Pediatric donor heart acceptance practices in the United States: What is really being considered?

BACKGROUND: Recent studies demonstrate high offer decline and organ non-utilization rates are associated with increased pediatric heart transplant waitlist mortality. We sought to determine which donor, candidate, and offer specific variables most importantly influenced these decisions using only data available at the time of each offer. METHODS: Retrospective review of pediatric (<18 years) heart donor offers made to pediatric candidates in the United States between 2010 and 2020. In addition to standard donor, candidate, and offer data available in UNOS, we extracted objective and qualitative valvar and myocardial function data from all available donor echocardiogram reports. RESULTS: During the study period, 5625 pediatric donor hearts produced 30 156 offers to 4905 unique candidates, of which 88.7% of all offers were declined and 39.2% of organs were not utilized by pediatric waitlisted candidates. Of the 60.8% utilized hearts, 89.7% had a 'cumulatively' normal echocardiogram at the time of offer acceptance; 62.9% of hearts not utilized for a pediatric candidate also had a cumulatively normal final echocardiogram. Random forest and logistic regression modeling demonstrated good predictive performance (AUROC ≥0.83) of likelihood to accept when utilizing donor, candidate, and offer specific variables. SHAP variable importance scores demonstrated number of prior offer declines and candidate institution's prior year acceptance rates as the two most important variables influencing offer decisions. CONCLUSIONS: Behavioral economics appear to play a significant role in pediatric heart transplant candidate institutions' acceptance practices, even when considering the arguably healthier pediatric donor population. Removal of prior institution's decisions from DonorNet may help increase donor utilization.

Paediatric kidney transplantation in under-resourced regions-a panoramic view.

Kidney transplantation is the ideal choice of kidney replacement therapy in children as it offers a low risk of mortality and a better quality of life. A wide variance in the access to kidney replacement therapies exists across the world with only 21% of low- and low-middle income countries (LLMIC) undertaking kidney transplantation. Pediatric kidney transplantation rates in these under-resourced regions are reported to be as low as < 4 pmcp [per million child population]. A robust kidney failure care program forms the cornerstone of a transplant program. Even the smallest transplant program entails a multidisciplinary workforce and expertise besides ensuring family commitment towards long-term care and economic burden. In general, the short-term graft survival rates from under-resourced regions are comparable to most high-income countries (HIC) and the challenge lies in the long-term outcomes. This review focuses on specific issues relevant to kidney transplants in children in under-resourced regions by highlighting limitations in the capacity and health workforce, regulatory norms, medical issues, economic burden, factors beyond financial hardship and ethical considerations relevant to these regions. Finally, the perspective of strengthening transplant programs in these regions should factor in the bigger challenges that exist in achieving the health-related sustainable development goals by 2030.

Screening Echocardiography Identifies Risk Factors for Pulmonary Hypertension at Discharge in Premature Infants with Bronchopulmonary Dysplasia.

HYPOTHESIS: Premature infants with bronchopulmonary dysplasia (BPD) are at increased risk of secondary pulmonary hypertension (BPD-PH). Prior studies yielded mixed results on the utility of echocardiographic screening at 36 weeks post-menstrual age (PMA). We present our experience using echocardiographic screening at the time of BPD diagnosis to identify infants at highest risk of BPD-PH at discharge. MATERIALS AND METHODS: Retrospective cohort analysis of clinical/ demographic data and screening echocardiograms in patients with BPD. Discharge echocardiograms identified infants with or without BPD-PH at discharge. 36 weeks PMA screening echocardiograms and clinical data were then reviewed to identify which factors were associated with increased odds of BPD-PH at discharge. Associations between echocardiographic findings were evaluated with 2- and 3-variable models to predict increased risk of BPD-PH at discharge. RESULTS: In our cohort of 64 infants with severe BPD, BPD-PH was present in 22/64 (34%) infants at discharge. There were no clinical differences at time of 36 weeks PMA screening evaluation (mean PMA 36.6 ± 2.9 weeks). PH at screening was poorly predictive of PH at discharge as PH at screening resolved in 49% of patients. However, having an ASD, RV dilation, hypertrophy, or reduced function on screening, especially in combination, were associated with BPD-PH at discharge. CONCLUSION: In our cohort of premature infants with BPD, 36 weeks PMA screening echocardiogram identified patients at increased risk for BPD-PH at discharge when ASD, RVH, or impaired RV function were present. Larger prospective studies are indicated to validate these findings.

Rapid multi-generational acclimation of coralline algal reproductive structures to ocean acidification.

