OPTN/SRTR 2020 Annual Data Report: Heart.

As we enter the third year of the new adult heart allocation policy, we are faced with the new challenges of the COVID-19 pandemic. In 2020, new listings (adult and pediatric) decreased slightly, with 4000 new listings in 2020, compared with 4087 in 2019; however, the number of adult heart transplants performed continued to increase, to 3715 in 2020. The number of pediatric heart transplants declined from 509 in 2019 to 465 in 2020. One-year and six-month posttransplant mortality rates in adult recipients have increased slightly since 2015 but have not significantly changed over the past decade. Overall, posttransplant mortality rates for adult recipients were 7.4% at six months and 9.4% at one year for transplants in 2019, 14.0% at three years for transplants in 2017, and 19.1% at five years for transplants in 2015. Although shorter-term posttransplant mortality rates have slightly increased, there has been a steady downward trend in longer-term mortality. Mortality rates for pediatric recipients were 5.7% at six months and 8.1% at one year for transplants in 2019, 11.6% at three years for transplants in 2017, and 15.2% at five years for transplants in 2015.

OPTN/SRTR 2019 Annual Data Report: Heart.

The new adult heart allocation policy was approved in 2016 and implemented in October 2018. This year's Annual Data Report provides early insight into the effects of this policy. In 2019, new listings continued to increase, with 4086 new candidates. Also in 2019, 3597 heart transplants were performed, an increase of 157 (4.6%) from 2018; 509 transplants occurred in children and 3088 in adults. Short- and long-term posttransplant mortality rates improved. Overall, Mortality rates for adult recipients were 6.4% at 6 months and 7.9% at 1 year for transplants in 2018, 14.4% at 3 years for transplants in 2016, and 20.1% at 5 years for transplants in 2014. Mortality rates for pediatric recipients were 6.3% at 6 months and 8.2% at 1 year for transplants in 2018, 10.3% at 3 years for transplants in 2016, and 17.8% at 5 years for transplants in 2014.

OPTN/SRTR 2018 Annual Data Report: Heart.

The new adult heart allocation policy was approved in 2016 and implemented in October 2018, so its effect was not yet evident in 2018 data. However, the more granular data being collected are anticipated to allow for improved analyses. In 2018, new listings continued to increase; 3883 new adult and 685 new pediatric candidates were added. In 2018, 3440 heart transplants were performed, an increase of 167 over 2017; 473 transplants occurred in pediatric recipients and 2967 in adult recipients. Short-term and long-term posttransplant mortality improved. Overall 1-year survival for adults who underwent heart transplant in 2011-2013 was 90.3%, 3-year survival was 84.7%, and 5-year survival was 79.6%. Mortality rates for pediatric recipients were 4.5% at 6 months and in 5.9% at 1 year posttransplant, 12.5% at 3 years for transplants in 2014-2015, 14.8% at 5 years for transplants in 2012-2013, and 29.8% at 10 years for transplants performed in 2008-2009.

OPTN/SRTR 2017 Annual Data Report: Heart.

In 2017, 3273 heart transplants were performed in the United States. New listings continued to increase, and 3769 new adults were listed for heart transplant in 2017. Over the past decade, posttransplant mortality has declined. The number of new pediatric listings increased over the past decade, as did the number of pediatric heart transplants, although some fluctuation has occurred more recently. New listings for pediatric heart transplants increased from 481 in 2007 to 623 in 2017. The number of pediatric heart transplants performed each year increased from 330 in 2007 to 432 in 2017, slightly fewer than in 2016. Short-term and long-term mortality improved. Among pediatric patients who underwent transplant between 2015-2016, 4.8% had died by 6 months and 6.2% by 1 year.

OPTN/SRTR 2016 Annual Data Report: Heart.

In 2016, 3209 heart transplants were performed in the United States. New, active listings increased 57% since 2005. The number of adult heart transplant survivors continued to increase, and in 2016, 30,622 recipients were living with heart transplants. Patient mortality following transplant has declined. The number of pediatric candidates and transplants performed also increased. New listings for pediatric heart transplants increased from 454 in 2005 to 624 in 2016. The number of pediatric heart transplants performed each year increased from 319 in 2005 to 445 in 2016. Among pediatric patients who underwent transplant in 2015, death occurred in 5.9% at 6 months and 7.2% at 1 year.

OPTN/SRTR 2015 Annual Data Report: Heart.

The number of heart transplant candidates and transplants performed continued to rise each year. In 2015, 2819 heart transplants were performed. In addition, the number of new adult candidates on the waiting list increased 51% since 2004. The number of adult heart transplant survivors continued to increase, and in 2015, 29,172 recipients were living with heart transplants. Patient mortality following transplant has declined. The number of pediatric candidates and transplants performed also increased. New listings for pediatric heart transplants increased from 451 in 2004 to 644 in 2015. The number of pediatric heart transplants performed each year increased from 297 in 2004 to 460 in 2015. Among pediatric patients who underwent transplant in 2014, death occurred in 7.2% at 6 months and 9.6% at 1 year.

