The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration.

The eIF4E family of translation initiation factors bind 5' methylated caps and act as the limiting step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c, for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting that Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.

Transient abnormal myelopoiesis requiring advanced neonatal intensive care treatment.

AIM: Five to thirty percent of neonates with trisomy 21 develop transient abnormal myelopoiesis (TAM) with a high mortality rate. The aim of the study was to identify contributing factors that determine mortality and need for chemotherapy in this patient group. METHODS: Six-year, single-centre, retrospective study of neonatal TAM cases requiring admission to intensive care. Data were collected from electronic patient records, laboratory and genetic results. The odds ratio was calculated to assess the likelihood of neonates with certain clinical characteristics having short-term mortality and needing chemotherapy. RESULTS: Twenty-one neonates were studied with a mortality rate of 28%. Neonates requiring inotropic support (OR 19, 95% CI: 0.9-399, p = 0.05) and inhaled nitric oxide (iNO) (OR 13, 95% CI: 1.4-124.3, p = 0.03) were less likely to survive to discharge. Neonates needing mechanical ventilation (OR 14, 95% CI: 1.1-185.5, p = 0.04), or a white cell count >50 × 109/L (OR 27, 95% CI: 1.2-605.7, p = 0.04) were more likely to receive chemotherapy. CONCLUSION: A high mortality rate was identified in TAM neonates with symptomatic pulmonary hypertension (PH) needing active treatment strategies, such as inotropes and iNO. The presence of PH should be considered in the clinical management, prognosis and parental counselling.

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis.

BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).

Epstein-Barr virus (EBV) deletions as biomarkers of response to treatment of chronic active EBV.

Chronic active Epstein-Barr virus (CAEBV) disease is a rare condition characterised by persistent EBV infection in previously healthy individuals. Defective EBV genomes were found in East Asian patients with CAEBV. In the present study, we sequenced 14 blood EBV samples from three UK patients with CAEBV, comparing the results with saliva CAEBV samples and other conditions. We observed EBV deletions in blood, some of which may disrupt viral replication, but not saliva in CAEBV. Deletions were lost overtime after successful treatment. These findings are compatible with CAEBV being associated with the evolution and persistence of EBV+ haematological clones that are lost on successful treatment.

Managing Ischemic Heart Disease in Women: Role of a Women's Heart Center.

PURPOSE OF REVIEW: Heart centers for women (HCW) were developed due to the rising cardiovascular morbidity and mortality in women in the United States in the early 1990s. Our review encompasses the epidemiology, risk factors, diagnostic strategies, treatments, and the role of HCW in managing women with ischemic heart disease (IHD). RECENT FINDINGS: HCW use a multidisciplinary team to manage women with IHD. Due to the paucity of randomized controlled trials investigating various manifestations of IHD, some treatments are not evidence-based such as those for coronary microvascular dysfunction and spontaneous coronary artery dissection. Sex-specific risk factors have been identified and multimodality cardiac imaging is improving in diagnosing IHD in women. Treatments are being studied to help improve symptoms and outcomes in women with IHD. There has been progress in the care of women with IHD. HCW can be instrumental in treating women with IHD, doing research, and being a source of research study participants.

Clinical Utility of Radiologic Disease Reassessment in the Management of Pediatric B-Cell Non-Hodgkin Lymphoma.

Although outcomes for children with B-cell non-Hodgkin lymphoma are excellent, between 20% and 40% demonstrate residual radiologic abnormalities at disease assessment during consolidation therapy, the significance of which remains uncertain. The authors report the outcomes for all children treated for B-cell non-Hodgkin lymphoma at our center over an 11-year period. Twenty-four of 64 (38%) children had residual radiologic abnormalities at disease remission assessment. Seven (29%) underwent histologic biopsies that were normal. No children with residual radiologic abnormalities experienced disease relapse or death, suggesting that imaging at this time point creates clinical uncertainty without indicating residual disease or predicting relapse.