The future of coral reef ecosystems is under threat because vital reef-accreting species such as coralline algae are highly susceptible to ocean acidification. Although ocean acidification is known to reduce coralline algal growth rates, its direct effects on the development of coralline algal reproductive structures (conceptacles) is largely unknown. Furthermore, the long-term, multi-generational response of coralline algae to ocean acidification is extremely understudied. Here, we investigate how mean pH, pH variability and the pH regime experienced in their natural habitat affect coralline algal conceptacle abundance and size across six generations of exposure. We show that second-generation coralline algae exposed to ocean acidification treatments had conceptacle abundances 60% lower than those kept in present-day conditions, suggesting that conceptacle development is initially highly sensitive to ocean acidification. However, this negative effect of ocean acidification on conceptacle abundance disappears after three generations of exposure. Moreover, we show that this transgenerational acclimation of conceptacle development is not facilitated by a trade-off with reduced investment in growth, as higher conceptacle abundances are associated with crusts with faster growth rates. These results indicate that the potential reproductive output of coralline algae may be sustained under future ocean acidification.

Coral resistance to ocean acidification linked to increased calcium at the site of calcification.

Ocean acidification threatens the persistence of biogenic calcium carbonate (CaCO3) production on coral reefs. However, some coral genera show resistance to declines in seawater pH, potentially achieved by modulating the chemistry of the fluid where calcification occurs. We use two novel geochemical techniques based on boron systematics and Raman spectroscopy, which together provide the first constraints on the sensitivity of coral calcifying fluid calcium concentrations ([Formula: see text]) to changing seawater pH. In response to simulated end-of-century pH conditions, Pocillopora damicornis increased [Formula: see text] to as much as 25% above that of seawater and maintained constant calcification rates. Conversely, Acropora youngei displayed less control over [Formula: see text], and its calcification rates strongly declined at lower seawater pH. Although the role of [Formula: see text] in driving calcification has often been neglected, increasing [Formula: see text] may be a key mechanism enabling more resistant corals to cope with ocean acidification and continue to build CaCO3 skeletons in a high-CO2 world.

Resistance of corals and coralline algae to ocean acidification: physiological control of calcification under natural pH variability.

Ocean acidification is a threat to the continued accretion of coral reefs, though some undergo daily fluctuations in pH exceeding declines predicted by 2100. We test whether exposure to greater pH variability enhances resistance to ocean acidification for the coral Goniopora sp. and coralline alga Hydrolithon reinboldii from two sites: one with low pH variability (less than 0.15 units daily; Shell Island) and a site with high pH variability (up to 1.4 pH units daily; Tallon Island). We grew populations of both species for more than 100 days under a combination of differing pH variability (high/low) and means (ambient pH 8.05/ocean acidification pH 7.65). Calcification rates of Goniopora sp. were unaffected by the examined variables. Calcification rates of H. reinboldii were significantly faster in Tallon than in Shell Island individuals, and Tallon Island individuals calcified faster in the high variability pH 8.05 treatment compared with all others. Geochemical proxies for carbonate chemistry within the calcifying fluid (cf) of both species indicated that only mean seawater pH influenced pHcf pH treatments had no effect on proxies for Ωcf These limited responses to extreme pH treatments demonstrate that some calcifying taxa may be capable of maintaining constant rates of calcification under ocean acidification by actively modifying Ωcf.

The genomic architecture of mastitis resistance in dairy sheep.

BACKGROUND: Mastitis is the most prevalent disease in dairy sheep with major economic, hygienic and welfare implications. The disease persists in all dairy sheep production systems despite the implementation of improved management practises. Selective breeding for enhanced mastitis resistance may provide the means to further control the disease. In the present study, we investigated the genetic architecture of four mastitis traits in dairy sheep. Individual animal records for clinical mastitis occurrence and three mastitis indicator traits (milk somatic cell count, total viable bacterial count in milk and the California mastitis test) were collected monthly throughout lactation for 609 ewes of the Greek Chios breed. All animals were genotyped with a custom-made 960-single nucleotide polymorphism (SNP) DNA array based on markers located in quantitative trait loci (QTL) regions for mastitis resistance previously detected in three other distinct dairy sheep populations. RESULTS: Heritable variation and strong positive genetic correlations were estimated for clinical mastitis occurrence and the three mastitis indicator traits. SNP markers significantly associated with these mastitis traits were confirmed on chromosomes 2, 3, 5, 16 and 19. We identified pathways, molecular interaction networks and functional gene clusters for mastitis resistance. Candidate genes within the detected regions were identified based upon analysis of an ovine transcriptional atlas and transcriptome data derived from milk somatic cells. Relevant candidate genes implicated in innate immunity included SOCS2, CTLA4, C6, C7, C9, PTGER4, DAB2, CARD6, OSMR, PLXNC1, IDH1, ICOS, FYB, and LYFR. CONCLUSIONS: The results confirmed the presence of animal genetic variability in mastitis resistance and identified genomic regions associated with specific mastitis traits in the Chios sheep. The conserved genetic architecture of mastitis resistance between distinct dairy sheep breeds suggests that across-breed selection programmes would be feasible.