Report From the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States.

Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less-than-optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

Heart.

As the number of candidates listed for heart transplant continues to rise, it is encouraging that the number of heart transplants also continues to rise steadily each year. Evaluation of waitlist activity demonstrates a growing number of adult candidates removed from the list due to undergoing transplant, but also growing numbers of adult candidates added to the list over the past 3 years. In 2014, 2679 heart transplants were performed, an increase of 28.4% since 2003, and the number of people living with a transplanted heart continued to increase. The number of new pediatric candidates added to the heart transplant waiting list increased to 593 in 2014. The number of pediatric heart transplants performed each year increased from 293 in 2003 to 410 in 2014. Almost 60% of pediatric candidates waiting on December 31, 2014, had been waiting for less than 1 year, compared with 43.0% in 2004. Among pediatric patients who underwent transplant in 2008-2012, overall cumulative incidence of death at 1, 3, and 5 years was 9.2%, 14.7%, and 18.3%, respectively.

Nickel and Copper Toxicity to Embryos of the Long-Spined Sea Urchin, Diadema savignyi.

The sensitivity of long-spined sea urchins (Diadema savignyi) collected from Guam (Northern Marianas Islands), USA, to nickel and copper in seawater was explored using 48-h embryo-larval development toxicity tests. The median effective concentrations (EC50) averaged 94 µg L(-1) for nickel, and 19 µg L(-1) from a single exposure to copper, and suggest relatively high sensitivity of this species to nickel compared with other sea urchin genera, but similar sensitivity to copper. Ambient nickel and copper concentrations concurrently sampled from 16 near-shore locations around Guam were one to two orders of magnitude lower than those that would be expected to result in adverse effects to D. savignyi embryos. Although nationally recommended chronic ambient water quality criteria, currently 8.2 and 3.1 µg L(-1) for nickel and copper, respectively, were not exceeded, recently derived qualifying toxicity data should be considered for updating these criteria to ensure protectiveness of sensitive tropical species.

What is a processing speed weakness? Importance of cognitive ability when defining processing speed in a child psychiatric population.

There is growing evidence that processing speed (PS) deficits in youth with neuropsychiatric conditions are associated with functional difficulties. However, there is no consistent definition of slower PS; specifically, whether slower PS should be defined as a discrepancy from same-aged peers (normative weakness) or as an intrapersonal deficit relative to overall cognitive ability (relative weakness). In a sample of clinically-referred youth, we calculated slower PS both ways and examined the impact on adaptive, academic, and psychopathology outcomes in relation to different levels of cognitive ability. Significant PS x cognitive ability interactions were found on adaptive and academic outcomes. A norm-based weakness in PS (PSI Standard Score <85) was associated with lower adaptive skills and lower academic skills regardless of cognitive ability. In the above average cognitive ability group, relatively lower PS (PSI >15 point difference from VCI) was associated with significantly lower academic performance. No significant associations were found for general psychopathology. Results suggest a normative weakness in PS impacts functional outcomes interactively and differently with level of general cognitive ability. Data suggest that higher cognitive ability may be somewhat protective from the impact of normatively weak PS on adaptive outcomes; however, youth across all abilities with normatively weak PS showed weaker academic performance. Second, children with high cognitive abilities and relatively weak PS showed discrepant performance compared to comparison group. Implications and areas for future research are discussed.

Neuropsychology consultation to identify learning disorders in children and adolescents: a proposal based on lessons learned during the COVID-19 pandemic.

Learning disorders are common neurodevelopmental conditions, occurring both idiopathically and in the context of other medical conditions. They are frequently comorbid with other neurodevelopmental and psychiatric conditions. Delayed identification and treatment have been associated with significant negative psychosocial consequences. The need for pediatric neuropsychologists to efficiently screen for learning disorders is likely to increase in the months and years following the COVID-19 pandemic, which has severely disrupted access to educational services, especially for children who also face racial and economic disparities. In this paper, we describe a consultation model that can be used to screen for learning disorders and can be completed using both in-person and telemedicine visits. Implementation may result in earlier intervention for struggling children, increase access to neuropsychological services without increasing wait times for comprehensive evaluations, and provide opportunities for collaborations with other health professionals (e.g., pediatricians, therapists, psychiatrists, and neurologists).

Linking Patient-Centered Outcomes to Neuropsychological Practice: A Conceptual Framework and Opportunities for Research.

