Surgical Protocol for Partial Heart Transplantation in Growing Piglets.

Partial heart transplantation is a new approach to deliver growing heart valve implants. Partial heart transplants differ from heart transplants because only the part of the heart containing the necessary heart valve is transplanted. This allows partial heart transplants to grow, similar to the valves in heart transplants. However, the transplant biology of partial heart transplantation remains unexplored. This is a critical barrier to progress of the field. Without knowledge about the specific transplant biology of partial heart transplantation, children with partial heart transplants are empirically treated like children with heart transplants because the valves in heart transplants are known to grow. In order to progress the field, an animal model for partial heart transplantation is necessary. Here, we contribute our surgical protocol for partial heart transplantation in growing piglets. All aspects of partial heart transplantation, including the donor procedure, the recipient procedure, and recipient perioperative care are described in detail. There are important nuances in the conduct of virtually all aspects of open heart surgery that differs in piglets from humans. Our surgical protocol, which is based on our experience with 34 piglets, will allow other investigators to leverage our experience to seek fundamental knowledge about the nature of partial heart transplants. This is significant because the partial heart transplant model in piglets is complex and very resource intensive.

Survival after partial heart transplantation in a piglet model.

Partial heart transplantation (PHT) is a novel surgical approach that involves transplantation of only the part of the heart containing a valve. The rationale for this approach is to deliver growing heart valve implants that reduce the need for future re-operations in children. However, prior to clinical application of this approach, it was important to assess it in a preclinical model. To investigate PHT short-term outcomes and safety, we performed PHT in a piglet model. Yorkshire piglets (n = 14) were used for PHT of the pulmonary valve. Donor and recipient pairs were matched based on blood types. The piglets underwent PHT at an average age of 44 days (range 34-53). Post-operatively, the piglets were monitored for a period of two months. Of the 7 recipient piglets, one mortality occurred secondary to anesthesia complications while undergoing a routine echocardiogram on post-operative day 19. All piglets had appropriate weight gain and laboratory findings throughout the post-operative period indicating a general state of good health and rehabilitation after undergoing PHT. We conclude that PHT has good short-term survival in the swine model. PHT appears to be safe for clinical application.

Parents' decision-making for their foetus or neonate with a severe congenital heart defect.

BACKGROUND: Parents who receive a diagnosis of a severe, life-threatening CHD for their foetus or neonate face a complex and stressful decision between termination, palliative care, or surgery. Understanding how parents make this initial treatment decision is critical for developing interventions to improve counselling for these families. METHODS: We conducted focus groups in four academic medical centres across the United States of America with a purposive sample of parents who chose termination, palliative care, or surgery for their foetus or neonate diagnosed with severe CHD. RESULTS: Ten focus groups were conducted with 56 parents (Mage = 34 years; 80% female; 89% White). Results were constructed around three domains: decision-making approaches; values and beliefs; and decision-making challenges. Parents discussed varying approaches to making the decision, ranging from relying on their "gut feeling" to desiring statistics and probabilities. Religious and spiritual beliefs often guided the decision to not terminate the pregnancy. Quality of life was an important consideration, including how each option would impact the child (e.g., pain or discomfort, cognitive and physical abilities) and their family (e.g., care for other children, marriage, and career). Parents reported inconsistent communication of options by clinicians and challenges related to time constraints for making a decision and difficulty in processing information when distressed. CONCLUSION: This study offers important insights that can be used to design interventions to improve decision support and family-centred care in clinical practice.

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study.

BACKGROUND: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. METHODS: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. FINDINGS: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. INTERPRETATION: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. FUNDING: Blueprint Medicines.

Left-sided congenitally unguarded tricuspid valve with congenitally corrected transposition of the great arteries: A rare diagnosis confirmed by three-dimensional echocardiography.

Left-sided unguarded tricuspid valve disease with congenitally corrected transposition of the great arteries (ccTGA) is a rare cardiac malformation, only reported a few times in the literature. Two-dimensional echocardiography (2DE) uses standard views to diagnose tricuspid valve disease. Advanced imaging techniques, such as three-dimensional echocardiography, allow for simultaneous visualization of the tricuspid valve annulus and all leaflets. Three-dimensional echocardiography (3DE) may be useful in distinguishing unguarded tricuspid valve orifice from other forms of tricuspid valve disease.

Medical Student Comfort With Procedural Skills Performance Based on Elective Experience and Career Interest.

