Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study.

BACKGROUND: Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study. METHODS: The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020. Data included medications administered, serial diagnostic tests, and transthoracic echocardiograms (TTEs) performed: (1) within 48 hours after brain death was formally diagnosed; and (2) 24±6 hours later if left ventricular (LV) dysfunction was initially present. LV dysfunction was defined as an LV ejection fraction <50% and was considered reversible if LV ejection fraction was >50% on the second TTE. TTEs were also examined for presence of LV regional wall motion abnormalities and their reversibility. We assessed associations between LV dysfunction, donor heart acceptance for transplantation, and recipient 1-year survival. RESULTS: An initial TTE was interpreted for 3794 of the 4333 potential donors by neurologic determination of death. A total of 493 (13%) of these TTEs showed LV dysfunction. Among those donors with an initial TTE, LV dysfunction was associated with younger age, underweight, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and troponin levels. A second TTE was performed within 24±6 hours for a subset of donors (n=224) with initial LV dysfunction; within this subset, 130 (58%) demonstrated reversibility. Sixty percent of donor hearts with normal LV function were accepted for transplant compared with 56% of hearts with reversible LV dysfunction and 24% of hearts with nonreversible LV dysfunction. Donor LV dysfunction, whether reversible or not, was not associated with recipient 1-year survival. CONCLUSIONS: LV dysfunction associated with brain death occurs in many potential heart donors and is sometimes reversible. These findings can inform decisions made during donor evaluation and help guide donor heart acceptance for transplantation.

Enantioselective synthesis of 3-hydroxy- and 3-amino-3-alkynyl-2-oxindoles by the dimethylzinc-mediated addition of terminal alkynes to isatins and isatin-derived ketimines.

A common protocol for enantioselective alkynylation of isatins and isatin-derived ketimines using terminal alkynes and Me2Zn in the presence of a catalytic amount of a chiral perhydro-1,3-benzoxazine with moderate to excellent enantioselectivity under mild reaction conditions is described. The additions to ketimines present a novel approach to chiral amines being derivatives of oxindoles. The reaction is broad in scope with respect to aryl- and alkyl-substituted terminal alkynes and isatin derivatives. In isatins, the alkynylation occurs at the Si face of the carbonyl group, whereas in the ketimine derivatives it occurs at the Re face of the imine.

Nutrition of free-living Neotropical psittacine nestlings and implications for hand-feeding formulas.

Psittacidae is one of the most endangered families of birds in the world. Knowledge of their nutrition is important for understanding their survival and productivity in the wild, as well as for their adequate husbandry under human care. Hand-rearing is a common practice for psittacines, however research on their nutrition is limited. We analysed the predicted metabolisable energy, crude protein, crude fat, minerals and the essential amino acid profiles of the crop contents from free-living nestlings of scarlet macaws (Ara macao) and red-and-green macaws (Ara chloropterus) from southeastern Peru, Cuban Amazons (Amazona leucocephala bahamensis) from the Bahamas, lilac-crowned Amazons (Amazona finschi) from northwestern Mexico and thick-billed parrots (Rhynchopsitta pachyrhyncha) from northern Mexico. The crop content of the different parrot species displayed remarkably similar nutritional profiles, considering their diversity in habitats, geographic ranges and food sources. The crude protein and crude fat concentrations in crop samples were particularly similar for the Ara and Amazona species, while the thick-billed parrot stood out for its higher crude fat and lower crude protein content. Wider variations were found among the concentrations of sodium (Na) and iron (Fe), proline and tryptophan. Compared with the requirements of 6-12 weeks leghorn chickens, all free-ranging parrot diets contained lower crude protein, calcium (Ca), potassium (P) and Na concentrations. The hand-feeding formulas contained lower crude fat, magnesium (Mg), arginine, valine and phenylalanine concentrations, as well as much higher levels of Ca and zinc (Zn), in comparison with parrot crop samples. Our data suggest that a single formulation could be used to hand-rear Ara and Amazona sp. of 3 weeks of age and older, while a different formulation would likely be more appropriated for Rhynchopsitta sp. Experimental studies should evaluate if increasing the concentration of crude fat, Mg, arginine, valine and phenylalanine enhances psittacine chick growth and health.