Challenges for paediatric transplantation in Africa.

Transplantation is the accepted mode of treatment for patients with end-stage organ disease affecting the heart, lungs, kidney, pancreas, liver and intestine. Long-term outcomes have significantly improved and the aim of management is no longer only long-term survival, but also focuses on quality of life especially in children. Transplantation in Africa faces a number of challenges including wide socioeconomic disparity, lack of legislation around brain death and organ donation in many countries, shortage of skilled medical personnel and facilities, infectious disease burden and insecure access to and monitoring of immunosuppression. Whilst there is a need for transplantation, the establishment and sustainability of transplant programmes require careful planning with national government and institutional support. Legislation regarding brain death diagnosis and organ retrieval/donation; appropriate training of the transplant team; and transparent and equitable criteria for organ allocation are important to establish before embarking on a transplant programme. Establishing sustainable, self-sufficient transplant programmes in Africa with equal access to all citizens is an important step towards curtailing transplant tourism and organ trafficking and has a further beneficial effect in raising the level of medical and surgical care in these countries.

The state of paediatric deceased-organ donation at a South African tertiary public- sector hospital: A 14-year analysis.

BACKGROUND: Solid-organ transplantation (SOT) has been proven to be a highly effective and life-saving treatment modality for adults and children suffering from end-stage organ failure. However, high paediatric waiting-list mortality has been reported, and children may suffer irreversible physical and deleterious psychological effects if not transplanted timeously. OBJECTIVES: To identify in-hospital barriers to organ donation and gain a better understanding of the paediatric donor landscape. METHODS: A retrospective descriptive study of consecutive deceased-donor referrals at Red Cross War Memorial Children's Hospital over a 14-year period, from 1 January 2007 to 31 December 2020. RESULTS: During the study period, 156 in-hospital deaths were recorded in the trauma unit and 1 425 in the paediatric intensive care unit. Ninety-three of the 1 581 patients (5.9%) were referred to the on-call transplant co-ordinator as potential organ donors, of whom 69% had been involved in a traumatic accident, including 52% in road traffic collisions. The mean age of the potential donors was 7 years with 60.2% being boys. On initial assessment, 67 of the 93 potential donors (72%) were assessed as eligible for donation of at least one solid organ. The transplant co-ordinator attempted to approach all families for consent; however, five families/next of kin could not be located despite multiple attempts. Among the remaining 62 eligible donors, 44 families/next-of-kin declined consent for solid-organ donation, resulting in a consent rate of 29% (n=18). Several families refused consent for religious reasons. One of the consented donors did not proceed to procurement as there were no suitable recipients. Seventeen donors proceeded to theatre, the intention being solid-organ procurement, but in 2 donors the organs were assessed as being unsuitable for transplant. From the remaining 15 donors, a total of 46 organs were procured and successfully transplanted: 14 livers, 30 kidneys and 2 hearts. CONCLUSION: During the 14-year study period, only 15 deceased donors could be utilised for SOT, as a result of low in-hospital referral (5.9%) and consent rates (29%). The reasons for low referral and consent rates are complex and often multifactorial, which the current study was not designed to investigate in sufficient detail. Future studies should be designed to further interrogate our findings, while accommodating for nuances specific to the paediatric deceased-donor population and their families.

Pregnancy following liver transplantation during childhood and adolescence.

More than 80% of pediatric transplant recipients will survive to reach adulthood, and many will consider having children. We report on outcomes and management of five pregnancies in four women undergoing orthotopic liver transplantation during childhood or adolescence and followed up at our Transplant Center. A retrospective clinical folder audit was performed. Mean age at transplantation was 13.3 ± 3.4 yr (range, 10-18 yr). Mean interval between transplantation and pregnancy was 15.4 ± 4.9 yr (range, 10-22 yr). Mean maternal age at conception was 28 ± 3.5 yr (range, 23-32 yr). Mean gestational age was 36.6 ± 1.7 wk. Mean birth weight was 2672 ± 249 g. Immunosuppression was cyclosporin based in three women and tacrolimus based in one woman. Pregnancy complications necessitating the induction of labor included fetal distress and rising maternal liver enzymes in two women, cholestasis of pregnancy and impaired renal graft function in one woman, fetal distress and preeclampsia in one woman. Modes of delivery were normal vaginal delivery in three women and cesarean section in one woman. No maternal or fetal deaths and no congenital malformations occurred. No episodes of rejection occurred during pregnancy. Two women experienced acute cellular rejection requiring an increase in baseline immunosuppression in the first year, following delivery. No graft losses occurred during a mean follow-up of 44 ± 17.9 months post-delivery. With careful management, pregnancy post-liver transplantation can have a successful outcome.