Introduction Despite increased efforts, studies suggest that exposure to procedural skills in undergraduate medical training is insufficient. As medical students have low self-reported competence in many skills, a significant concern is that medical students are underprepared for a clerkship. Furthermore, pre-clerkship electives selected based on student career interests can provide students with additional skills learning opportunities. The impact of career interest and elective choice on student comfort with procedural skills is unclear. This study examines the relationship between student procedural skills comfort, career interest, and elective choices. Materials and methods An evidence-based questionnaire was synthesized following a literature search using PubMed, Embase, and Google Scholar. Surveys were completed by second-year medical students. A Likert scale was used to evaluate students' exposure, comfort, and motivation to learn common procedural skills. Descriptive, Pearson's chi-square and Spearman's rho correlation coefficient analyses were performed to evaluate the relationship between career interests, elective exposure, and procedural skills. Results Medical students (>60%) reported poor comfort levels for most skills, despite >80% of students displaying high motivation to learn. Elective choice impacted student comfort levels as students who completed electives in anesthesiology were more comfortable with performing intubation (23% vs 10%, p = 0.026) and IV insertion (38% vs 13%, p = 0.002). Those with surgical career interests were less comfortable performing Foley catheter insertion in males (7% vs 5%, p = 0.033) and in females (7% vs 5%, p = 0.008). Conclusions This study supports that medical students feel low levels of comfort with performing procedural skills despite high motivation for learning. Comfort was influenced by both career interest and elective experience. Programs aiming to increase students' comfort levels in performing procedural skills should adapt curricula toward increasing early exposure to these skills.

Gestational Age, Birth Weight, and Outcomes Six Years After the Norwood Procedure.

BACKGROUND: Preterm delivery and low birth weight (LBW) are generally associated with worse outcomes in hypoplastic left heart syndrome (HLHS), but an individual preterm or small neonate may do well. We sought to explore the interactions between gestational age, birth weight, and birth weight for gestational age with intermediate outcomes in HLHS. METHODS: We analyzed survival, growth, neurodevelopment, length of stay, and complications to age 6 years in subjects with HLHS from the Single Ventricle Reconstruction trial. Univariate and multivariable survival and regression analyses examined the effects and interactions of LBW (<2500 g), weight for gestational age, and gestational age category. RESULTS: Early-term delivery (n = 234) was more common than term (n = 219) delivery. Small for gestational age (SGA) was present in 41% of subjects, but only 14% had LBW. Preterm, compared with term, delivery was associated with an increased risk of death or transplant at age 6 years (all: hazard ratio = 2.58, confidence interval = 1.43-4.67; Norwood survivors: hazard ratio = 1.96, confidence interval = 1.10-3.49) independent of LBW and weight for gestational age. Preterm delivery, early-term delivery, LBW, and SGA were each associated with lower weight at 6 years. Neurodevelopmental outcomes were worst in the LBW cohort. CONCLUSIONS: Preterm delivery in HLHS was associated with worse survival, even beyond Norwood hospitalization. LBW, SGA, and early-term delivery were associated with worse growth but not survival. LBW was associated with worse neurodevelopment, despite similar length of stay and complications. These data suggest that preterm birth and LBW (although often concomitant) are not equivalent, impacting clinical outcomes through mechanisms independent of perioperative course complexity.

Improving maternal-infant bonding after prenatal diagnosis of CHD.

BACKGROUND: Infants with prenatally diagnosed CHD are at high risk for adverse outcomes owing to multiple physiologic and psychosocial factors. Lack of immediate physical postnatal contact because of rapid initiation of medical therapy impairs maternal-infant bonding. On the basis of expected physiology, maternal-infant bonding may be safe for select cardiac diagnoses. METHODS: This is a single-centre study to assess safety of maternal-infant bonding in prenatal CHD. RESULTS: In total, 157 fetuses with prenatally diagnosed CHD were reviewed. On the basis of cardiac diagnosis, 91 fetuses (58%) were prenatally approved for bonding and successfully bonded, 38 fetuses (24%) were prenatally approved but deemed not suitable for bonding at delivery, and 28 (18%) were not prenatally approved to bond. There were no complications attributable to bonding. Those who successfully bonded were larger in weight (3.26 versus 2.6 kg, p<0.001) and at later gestation (39 versus 38 weeks, p<0.001). Those unsuccessful at bonding were more likely to have been delivered via Caesarean section (74 versus 49%, p=0.011) and have additional non-cardiac diagnoses (53 versus 29%, p=0.014). There was no significant difference regarding the need for cardiac intervention before hospital discharge. Infants who bonded had shorter hospital (7 versus 26 days, p=0.02) and ICU lengths of stay (5 versus 23 days, p=0.002) and higher survival (98 versus 76%, p<0.001). CONCLUSION: Fetal echocardiography combined with a structured bonding programme can permit mothers and infants with select types of CHD to successfully bond before ICU admission and intervention.

Reproducibility of Left Ventricular Dimension Versus Area Versus Volume Measurements in Pediatric Patients With Dilated Cardiomyopathy.