Evaluation of the Performance of the Loopamp Trypanosoma cruzi Detection Kit for the Diagnosis of Chagas Disease in an Area Where It Is Not Endemic, Spain.

In Spain, PCR is the tool of choice for the diagnosis of congenital Chagas disease (CD) and serology for diagnosing chronic CD. A loop-mediated isothermal amplification test for Trypanosoma cruzi DNA detection showed good analytical performance and ease of use. We aimed to evaluate the performance of the Loopamp Trypanosoma cruzi detection kit (Eiken Chemical Co. Ltd., Japan) (Tcruzi-LAMP) for congenital and chronic CD diagnosis using well-characterized samples. We included samples from 39 congenital and 174 chronic CD cases and from 48 uninfected children born to infected mothers and 34 nonchagasic individuals. The sensitivity, specificity, and accuracy of Tcruzi-LAMP were estimated using standard case definitions for congenital CD (positive result by parasitological or PCR tests or serology after 9 months of age) and chronic CD (positive serology by at least two tests). The Tcruzi-LAMP results were read by visual examination and a real-time fluorimeter. For congenital CD, Tcruzi-LAMP sensitivity was 97% for both types of reading; specificity was 92% by visual examination and 94% by fluorimeter. For chronic CD, sensitivity was 47% and specificity 100%. The accuracy in congenital CD was >94% versus 56% in chronic CD. The agreement of Tcruzi-LAMP with PCR tests was better in congenital CD (kappa, 0.86 to 0.91) than in chronic CD (kappa, 0.67 to 0.83). The Loopamp Trypanosoma cruzi detection kit showed good performance for the diagnosis of congenital CD. Tcruzi-LAMP, like PCR, can be useful for the screening and early diagnosis of congenital infection.

Dimethylzinc-mediated enantioselective addition of terminal alkynes to 1,2-diketones using perhydro-1,3-benzoxazines as ligands.

A conformationally restricted perhydro-1,3-benzoxazine derived from (-)-8-aminomenthol behaves as a good chiral ligand in the dimethylzinc-mediated enantioselective monoaddition of aromatic and aliphatic terminal alkynes to 1,2-diketones. The corresponding α-hydroxyketones were obtained in good yields with high enantioselectivities starting from both aromatic and aliphatic 1,2-diketones. The alkynylation of unsymmetrical 1,2-diketones with electronically different substituents also proceeds with high regio- and enantioselectivity. This reaction provides a practical method to synthesize ketones bearing a chiral tertiary propargylic alcohol.

Antileishmanial efficacy and tolerability of combined treatment with non-ionic surfactant vesicle formulations of sodium stibogluconate and paromomycin in dogs.

Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.

The impacts of acquisition and extinction cues on ABC renewal of voluntary behaviors.

In two instrumental conditioning experiments with rats, we examined the impacts of acquisition and extinction cues on ABC renewal of instrumental behavior. Animals were reinforced with food for lever pressing in one context, followed by extinction of the response in a second one. Presentations of a brief tone accompanied extinction in Experiment 1 (extinction cue), and acquisition in Experiment 2 (acquisition cue). A final test in a third context revealed that instrumental responding was decreased in the presence of the extinction cue, whereas it was increased in the presence of the acquisition cue. We discuss theoretical and clinical implications of our results.

Ankle-brachial index and arterial vascular events in systemic lupus erythematosus patients: a 5-year prospective cohort.