COVID-19: Experience of a tertiary children's hospital in Western Cape Province, South Africa.

The COVID-19 pandemic necessitated rapid changes in healthcare systems and at Red Cross War Memorial Children's Hospital (RCWMCH), Cape Town, South Africa. Paediatric services in particular required adjustment, not only for the paediatric patients but also for their carers and the staff looking after them. Strategies were divided into streams, including the impact of COVID-19 on the hospital and the role of RCWMCH in Western Cape Province, communication strategies, adaptation of clinical services at the hospital, specifically with a paediatric-friendly approach, and staff engagement. Interventions utilised: (i) Specific COVID-19 planning was required at a children's hospital, and lessons were learnt from other international children's hospitals. A similar number of patients and staff were infected by the virus (244 patients and 212 staff members by 21 December 2020). (ii) Measures were put in place to assist creation of capacity at metro hospitals' adult services by accepting children with emergency issues directly to RCWMCH, as well as accepting adolescents up to age 18 years. (iii) The communication strategy was improved to include daily engagement with heads of departments/supervisors by earlymorning structured information meetings. There were also changes in the methods of communication with staff using media such as Zoom, MS Teams and WhatsApp. Hospital-wide information and discussion sessions were held both on social platforms and in the form of smallgroup physical meetings with senior hospital administrators (with appropriate distancing). Labour union representatives were purposefully directly engaged to assess concerns. (iv) Clinical services at the hospital were adapted. These included paediatric-friendly services and physical changes to the hospital environment. (v) Staff engagement was particularly important to assist in allaying staff anxiety, developing a staff screening programme, and provision and training in use of personal protective equipment, as well as focusing on staff wellness. In conclusion, visible management and leadership has allowed for flexibility and adaptability to manage clinical services in various contexts. It is important to utilise staff in different roles during a crisis and to consider the different perspectives of people involved in the services. The key to success, that included very early adoption of the above measures, has been hospital staff taking initiative, searching for answers and identifying and implementing solutions, effective communication, and leadership support. These lessons are useful in dealing with second and further waves of the COVID-19 pandemic.

South African guidelines on the determination of death.

Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points • Brain death and circulatory death are the accepted terms for defining death in the hospital context. • Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met. • The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation. • Brain-death testing while on extra-corporeal membrane oxygenation is outlined. • Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation. • The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.

South African guidelines on the determination of death.

Summary: Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points: Brain death and circulatory death are the accepted terms for defining death in the hospital context.Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met.The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation.Brain-death testing while on extra-corporeal membrane oxygenation is outlined.Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation.The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.

Practice variation in the diagnosis of acute rejection among pediatric heart transplant centers: An analysis of the pediatric heart transplant society (PHTS) registry.

BACKGROUND: Freedom from rejection in pediatric heart transplant recipients is highly variable across centers. This study aimed to assess the center variation in methods used to diagnose rejection in the first-year post-transplant and determine the impact of this variation on patient outcomes. METHODS: The PHTS registry was queried for all rejection episodes in the first-year post-transplant (2010-2019). The primary method for rejection diagnosis was determined for each event as surveillance biopsy, echo diagnosis, or clinical. The percentage of first-year rejection events diagnosed by surveillance biopsy was used to approximate the surveillance strategy across centers. Methods of rejection diagnosis were described and patient outcomes were assessed based on surveillance biopsy utilization among centers. RESULTS: A total of 3985 patients from 56 centers were included. Of this group, 873 (22%) developed rejection within the first-year post-transplant. Surveillance biopsy was the most common method of rejection diagnosis (71.7%), but practices were highly variable across centers. The majority (73.6%) of first rejection events occurred within 3-months of transplantation. Diagnosis modality in the first-year was not independently associated with freedom from rejection, freedom from rejection with hemodynamic compromise, or overall graft survival. CONCLUSIONS: Rejection in the first-year after pediatric heart transplant occurs in 22% of patients and most commonly in the first 3 months post-transplant. Significant variation exists across centers in the methods used to diagnose rejection in pediatric heart transplant recipients, however, these variable strategies are not independently associated with freedom from rejection, rejection with hemodynamic compromise, or overall graft survival.