In the current healthcare climate, reimbursement for services is increasingly linked to the ability to demonstrate beneficial patient outcomes. Neuropsychology faces some unique challenges in outcomes research, namely, that neuropsychologists often do not follow patients over time and the effect of neuropsychological services on patient outcomes may not be fully realized until under another provider's care. Yet there is an urgent need for empirical evidence linking neuropsychological practice to positive patient outcomes. To provide a framework for this research, we define a core set of patient-centered outcomes and neuropsychological processes that apply across practice settings and patient populations. Within each area, we review the available existing literature on neuropsychological outcomes, identifying substantial gaps in the literature for future research. This work will be critical for the field to demonstrate the benefit of neuropsychological services, to continue to advocate effectively for reimbursement, and to ensure high-quality patient care.

Tracking and Assessing Oil Spill Toxicity to Aquatic Organisms: A Novel Approach.

An in situ exposure and effects bioassay system was developed for assessing the toxicity of oil spills to aquatic organisms. The assessment tool combines components of 2 previously developed systems, the sediment ecotoxicity assessment ring (SEA Ring) and the drifting particle simulator. The integrated drifting exposure and effects assessment ring (DEEAR) is comprised of a Global Positioning System (GPS) float, a drifter drogue, the SEA Ring, and the Cyclops-7 fluorescent sensor. Polyethylene passive sampling devices (PED) were mounted for an additional means to characterize water quality conditions and exposures. The DEEAR is optimized for evaluating oil exposure and toxicity in the shallow surface mixing layer of marine waters. A short-term preliminary test was conducted in San Diego, California, USA, to verify the operation of the GPS tracking, the iridium communications, and the integrated SEA Ring exposure system. Further, a proof-of-concept demonstration was conducted offshore in the Santa Barbara Channel, where natural oil seeps produce surface slicks and sheens. Two DEEAR units were deployed for 24 h-one within the oil slick and one in an area outside observable slicks. An aerial drone provided tracking of the surface oil and optimal sites for deployment. The DEEAR proof-of-concept demonstrated integrated real-time tracking and characterization of oil exposures by grab samples, PED, and fluorescent sensors. Oil exposures were directly linked to toxic responses in fish and mysids. This novel integrated system shows promise for use in a variety of aquatic sites to more accurately determine in situ oil exposure and toxicity. Environ Toxicol Chem 2021;40:1452-1462. © 2021 SETAC.

In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T-B cell collaboration.

The alkylating agent cyclophosphamide may suppress or enhance immune responses in vivo but is inactive in vitro unless metabolized by microsomal enzyme activation. 4-hydroperoxycyclophosphamide (4-HC) is a synthetic compound that is spontaneously converted in aqueous solution to the active metabolites. In this report, we examined the in vitro sensitivity of functional human T cell subsets to 4-HC in a polyclonal B cell differentiation assay and in the generation of mitogen-induced suppressor cells for effector B cell function. Con A-induced T suppression of B cell differentiation is completely abrogated by a 1-h pretreatment of T cells at very low concentrations of between 10(-2) and 20 nmol/ml, whereas inducer T cell function is sensitive only to concentrations in greater than 40 nmol/ml. The effects of 4-HC on suppressor T cells appear to occur at concentrations that do not result in DNA cross-linking or decreased blastogenesis. Con A-induced T suppressors are generated from within the OKT4+, OKT8- subset and are sensitive to low-dose 4-HC only before activation, whereas differentiated suppressor cells are resistant to concentrations in greater than 80 nmol/ml. Low-dose 4-HC pretreatment of the B cell population results in abrogation of immunoglobulin secretion when treated B cells are cocultured with unfractionated T cells, however, this effect is completely reversible if pretreated B cells are cocultured with T cells devoid of suppressor activity. These results demonstrate that human presuppressor cells for B-effector function differentiate in response to Con A from the OKT4+, OKT8- subset and are exquisitely sensitive to low concentrations of CYP whereas mature suppressor and inducer functions are resistant to all but very high concentrations in vitro. The differential sensitivity of functional T and B cell subsets to 4-HC in vitro can be a very useful probe in dissecting immunoregulatory interactions with man.

Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel).