OBJECTIVES: To determine the potential predictive value in patients with systemic lupus erythematous of the ankle-brachial index (ABI) for the occurrence of arterial vascular events. METHODS: 216 lupus patients from a prospective clinical cohort were evaluated using the ABI at the start of the study and then followed up for 5 years. Abnormal ABI was defined as an index ≤0.9 or >1.4. Several potential vascular risk factors were also evaluated. Arterial vascular events (AVE): coronary events, cerebrovascular events, peripheral arterial disease and death related to vascular disease. Survival analysis was performed using a competitive risk regression approach, considering non-vascular death as a competitive event. RESULTS: 18 arterial events and 14 deaths were identified. In the competitive risk regression analysis, independent predictors of higher risk were identified: family history of early AVE [subdistribution hazard ratio (SHR) 5.44, 95% confidence interval (CI) 1.69-17.50, p=0.004)], cumulative prednisone (grams) (SHR 1.01, 95% CI 1.01-1.03, p=0.007) and a personal history of arterial thrombosis (SHR 5.44, 95% CI 1.45-14.59, p=0.004). Female gender was a protective factor (SHR 0.22, 95% CI 0.07-0.77, p=0.017). A statistical trend was detected with abnormal ABI (SHR 2.65, 95% CI 0.86-8.14, p=0.089). CONCLUSIONS: Male gender, exposure to high cumulative doses of prednisone, family history of early arterial vascular disease and occurrence of previous arterial thrombosis are independent risk predictors of arterial vascular events in patients with systemic lupus erythematosus. Abnormal ABI may be related to high risk for arterial vascular events.

Prevalence of asymptomatic Leishmania infection and associated risk factors, after an outbreak in the south-western Madrid region, Spain, 2015.

BackgroundA large outbreak of leishmaniasis with 758 cutaneous and visceral leishmaniasis cases occurred in 2009 in Fuenlabrada, in the south-west of the Madrid region of Spain.AimWe aimed to determine the prevalence of asymptomatic Leishmania infection after this outbreak, and its associated risk factors.MethodsA cross-sectional study of 804 healthy individuals living in Fuenlabrada who had no history of leishmaniasis, was conducted between January and July 2015. Asymptomatic infections were sought by either a combination of PCR, immunofluorescent antibody titre, and direct agglutination tests, or by whole blood stimulation assay (WBA) with interleukin-2 (IL-2) quantification.ResultsUsing the first approach, prevalence of asymptomatic individuals was 1.1% (9/804), while the second returned a value of 20.7% (143/804). Older age, being male, proximity to the park where the focus of infection was identified, and living in a detached house, were all strongly associated with the prevalence of asymptomatic infection.ConclusionsThe true number of infected individuals may be underestimated if only serological methods are used. The combination of WBA with IL-2 quantification may allow to better determine the prevalence of asymptomatic Leishmania infection, which would be useful in establishing control measures and in quantifying their impact. In our study, the use of WBA with IL-2 quantification also helped establish the risk factors that influence exposure to and infection by Leishmania.

High-Level Modeling and Simulation Tool for Sensor Conditioning Circuit Based on Artificial Neural Networks.

For current microelectronic integrated systems, the design methodology involves different steps that end up in the full system simulation by means of electrical and physical models prior to its manufacture. However, the higher the circuit complexity, the more time is required to complete these simulations, jeopardizing the convergence of the numerical methods and, hence, meaning that the reliability of the results are not guaranteed. This paper shows the use of a high-level tool based on Matlab to simulate the operation of an artificial neural network implemented in a mixed analog-digital CMOS process, intended for sensor calibration purposes. The proposed standard tool enables modification of the neural model architecture to adapt its characteristics to those of the electronic system, resulting in accurate behavioral models that predict the complete microelectronic IC system behavior under different operation conditions before its physical implementation with a simple, time-efficient, and reliable solution.

Venous thrombosis and relapses in patients with Behçet's disease. Descriptive analysis from Spanish network of Behçet's disease (REGEB cohort).

