Elderly do benefit from induction chemotherapy: High dose mitoxantrone-based ("5 + 1") induction chemotherapy regimen in newly diagnosed acute myeloid leukemia.

An intensive "5 + 1" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m2 once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m2 on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%), respectively. The overall response (complete remission [CR] + CRi) was 76.2% (77/101). The median overall survival (OS) stratified by age group <60, 60-69 and ≥70 years were 56, 31 and 9 months respectively (log-rank, P = 0.02). 51.7% (45/84) of patients with intermediate/adverse risk category proceeded to allogeneic stem cell transplants. Among these 84 patients, the percentage of patients able to proceed to transplant in age groups <60, 60-69, and ≥ 70 years were 75% (18/24), 60.7% (17/28), and 31.2% (10/32), respectively. In conclusion, HDM-based chemotherapy regimen produces high CR rates, is well tolerated and more patients can undergo curative postremission therapy including stem cell transplant.

Fetal Pericardial Teratoma: Perinatal Management and Example of Preterm Cesarean Birth to Resection.

A very large fetal pericardial teratoma was diagnosed at 28 weeks' gestation, prompting urgent multidisciplinary expert consultations to weigh the risks and benefits of various prenatal invasive procedures and preterm delivery for postnatal surgical management. Ultimately, the infant was born by planned cesarean section and underwent immediate cardiopulmonary bypass and surgical resection.

Hyperbilirubinemia and Choledocholithiasis in an Extremely Premature Neonate.

Cholestasis affects 2% of newborns admitted to the neonatal intensive care unit and 20% of premature infants and requires a thoughtful evaluation and diagnostic workup.There may be a single responsible etiology, or its development may be multifactorial. Premature neonates are especially predisposed because of their increased risk of infections and acute illness, need for parenteral nutrition, and exposure to certain medications. Clinically, an infant may present with jaundice, evidence of hepatic injury, or worsening hepatic function. Diagnosis may be made in consultation with various pediatric subspecialists including gastroenterology, genetics, and surgery. Treatment depends on the etiology but may include medications or surgical interventions. Timely recognition and intervention improve outcomes. [Pediatr Ann. 2023;52(8):e297-e302.].

Prenatal Congenital Heart Disease and Placental Phenotypes: Preserved Neonatal Weight Despite Small Placentas.

Background: Congenital heart disease (CHD) affects 8 in 1,000 live births with significant postnatal implications including growth failure, neurodevelopmental delay, and mortality. The placenta develops concomitantly with the fetal heart. High rates of placental pathology and discordant growth in pregnancies affected by CHD highlight the significance of the fetal-placental-cardiac axis. Objectives: This study aimed to characterize the relationship between neonatal birthweight (BW), head circumference, placental weight (PW), and placental pathology in pregnancies affected by CHD. PW:BW provides a surrogate to assess placental efficiency, or nutrient exchange and delivery by the placenta, across CHD phenotypes. Methods: Retrospective cohort of 139 live-born singletons with postnatally confirmed CHD with placental pathology. Placental examination, infant BW, head circumference, and CHD categories (septal defects, right-sided defects, left-sided defects, conotruncal anomalies, and others) were included. Chi-square, Fisher's exact, or Kruskall-Wallis tests and multinomial logistic regressions, as appropriate. Results: Median birthweight and head circumference percentile was 33 and 35, respectively. Placental pathology was documented in 37% of cases. PW to BW ratios were <10th percentile for 78% and <3rd percentile for 54% of the cohort, with no difference between CHD categories (P = 0.39 and P = 0.56, respectively). Conclusions: Infants with CHD have preserved BW and head circumferences in the setting of small placentas and increased prevalence of placental pathology, suggesting placental efficiency. Detection of abnormal placental growth could add prenatal diagnostic value. Placental and neonatal discordant growth may allude to a vascular anomaly predisposing fetuses to developing CHD. Further studies are needed to explore fetal nutrient delivery and utilization efficiency.

Integration of Prenatal Cardiovascular Magnetic Resonance Imaging in Congenital Heart Disease.

Standard of care echocardiography can have limited diagnostic accuracy in certain cases of fetal congenital heart disease. Prenatal cardiovascular magnetic resonance (CMR) imaging has potential to provide additional anatomic imaging information, including excellent soft tissue images in multiple planes, improving prenatal diagnostics and in utero hemodynamic assessment. We conducted a literature review of fetal CMR, including its development and implementation into clinical practice, and compiled and analyzed the results. Our findings included the fact that technological and innovative approaches are required to overcome some of the challenges in fetal CMR, in part due to the dynamic nature of the fetal heart. A number of reconstruction algorithms and cardiac gating strategies have been developed over time to improve fetal CMR image quality, allowing unique investigations into fetal hemodynamics, oxygenation, and growth. Studies demonstrate that incorporating CMR in the prenatal arena influences postnatal clinical management. With further refinement and experience, fetal CMR in congenital heart disease continues to evolve and demonstrate ongoing potential as a complementary imaging modality to fetal echocardiography in the care of these patients.

Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models.

Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic, latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins, with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing-antibody titers were higher at 1 month and declined far less by 8 months in mRNA- compared with protein-immunized animals. Both vaccines protected against death and genital lesions when infected 1 month after immunization; however, protection was more durable in the mRNA group compared with the protein group when infected after 8 months, an interval representing greater than 15% of the animal's lifespan. Serum and vaginal neutralizing-antibody titers correlated with protection against infection, as measured by genital lesions and vaginal virus titers 2 days after infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times after immunization that persisted for up to 1 year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.

Vaccines to prevent genital herpes.

Genital herpes increases the risk of acquiring and transmitting Human Immunodeficiency Virus (HIV), is a source of anxiety for many about transmitting infection to intimate partners, and is life-threatening to newborns. A vaccine that prevents genital herpes infection is a high public health priority. An ideal vaccine will prevent both genital lesions and asymptomatic subclinical infection to reduce the risk of inadvertent transmission to partners, will be effective against genital herpes caused by herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and will protect against neonatal herpes. Three phase 3 human trials were performed over the past 20 years that used HSV-2 glycoproteins essential for virus entry as immunogens. None achieved its primary endpoint, although each was partially successful in either delaying onset of infection or protecting a subset of female subjects that were HSV-1 and HSV-2 uninfected against HSV-1 genital infection. The success of future vaccine candidates may depend on improving the predictive value of animal models by requiring vaccines to achieve near-perfect protection in these models and by using the models to better define immune correlates of protection. Many vaccine candidates are under development, including DNA, modified mRNA, protein subunit, killed virus, and attenuated live virus vaccines. Lessons learned from prior vaccine studies and select candidate vaccines are discussed, including a trivalent nucleoside-modified mRNA vaccine that our laboratory is pursuing. We are optimistic that an effective vaccine for prevention of genital herpes will emerge in this decade.

Protection against herpes simplex virus type 2 infection in a neonatal murine model using a trivalent nucleoside-modified mRNA in lipid nanoparticle vaccine.

Neonatal herpes is a dreaded complication of genital herpes infection in pregnancy. We recently compared two vaccine platforms for preventing genital herpes in female mice and guinea pigs and determined that HSV-2 glycoproteins C, D and E expressed using nucleoside-modified mRNA in lipid nanoparticles provided better protection than the same antigens produced as baculovirus proteins and administered with CpG and alum. Here we evaluated mRNA and protein immunization for protection against neonatal herpes. Female mice were immunized prior to mating and newborns were infected intranasally with HSV-2. IgG binding and neutralizing antibody levels in mothers and newborns were comparable using the mRNA or protein vaccines. Both vaccines protected first and second litter newborns against disseminated infection based on virus titers in multiple organs. We conclude that both vaccines are efficacious at preventing neonatal herpes, which leaves the mRNA vaccine as our preferred candidate based on better protection against genital herpes.

The Immunogenicity of Peptoid-Protein Conjugates.

We demonstrate that a peptoid composed of five monomers and attached via a maleimide linker to a carrier protein elicits anti-peptoid, anti-linker and anti-carrier antibodies in rabbits. Specific anti-peptoid antibodies were affinity purified and used to reproducibly retrieve three specific peptoid-coupled beads from 20,000 irrelevant peptoid-beads using magnetic screening.

Cdx4 and menin co-regulate Hoxa9 expression in hematopoietic cells.

BACKGROUND: Transcription factor Cdx4 and transcriptional coregulator menin are essential for Hoxa9 expression and normal hematopoiesis. However, the precise mechanism underlying Hoxa9 regulation is not clear. METHODS AND FINDINGS: Here, we show that the expression level of Hoxa9 is correlated with the location of increased trimethylated histone 3 lysine 4 (H3K4M3). The active and repressive histone modifications co-exist along the Hoxa9 regulatory region. We further demonstrate that both Cdx4 and menin bind to the same regulatory region at the Hoxa9 locus in vivo, and co-activate the reporter gene driven by the Hoxa9 cis-elements that contain Cdx4 binding sites. Ablation of menin abrogates Cdx4 access to the chromatin target and significantly reduces both active and repressive histone H3 modifications in the Hoxa9 locus. CONCLUSION: These results suggest a functional link among Cdx4, menin and histone modifications in Hoxa9 regulation in hematopoietic cells.