Kell (ECE-3), a highly polymorphic blood group glycoprotein, displays more than 30 antigens that produce allo-antibodies and, on red blood cells (RBCs), is complexed through a single disulfide bond with the integral membrane protein, XK. XK is a putative membrane transporter whose absence results in a late onset form of neuromuscular abnormalities known as the McLeod syndrome. Although Kell glycoprotein is known to be an endothelin-3-converting enzyme, the full extent of its physiological function is unknown. To study the functions of Kell glycoprotein, we undertook targeted disruption of the murine Kel gene by homologous recombination. RBCs from Kel(-/-) mice lacked Kell glycoprotein, Kell/XK complex, and endothelin-3-converting enzyme activity and had reduced levels of XK. XK mRNA levels in spleen, brain, and testis were unchanged. In Kel(-/-) mice RBC Gardos channel activity was increased and the normal enhancement by endothelin-3 was blunted. Analysis of the microvessels of tumors produced from LL2 cells indicated that the central portion of tumors from wild-type mice were populated with many mature blood vessels, but that vessels in tumors from Kel(-/-) mice were fewer and smaller. The absence of Kell glycoprotein mildly affected some motor activities identified by foot splay on the drop tests. The targeted disruption of Kel in mouse enabled us to identify phenotypes that would not be easily detected in humans lacking Kell glycoprotein. In this regard, the Kell knockout mouse provides a good animal model for the study of normal and/or pathophysiological functions of Kell glycoprotein.

Substituted 3-phenylpropenoates and related analogs: electron ionization mass spectral fragmentation and density functional theory calculations.

Analysis of ethyl 3-(2-chlorophenyl)propenoate by electron ionization mass spectrometry showed the distinct loss of an ortho chlorine. To characterize the structural requisites for the observed mass fragmentation, a series of 30 halogen-substituted 3-phenylpropenoate-related structures were examined. All ester-containing alkene derivatives exhibited loss of the distinctive chlorine from the 2-position of the phenyl ring. Analogous derivatives with the halogen (chlorine or bromine) in the para position did not evidence selective halogen loss. Results demonstrated that substituted 3-phenylpropenoates and their analogs fragment via the formation of a previously reported benzopyrylium intermediate. To understand the correlation between the intramolecular radical substitution and the abundance and selectivity of the chlorine (or other halogen) displacement, density functional theory calculations were performed to determine the charge on the principal cation involved in the chlorine loss (in the ortho, meta, and para positions), the charge for the neutral radical (noncation), the excess alpha-electron density on the relevant atom and the energy to form the cation from the neutral atom (ionization energy). Results showed that the selectivity and extent of halogen displacement correlated highly to the electrophilicity of the radical cation as well as the neutral radical. These data further support the proposed fragmentation mechanism involving intramolecular radical elimination.

Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases.

The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.

Identification of two new members, XPLAC and XTES, of the XK family.

XK, a putative membrane transporter, is a component of the XK/Kell complex of the Kell blood group system. XK's substrate is unknown but absence of the protein, as occurs in the McLeod phenotype, is associated with red cell acanthocytosis and late onset central nervous system and neuromuscular abnormalities known as the McLeod syndrome. We have cloned two cDNAs, XPLAC (GenBank accession no. AY589511) and XTES (GenBank accession no. AY989815), which are closely related to XK and define them together as the XK family. XPLAC has a 2.9 kb cDNA that encodes 462 amino acids and XTES has a 1.6 kb cDNA coding 459 amino acids. The predicted molecular weights are 53.6 kDa for XPLAC and 53.4 kDa for XTES, which are similar to that of XK, which is 50.9 kDa. Unlike XK which is ubiquitously expressed XPLAC is expressed mostly in placenta and adrenal gland while XTES is exclusively expressed in primate testis. XPLAC has 37% and XTES has 31% amino acid identity with XK protein and they are predicted to have a similar topology to XK. XPLAC, like XK, has 3 exons and is located on X chromosome at q22.1, while XTES has 4 exons and is located at 22q11.1. Phylogenetic analysis shows that there are at least 5 additional vertebrate genes that are evolutionarily distantly related to the XK family. A domain with consensus sequences (ced-8 domain) for the extended family is described.

A QSAR for the mutagenic potencies of twelve 2-amino-trimethylimidazopyridine isomers: structural, quantum chemical, and hydropathic factors.

An isomeric series of heterocyclic amines related to one found in heated muscle meats was investigated for properties that predict their measured mutagenic potency. Eleven of the 12 possible 2-amino-trimethylimidazopyridine (TMIP) isomers were tested for mutagenic potency in the Ames/Salmonella test with bacterial strain TA98, and resulted in a 600-fold range in potency. Structural, quantum chemical, and hydropathic data were calculated on the parent molecules and the corresponding nitrenium ions of all of the tested isomers to establish models for predicting the potency of the unknown isomer. The principal determinants of higher mutagenic potency in these amines are: (1) a small dipole moment, (2) the combination of b-face ring fusion and N3-methyl group, (3) a lower calculated energy of the pi electron system, (4) a smaller energy gap between the amine HOMO and LUMO orbitals (Pearson "softness"), and (5) a more stable nitrenium ion. Based on predicted potency from the average of six regression models, the isomer not yet synthesized and tested is expected to have a mutagenic potency of 0.77 revertants/microg in tester strain TA98, which is near the low end of the potency range of the isomers.