OBJECTIVES: To describe the characteristics of patients with Behçet's disease (BD) who presented with venous thrombosis. In addition, we identified the factors associated with this venous involvement and those related with recurrent venous thrombosis. METHODS: Up to January 2015, 544 BD patients from 20 Spanish hospitals had been included in the REGEB (REGistro de la Enfermedad de Behçet as Spanish nomenclature). We selected those patients who presented venous thrombosis. Descriptive analysis was performed and factors related with venous thrombosis were identified. RESULTS: Overall, 99 (18.2%) BD patients had vascular thrombosis, 91 (16.7%) of them (16.7%) involving venous vessels and 18 (19.7%) suffered from venous thrombotic relapse. Lower limbs were the most common location of deep venous thrombosis present in up to 60% of patients. In 12 (13.2%) patients, venous thrombosis affected two vascular territories simultaneously and in 6 (6.6%) the venous and arterial involvement coincided in time. Overall, at the diagnosis of venous thrombosis, 97.6% of patients presented concomitantly other clinical symptoms attributable to BD. In logistic regression multivariate analysis factors associated to venous thrombosis were male sex (Odds ratio [OR] 4.3, 95% confidence interval [CI] 2.5-7.7), erythema nodosum (OR 2.4, 95%CI 1.4-4.1), fever (OR 2.0, 95%CI 1.1-3.8), and central nervous system (CNS) involvement (OR 2.5, 95%CI 1.3-4.8). Considering relapses, CNS involvement was an independent risk factor according logistic regression. However, Cox multivariate analysis did not confirm this finding. CONCLUSIONS: We identified factors related with venous involvement in patients included in the REGEB cohort.

Removing but not adding elements of a context affects generalization of instrumental responses.

Three experiments with rats investigated whether adding or removing elements of a context affects generalization of instrumental behavior. Each of the experiments used a free operant procedure. In Experiments 1 and 2, rats were trained to press a lever for food in a distinctive context. Then, transfer of lever pressing was tested in a context created either by adding an element to the context of initial acquisition or by removing one of the acquisition context's elements. In Experiment 3, a similar generalization test was conducted after rats received acquisition and extinction within the same context. For Experiments 1 and 2, we observed that removing elements from the acquisition context disrupted acquisition performance, whereas the addition of elements to the context did not. Experiment 3 revealed that removing elements from but not adding elements to the original context improved extinction performance. Our results are consistent with an elemental view of context representation.

A reminder of extinction reduces relapse in an animal model of voluntary behavior.

One experiment with rats explored whether an extinction-cue prevents the recovery of extinguished lever-pressing responses. Initially, rats were trained to perform one instrumental response (R1) for food in Context A, and a different instrumental response (R2) in Context B. Then, responses were extinguished each in the alternate context (R1 in Context B; R2 in Context A). For one group, extinction of both responses was conducted in the presence of an extinction-cue, whereas in a second group, the extinction-cue only accompanied extinction of R1. During a final test, we observed that returning the rats to the initial acquisition context renewed performance and that response recovery was attenuated in the presence of the cue that accompanied extinction of the response. The impact of the extinction-cue, however, was not transferred to the response that has been extinguished without the cue. Our results are consistent with the idea that extinction established an inhibitory cue-response association.

7-endo selenocyclization reactions on chiral 3-prenyl and 3-cinnamyl-2-hydroxymethylperhydro-1,3-benzoxazine derivatives. A way to enantiopure 1,4-oxazepanes.

Enantiopure 1,4-oxazepane derivatives have been prepared by selenocyclofunctionalization of chiral 3-prenyl- and 3-cinnamyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The 7-endo-cyclization occurs in high yields and diastereoselection. The regio- and stereochemistry of the cyclization products was dependent on the substitution pattern of the double bond, the nature of the hydroxyl group and the experimental conditions.

Comparative evaluation of 11 commercialized rapid diagnostic tests for detecting Trypanosoma cruzi antibodies in serum banks in areas of endemicity and nonendemicity.

