoms were often reported, the most frequent of which comprised menorrhagia, epistaxis, easy bruising, and bleeding after teeth extraction/in oral cavity. Eight unaffected family members were also studied. The prevalence of VWD2B within families was 0.826, and the penetrance of mutations was complete, making it mandatory to study entire family sets to complete diagnostic profiles. Seven heterozygous missense mutations were found, the most common being p.V1316M. In the p.R1308C group, 75% of the AFMs showed absence of RIPA at 0.5 mg/mL, 66.6% of whom had VWF:RCo < 10 IU/dL, and 50% of whom had VWF:CB < 10 IU/dL. In the p.S1310F group, none of the AFMs had VWF:RCo/VWF:Ag < 0.6 (RCo/Ag), but 100% had VWF:CB/VWF:Ag < 0.6/(CB/Ag). Patients with p.P1266L and p.R1304V were characterized as atypical VWD2B. Two de novo mutations were found in four AFMs belonging to two families. We also describe a novel mutation: p.Y1258C. Of our patients, 70.5% had O blood group. In conclusion, a normal RCo/Ag and a negative RIPA at 0.5 mg/mL do not necessarily rule out a diagnosis of VWD2B.

How Do Healthcare Providers Feel About Family Presence During Cardiopulmonary Resuscitation?

The presence of patients' families during cardiopulmonary resuscitation (CPR) is a controversial topic, due to its repercussions for clinical practice. While family members' presence may help them to overcome their grief, it could be detrimental, as it may case posttraumatic stress disorder (PTSD), and there is the possibility that family members may interfere with the procedure. For these reasons, families' presence during CPR has rejected by some healthcare providers. To research concerns about families' presence among providers dealing with CPR in the Fundación Hospital Alcorcón (Madrid), I performed this study. Of the 190 providers surveyed, 115 submitted a complete questionnaire. The most frequently reported concerns were interference (78.3 percent of respondents), and PTSD (69.6 percent of respondents). Fewer pediatric providers were concerned about PTSD than other providers (41.2% percent versus 74.5 percent, p = 0.01). Providers were reluctant to offer families the option of being present unless they had requested it, and would only permit it under certain conditions. Having a staff member to support the family was of great value to most respondents. The author believes families have a negative right to be present during CPR and so should be invited to stay.

A splice acceptor site mutation in TaGW2-A1 increases thousand grain weight in tetraploid and hexaploid wheat through wider and longer grains.

KEY MESSAGE: Across 13 experiments the gw2 - A1 mutant allele shifts grain size distribution consistently across all grains significantly increasing grain weight (6.6 %), width (2.8 %) and length (2.1 %) in tetraploid and hexaploid wheat. There is an urgent need to identify, understand and incorporate alleles that benefit yield in polyploid wheat. The rice OsGW2 gene functions as a negative regulator of grain weight and width and is homologous to the wheat TaGW2 gene. Previously it was shown that transcript levels of the A-genome homoeologue, TaGW2-A1, are negatively associated with grain width in hexaploid wheat. In this study we screened the tetraploid Kronos TILLING population to identify mutants in TaGW2-A1. We identified a G to A transition in the splice acceptor site of exon 5 which leads to mis-splicing in TaGW2-A1. We backcrossed the mutant allele into tetraploid and hexaploid wheat and generated a series of backcross derived isogenic lines which were evaluated in glasshouse and field conditions. Across 13 experiments the GW2-A1 mutant allele significantly increased thousand grain weight (6.6 %), grain width (2.8 %) and grain length (2.1 %) in tetraploid and hexaploid wheat compared to the wild type allele. In hexaploid wheat, this led to an increase in spike yield since no differences were detected for spikelet or grain number between isogenic lines. The increase in grain width and length was consistent across grains of different sizes, suggesting that the effect of the mutation is stable across the ear and within spikelets. Differences in carpel size and weight between alleles were identified as early as 5 days before anthesis, suggesting that TaGW2-A1 acts on maternal tissue before anthesis to restrict seed size. A single nucleotide polymorphism marker was developed to aid the deployment of the mutant allele into breeding programmes.