Linear naphtho-gamma-pyrones: a naturally occurring scaffold of biological importance.

The linear naphtho-gamma-pyrone (LNGP) moiety is a naturally occurring scaffold with broad biological activity ranging through antimicrobial, antiviral, insecticidal and anti-estrogenic activity. This review, the first of its kind, surveys the chemical literature in an effort directed toward assembling data that will facilitate the construction of activity profiles associated with this emerging class of compounds. The structural and associated biological information has been presented in tabular format with all structures revealed throughout the document and referencing that will allow the reader to rapidly access the literature pertaining to a specific activity or structural class.

Survival of, and competition between, oligodendrocytes expressing different alleles of the Plp gene.

Mutations in the X-linked Plp gene lead to dysmyelinating phenotypes and oligodendrocyte cell death. Here, we exploit the X inactivation phenomenon to show that a hierarchy exists in the influence of different mutant Plp alleles on oligodendrocyte survival. We used compound heterozygote mice to study the long-term fate of oligodendrocytes expressing either the jimpy or rumpshaker allele against a background of cells expressing a Plp-null allele. Although mutant and null oligodendrocytes were generated in equal numbers, the proportion expressing the mutant allele subsequently declined, but whereas those expressing the rumpshaker allele formed a reduced but stable population, the number of jimpy cells fell progressively. The age of decline in the jimpy cells in different regions of the CNS correlated with the temporal sequence of myelination. In compound heterozygotes expressing rumpshaker and jimpy alleles, oligodendrocytes expressing the former predominated and were more abundant than when the rumpshaker and null alleles were in competition. Thus, oligodendrocyte survival is not determined solely by cell intrinsic factors, such as the conformation of the misfolded PLP, but is influenced by neighboring cells, possibly competing for cell survival factors.

Sm-nd and rb-sr chronology of continental crust formation.

Samarium-neodymium and rubidium-strontium isotopic systematics together with plausible assumptions regarding the geochemical evlution of continental crust material, have been used to ascertain the times at which segments of continental crust were formed. Analyses of composites from the Canadian Shield representing portions of the Superior, Slave, and Churchill structural provinces indicate that these provinces were all formed within the period 2.5 to 2.7 aeons. It has been possible to determine the mean age of sediment provenances, as studies of sedimentary rocks suggest that the samarium-neodymium isotopic system is not substantially disturbed during sedimentation or diagenesis.

Retina-dependent activation by apomorphine of metabolic activity in the superficial layer of the superior colliculus.

Studies of the effect of the dopamine agonist apomorphine on local cerebral glucose utilization by means of the carbon-14-labeled deoxyglucose method demonstrate a dose-dependent metabolic activation in the superficial layer of the superior colliculus in the rat. Apomorphine stimulated glucose utilization in a number of other cerebral structures, but only the effect in the superficial layer of the superior colliculus depended on an intact retinal input. This effect was present with the animal in the light or in the dark, but was abolished by enucleation, which left the effects in other cerebral structures unimpaired. Activation of the superificial layer of the superior colliculus appears, therefore, to be secondary to an action of apomorphine on dopaminergic systems within the retina.

Orbital forcing of the marine isotope stage 9 interglacial.

Milankovitch orbital forcing theory has been used to assign time scales to many paleoclimate records. However, the validity of this theory remains uncertain, and independent sea-level chronologies used to test its applicability have been restricted largely to the past approximately 135,000 years. Here, we report U-series ages for coral reefs formed on Henderson Island during sea-level high-stands occurring at approximately 630,000 and approximately 330,000 years ago. These data are consistent with the hypothesis that interglacial climates are forced by Northern Hemisphere summer solar insolation centered at 65 degrees N latitude, as predicted by Milankovitch theory.

Variability in the El Niño-Southern Oscillation through a glacial-interglacial cycle.

The El Niño-Southern Oscillation (ENSO) is the most potent source of interannual climate variability. Uncertainty surrounding the impact of greenhouse warming on ENSO strength and frequency has stimulated efforts to develop a better understanding of the sensitivity of ENSO to climate change. Here we use annually banded corals from Papua New Guinea to show that ENSO has existed for the past 130,000 years, operating even during "glacial" times of substantially reduced regional and global temperature and changed solar forcing. However, we also find that during the 20th century ENSO has been strong compared with ENSO of previous cool (glacial) and warm (interglacial) times. The observed pattern of change in amplitude may be due to the combined effects of ENSO dampening during cool glacial conditions and ENSO forcing by precessional orbital variations.