Chagas disease is one of the main public health issues in Latin America. Increasingly during the past few decades, Trypanosoma cruzi infection has been detected in North America, Europe, and the Western Pacific, mainly as a result of population movement. The limited availability of rapid serological diagnostic tests hinders rapid diagnosis and early treatment in areas of endemicity and nonendemicity. In collaboration with 11 national reference laboratories (NRLs) from different geographical areas, we evaluated the performances of commercialized serological rapid diagnostic tests (RDT) for T. cruzi infection. Eleven commercialized T. cruzi infection RDTs were evaluated on a total of 474 samples extensively tested with at least three different techniques for Chagas disease, maintained at controlled low temperatures, and stored in the serum banks of the 11 NRLs. We measured the sensitivity, specificity, and concordance of each RDT and provided an additional questionnaire to evaluate its ease of use. The selected RDTs in this study were performed under controlled laboratory conditions. Out of the 11 RDTs, we found 8 of them to be useful, with the cassette format favored over the strip. We did not observe significant differences in RDT performances in the different regions. Overall, the performance results were lower than those disclosed by the manufacturers. The results of this evaluation validate the possibility of using RDTs to diagnose Chagas disease, thereby decreasing the time to treatment at a primary health care facility for patients who are willing to be treated. Further studies should be conducted in the laboratory and in the field to confirm these data, expressly to evaluate reproducibility in resource-limited settings, or using whole blood in clinical settings in areas of endemicity and nonendemicity.

Tandem diastereo- and enantioselective preparation of aryl and alkyl cyclopropyl carbinols with three adjacent stereocenters using perhydrobenzoxazines and diethylzinc.

The enantio- and diastereoselective one-pot ethylation/cyclopropanation is efficiently promoted by a chiral perhydrobenzoxazine. The catalytic system tolerates a wide range of di- and trisubstituted α,ß-unsaturated aldehydes and has been found to be highly diastereo- and enantioselective. Enals leading to intermediates lacking allylic strain or with either A(1,2) or A(1,3) strain afford the corresponding syn hydroxycyclopropanes very selectively. While α-methyl enals are successfully ethylated/cyclopropanated, the presence of bulky substituents at the alpha position of the enal constitutes a limitation to the substrate scope. The use of 1,1-diiodoethane allows the obtention of the corresponding enantioenriched cyclopropylcarbinol, which bears carbon-substituents at all three positions of the ring, with good enantiocontrol, although moderate diastereoselectivity. A procedure for the asymmetric one-pot arylation/cyclopropanation of enals is proposed, which involves the use of triarylboroxin, diethylzinc and diiodomethane.

ABA and AAB renewal of alcohol seeking in rats are reduced by exposure to beer before extinction.

Three experiments with rats examined the impact of a retrieval-extinction procedure on ABA and AAB renewal of instrumental learning. In all experiments, rats were trained to run down an alley for alcoholic beer in Context A. Then, the instrumental response underwent extinction, which was conducted in Context B for Experiments 1 and 2, and in Context A for Experiment 3. In each experiment, one group of animals received a brief exposure to the beer prior to each extinction session, whereas this beer exposure was omitted for a second group. Moreover, Experiment 2 comprised a third group that was exposed to non-alcoholic beer before each extinction session. Finally, all rats were tested in their extinction context and in a second context, which was Context A for Experiments 1 and 2, and Context B for Experiment 3. We found ABA (Experiments 1 and 2) and AAB (Experiment 3) renewal of beer seeking in those animals for which beer exposure prior to extinction was omitted. However, response recovery was not evident when animals received exposure to beer before extinction, regardless of whether alcoholic or non-alcoholic beer was used. Our results suggest that the renewal of alcohol seeking can be prevented by means of the retrieval-extinction paradigm.

Zoonotic Cycle of American Trypanosomiasis in an Endemic Region of the Argentine Chaco, Factors That Influenced a Paradigm Shift.