Thrombosis: a major contributor to global disease burden.

Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low- and middle-income countries, and second in high-income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden.

When is directed deceased donation justified? Practical, ethical, and legal issues.

This paper explores whether directed deceased organ donation should be permitted, and if so under which conditions. While organ donation and allocation systems must be fair and transparent, might it be "one thought too many" to prevent directed donation within families? We proceed by providing a description of the medical and legal context, followed by identification of the main ethical issues involved in directed donation, and then explore these through a series of hypothetical cases similar to those encountered in practice. Ultimately, we set certain conditions under which directed deceased donation may be ethically acceptable. We restrict our discussion to the allocation of organs to recipients already on the waiting list.

Review of the allocation criteria for heart transplant in Spain in 2023. SEC-Heart Failure Association/ONT/SECCE consensus document.

Heart transplant (HT) remains the best therapeutic option for patients with advanced heart failure (HF). The allocation criteria aim to guarantee equitable access to HT and prioritize patients with a worse clinical status. To review the HT allocation criteria, the Heart Failure Association of the Spanish Society of Cardiology (HFA-SEC), the Spanish Society of Cardiovascular and Endovascular Surgery (SECCE) and the National Transplant Organization (ONT), organized a consensus conference involving adult and pediatric cardiologists, adult and pediatric cardiac surgeons, transplant coordinators from all over Spain, and physicians and nurses from the ONT. The aims of the consensus conference were as follows: a) to analyze the organization and management of patients with advanced HF and cardiogenic shock in Spain; b) to critically review heart allocation and priority criteria in other transplant organizations; c) to analyze the outcomes of patients listed and transplanted before and after the modification of the heart allocation criteria in 2017; and d) to propose new heart allocation criteria in Spain after an analysis of the available evidence and multidisciplinary discussion. In this article, by the HFA-SEC, SECCE and the ONT we present the results of the analysis performed in the consensus conference and the rationale for the new heart allocation criteria in Spain.

Dignifying death and the morality of elective ventilation.

In this paper we defend that elective ventilation (EV), even if conceived as the instrument to maximise the chances of organ recovery, is mainly the means to provide the patient who is dying with a dignified death in several ways, one of them being the possibility of becoming an organ donor. Because EV does not harm the patient and permits the medical team a better assessment of the patient's clinical trajectory and a better management of the dying process by the family, EV does not violate the principle of non-beneficence nor the principle of autonomy if we restrict the initiation of EV to those cases in which it is not known what the previous wishes of the patient were as regards to his or her care at the end of life.

Organ and Tissue Donation Consent Model and Intent to Donate Registries: Recommendations From an International Consensus Forum.

Consent model and intent to donate registries are often the most public facing aspects of an organ and tissue donation and transplantation (OTDT) system. This article describes the output of an international consensus forum designed to give guidance to stakeholders considering reform of these aspects of their system. Methods: This Forum was initiated by Transplant Québec and cohosted by the Canadian Donation and Transplantation Program partnered with multiple national and international donation and transplantation organizations. This article describes the output of the consent and registries domain working group, which is 1 of 7 domains from this Forum. The domain working group members included administrative, clinical, and academic experts in deceased donation consent models in addition to 2 patient, family, and donor partners. Topic identification and recommendation consensus was completed over a series of virtual meetings from March to September 2021. Consensus was achieved by applying the nominal group technique informed by literature reviews performed by working group members. Results: Eleven recommendations were generated and divided into 3 topic groupings: consent model, intent to donate registry structure, and consent model change management. The recommendations emphasized the need to adapt all 3 elements to the legal, societal, and economic realities of the jurisdiction of the OTDT system. The recommendations stress the importance of consistency within the system to ensure that societal values such as autonomy and social cohesion are applied through all levels of the consent process. Conclusions: We did not recommend one consent model as universally superior to others, although considerations of factors that contribute to the successful deployment of consent models were discussed in detail. We also include recommendations on how to navigate changes in the consent model in a way that preserves an OTDT system's most valuable resource: public trust.