BACKGROUND: Multiple echocardiographic methods are used to measure left ventricular size and function. Clinical management is based on individual evaluations and longitudinal trends. The Pediatric Heart Network VVV study (Ventricular Volume Variability) in pediatric patients with dilated cardiomyopathy has reported reproducibility of several of these measures, and how disease state and number of beats impact their reproducibility. In this study, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the best method for both individual and sequential evaluations. METHODS AND RESULTS: In 8 centers, echocardiograms were obtained on 169 patients prospectively. During the same visit, 2 different sonographers acquired the same imaging protocol on each patient. Each acquisition was analyzed by 2 different observers; first observer analyzed the first acquisition twice. Intraobserver, interobserver, interacquisition, and interobserver-acquisition (different observers and different acquisition) reproducibility were assessed on measurements of left ventricular end-diastolic dimension, area, and volume. Left ventricular shortening fraction, ejection fraction, mass, and fractional area change were calculated. Percent difference was calculated as (interobservation difference/mean)×100. Interobserver reproducibility for both acquisitions was better for both volume and dimension measurements (P≤0.002) compared with area measurements, whereas intraobserver, interacquisition (for both observers), and interobserver-acquisition reproducibilities (for both observer-acquisition sets) were best for volume measurements (P≤0.01). Overall, interobserver-acquisition percent differences were significantly higher than interobserver and interacquisition percent differences (P<0.001). CONCLUSIONS: In pediatric patients with dilated cardiomyopathy, compared with dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00123071.

Traumatic Gerbode ventricular septal defect and third-degree heart block.

We present an interesting and rare case of traumatic Gerbode ventricular septal defect and complete heart block. The multimodality images illustrate the diagnosis well. This case is an excellent demonstration of the diagnostic utility of multimodality imaging.

Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles.

OBJECTIVE: To assess the variability in asymmetric growth and its association with neurodevelopment in infants with single ventricle (SV). STUDY DESIGN: We analyzed weight-for-age z-score minus head circumference-for-age z-score (HCAZ), relative head growth (cm/kg), along with individual growth variables in subjects prospectively enrolled in the Infant Single Ventricle Trial. Associations between growth indices and scores on the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II (BSID-II) at 14 months were assessed. RESULTS: Of the 230 subjects enrolled in the Infant Single Ventricle trial, complete growth data and BSID-II scores were available in 168 (73%). Across the cohort, indices of asymmetric growth varied widely at enrollment and before superior cavopulmonary connection (SCPC) surgery. BSID-II scores were not associated with these asymmetry indices. In bivariate analyses, greater pre-SCPC HCAZ correlated with higher MDI (r = 0.21; P = .006) and PDI (r = 0.38; P < .001) and a greater HCAZ increase from enrollment to pre-SCPC with higher PDI (r = 0.15; P = .049). In multivariable modeling, pre-SCPC HCAZ was an independent predictor of PDI (P = .03), but not MDI. CONCLUSION: In infants with SV, growth asymmetry was not associated with neurodevelopment at 14 months, but pre-SCPC HCAZ was associated with PDI. Asymmetric growth, important in other high-risk infants, is not a brain-sparing adaptation in infants with SV. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00113087.

Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants.

OBJECTIVE: Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. METHODS: The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. RESULTS: Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058). CONCLUSIONS: These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

Anti-hypertensive drugs in children and adolescents.

Worldwide the prevalence of essential hypertension in children and adolescents continues to increase. Traditionally providers have used "off-label" drugs to treat pediatric hypertension, meaning that rigorous clinical trials of these drugs have not been specifically performed in pediatric patient populations. Consequently providers have extrapolated dosing, safety and efficacy from trials in adults. This practice is sub-optimal as children demonstrate unique differences in drug metabolism and response. Use of unstudied or understudied drugs increases risk of adverse events and/or can lead to sub-optimal efficacy. Recognizing these concerns, regulatory agencies have created financial incentives for industry to conduct pediatric clinical trials. These incentives, coupled with the emerging pediatric hypertension epidemic, have spurred over 30 clinical trials of anti-hypertensive drugs over the past 15 years and have resulted in labeling of 10 new drugs by the United States Food and Drug Administration for treatment of hypertension in children and adolescents. Unfortunately the financial incentive structures focus on newer drugs and drug classes. Consequently there is now a relative dearth of trial data for older but sometimes commonly prescribed pediatric antihypertensive drugs. This article reviews recent pediatric antihypertensive drug trials with a focus on trial design and endpoints, drug dosing, safety, efficacy and specific drug indications. We also review the available data and experience for some of the more commonly prescribed, but less well studied "older" pediatric antihypertensive drugs.

Corynebacterium endocarditis of a percutaneously placed transcatheter pulmonary valve.

We report a case of endocarditis of a transcatheter pulmonary valve-in-valve in a 14-year-old boy with tetralogy of Fallot. He presented with recurrent low-grade fevers, lethargy, and anorexia. Multiple blood cultures grew a gram-positive rod, Corynebacterium pseudodiphtheriticum. He was taken to the operating room for removal of the vegetative endocarditis and pulmonary valve replacement.

Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents.

OBJECTIVE: The importance of maternal autoantibody levels in congenital heart block and elucidation of maternal factors that may reduce disease burden require further clarification. STUDY DESIGN: Pregnancies complicated by maternal anti-Ro antibodies from 2007 through 2011 were retrospectively reviewed. RESULTS: In all, 33 women were followed up throughout pregnancy. Semiquantitative maternal anti-La levels were significantly higher in pregnancies complicated by fetal heart block of any degree (median difference, 227.5; P = .04), but there was no difference in maternal anti-Ro levels. In all, 94% of fetuses maintained normal conduction when the mother was treated with hydroxychloroquine or daily prednisone therapy throughout pregnancy, compared to 59% in the untreated group (odds ratio, 0.1; P = .04). CONCLUSION: Pregnancies complicated by fetal heart block did not have higher levels of maternal anti-Ro antibodies. Maternal anti-La level may be a useful predictor of fetal heart block. Maternal treatment with either hydroxychloroquine or daily low-dose prednisone throughout pregnancy may provide a protective effect.

Does initial shunt type for the Norwood procedure affect echocardiographic measures of cardiac size and function during infancy?: the Single Vventricle Reconstruction trial.

BACKGROUND: The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle-pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age. METHODS AND RESULTS: A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5 ± 13.4 days), before stage II procedure (age 4.8 ± 1.8 months), and at 14 months (age 14.3 ± 1.2 months). Mean right ventricular ejection fraction was <50% at all intervals for both groups and was higher in the RVPAS group after Norwood procedure (49 ± 7% versus 44 ± 8%; P<0.001) but was similar by 14 months. Tricuspid and neoaortic regurgitation, diastolic function, and pulmonary artery and arch dimensions were similar in the 2 groups at all intervals. Neoaortic annulus area (4.2 ± 1.2 versus 4.9 ± 1.2 cm(2)/m(2)), systolic ejection times (214.0 ± 29.4 versus 231.3 ± 28.6 ms), neoaortic flow (6.2 ± 2.4 versus 9.4 ± 3.4 L/min per square meter), and peak arch velocity (1.9 ± 0.7 versus 2.2 ± 0.7 m/s) were lower at both interstage examinations in the RVPAS compared with the modified Blalock-Taussig shunt group (P<0.001 for all), but all were similar at 14 months. CONCLUSIONS: Indices of cardiac size and function after the Norwood procedure are similar for modified Blalock-Taussig shunt and RVPAS by 14 months of age. Interstage differences between shunt types can likely be explained by the physiology created when the shunts are in place rather than by intrinsic differences in cardiac function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Isolated right subclavian artery arising from the right pulmonary artery via a right-sided ductus arteriosus with associated pulmonary steal phenomenon.

We present a patient with DiGeorge syndrome and an isolated right subclavian artery arising from the right pulmonary artery via a right-sided ductus arteriosus. The patient showed a subclavian and pulmonary steal with perfusion of the right arm and right lung via retrograde circulation in the right vertebral artery. The patient underwent successful surgical repair.

Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor.

OBJECTIVE: Increasing HDL levels is a potential strategy for the treatment of atherosclerosis. METHODS AND RESULTS: ITX5061, a molecule initially characterized as a p38 MAPK inhibitor, increased HDL-C levels by 20% in a human population of hypertriglyceridemic subjects with low HDL levels. ITX5061 also moderately increased apoA-I but did not affect VLDL/LDL cholesterol or plasma triglyceride concentrations. ITX5061 increased HDL-C in WT and human apoA-I transgenic mice, and kinetic experiments showed that ITX5061 decreased the fractional catabolic rate of HDL-CE and reduced its hepatic uptake. In transfected cells, ITX5061 inhibited SR-BI-dependent uptake of HDL-CE. Moreover, ITX5061 failed to increase HDL-C levels in SR-BI(-/-) mice. To assess effects on atherosclerosis, ITX5061 was given to atherogenic diet-fed Ldlr(+/-) mice with or without CETP expression for 18 weeks. In both the control and CETP-expressing groups, ITX5061-treated mice displayed reductions of early atherosclerotic lesions in the aortic arch -40%, P<0.05), and a nonsignificant trend to reduced lesion area in the proximal aorta. CONCLUSIONS: Our data indicate that ITX5061 increases HDL-C levels by inhibition of SR-BI activity. This suggests that pharmacological inhibition of SR-BI has the potential to raise HDL-C and apoA-I levels without adverse effects on VLDL/LDL cholesterol levels in humans.

Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist.

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34(+) bone marrow cells into CD41(+) megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.

Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.

A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.