Trypanosoma cruzi, the causative agent of Chagas disease (American trypanosomiasis), is a highly complex zoonosis that is present throughout South America, Central America, and Mexico. The transmission of this disease is influenced by various factors, including human activities like deforestation and land use changes, which may have altered the natural transmission cycles and their connection to the environment. In this study conducted in the Argentine Chaco region, we examined the transmission dynamics of T. cruzi by collecting blood samples from wild and domestic animals, as well as triatomine bugs from human dwellings, across five sites of varying anthropic intervention. Samples were analyzed for T. cruzi infection via qPCR, and we additionally examined triatomines for bloodmeal analysis via NGS amplicon sequencing. Our analysis revealed a 15.3% infection rate among 20 wild species (n = 123) and no T. cruzi presence in 9 species of domestic animals (n = 1359) or collected triatomines via qPCR. Additionally, we found chicken (34.28%), human (21.59%), and goat (19.36%) as the predominant bloodmeal sources across all sites. These findings suggest that anthropic intervention and other variables analyzed may have directly impacted the spillover dynamics of T. cruzi's sylvatic cycle and potentially reduced its prevalence in human habitats.

Prediction of Donor Heart Acceptance for Transplant and Its Clinical Implications: Results From The Donor Heart Study.

BACKGROUND: Despite a shortage of potential donors for heart transplant in the United States, most potential donor hearts are discarded. We evaluated predictors of donor heart acceptance in the United States and applied machine learning methods to improve prediction. METHODS: We included a nationwide (2005-2020) cohort of potential heart donors in the United States (n=73 948) from the Scientific Registry of Transplant Recipients and a more recent (2015-2020) rigorously phenotyped cohort of potential donors from DHS (Donor Heart Study; n=4130). We identified predictors of acceptance for heart transplant in both cohorts using multivariate logistic regression, incorporating time-interaction terms to characterize their varying effects over time. We fit models predicting acceptance for transplant in a 50% training subset of DHS using logistic regression, least absolute shrinkage and selection operator, and random forest algorithms and compared their performance in the remaining 50% (test) of the subset. RESULTS: Predictors of donor heart acceptance were similar in the nationwide and DHS cohorts. Among these, older age (P value for time interaction, 0.0001) has become increasingly predictive of discard over time while other factors, including those related to drug use, infection, and mild cardiac diagnostic abnormalities, have become less influential (P value for time interaction, <0.05 for all). A random forest model (area under the curve, 0.908; accuracy, 0.831) outperformed other prediction algorithms in the test subset and was used as the basis of a novel web-based prediction tool. CONCLUSIONS: Predictors of donor heart acceptance for transplantation have changed significantly over the last 2 decades, likely reflecting evolving evidence regarding their impact on posttransplant outcomes. Real-time prediction of donor heart acceptance, using our web-based tool, may improve efficiency during donor management and heart allocation.

Just a number? Donor age and (lack of) associated reasons for heart offer refusal.

The use of 50+ year-old donors for heart transplant (HT) is rare in the United States. We assessed reasons for this-and whether it reflects concern about age itself or associated risk factors-using a survey of US HT centers. The Donor Heart Study enrolled US adult potential heart donors from 2015 to 2020. A total of 6,814 surveys across 2,197 donors cited, on average, 2.4 reasons (per donor) for offer refusal. Age was cited often (by ≥50% of centers surveyed) for 715 donors (33%). In this subgroup, accompanying donor-related reasons for refusal were infrequent, with no cardiac abnormality cited in most cases. Donor age showed associations with (1) age as a reason for refusal and (2) discard. Both abruptly increased at age 50: 55% of 50 to 51-year-old donors were refused often due to age (vs 38% of 48-49-year-olds), and 72% were discarded (vs 55% of 48-49-year-olds), despite no evidence of a threshold effect of age on outcomes.