The prevalence, severity, and risk factors for dry eye disease in Dubai - a cross sectional study.

BACKGROUND: The prevalence of dry eye disease is increasing globally and requires the attention of healthcare professionals as it worsens patients' quality of life. No published studies on the epidemiology of dry eyes have been found in Dubai. PURPOSE: To describe the epidemiology, prevalence, severity, and associated factors of dry eyes in Dubai, United Arab Emirates, in 2019. METHODS: This was an analytical, cross-sectional, survey-based study. An online survey was distributed by email to Mohammed Bin Rashid University students, staff, and faculty and to the staff at Mediclinic City and Parkview Hospitals in Dubai, United Arab Emirates, from April-June 2019. The survey included demographic questions and the Ocular Surface Disease Index (OSDI). RESULTS: The survey was completed by 452 participants; the majority were females (288/452; 63.7 %). The prevalence of dry eyes in Dubai was estimated to be 62.6 % (283/452), with severely dry eyes being the most prevalent (119/283; 42 %). Females, high daily screen time (> 6 h), and the use of contact lenses were found to be associated with dry eyes (P-value < 0.05, 95 % confidence interval). Age was found to be negatively correlated with prevalence of dry eyes. Exposure to smoking/shisha, history of eye injury/surgery, and nationality were not associated with dry eyes. CONCLUSIONS: This is the first cross-sectional study to investigate the prevalence of dry eyes in Dubai (62.6 %). The majority of participants had severe dry eyes symptoms. Severely dry eyes were more common among females and users of contact lenses.

Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis.

Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered.

Expecting the unexpected: Echo laboratory preparedness in the time of COVID-19.

COVID-19 poses a unique set of challenges to the healthcare system due to its rapid spread, intensive resource utilization, and relatively high morbidity and mortality. Healthcare workers are at especially high risk of exposure given the viruses spread through close contact. Reported cardiac complications of COVID-19 include myocarditis, acute coronary syndrome, cardiomyopathy, pericardial effusion, arrhythmia, and shock. Thus, echocardiography is integral in the timely diagnosis and clinical management of COVID-19 patients. Rush University Medical Center has been at the forefront of the COVID-19 response in Illinois with high numbers of cases reported in Chicago and surrounding areas. The echocardiography laboratory at Rush University Medical Center (RUMC) proactively took numerous steps to balance the imaging needs of a busy, nearly 700-bed academic medical center while maintaining safety.

Leydig cell failure with testicular radiation doses <20Gy: The clinical effects of total body irradiation conditioned haematopoietic stem cell transplantation for childhood leukaemia during long-term follow-up.

OBJECTIVE: Testosterone replacement is generally considered likely to be required only at testicular radiation doses in excess of 20Gy. Long-term data are not available for patients receiving 9-14.4Gy as part of Total Body Irradiation in childhood. DESIGN: Retrospective cohort study. DATA COLLECTION: notes review, laboratory results, prescription of testosterone. PATIENTS: Forty-two of 96 boys who received Total Body Irradiation (9-14.4Gy) and Haematopoietic Stem Cell Transplantation for childhood leukaemia at Great Ormond Street Hospital between 1981-2011 and survived >5 years. MEASUREMENTS: The serum concentrations of testosterone and gonadotrophins and the prescription of testosterone were recorded. RESULTS: Of the 42 boys included, 37 (88%) entered puberty spontaneously and 5 required induction. Median length of follow-up was 19.4 years (range 5-33.1). At last follow-up, 23 of the 37 (62%) with spontaneous puberty were receiving testosterone replacement and 4 of the 5 (80%) with induced puberty. CONCLUSION: This study with the benefit of long follow-up indicates that Leydig cell failure occurs with radiation doses <20Gy. It may occur many years after irradiation and mandates long-term screening for hypogonadism.

Neonatal leukaemia.

Neonatal leukaemia is defined as occurring within the first 28 days of life and most, if not all, cases are congenital. With the exception of Down syndrome-associated transient abnormal myelopoiesis, which is not considered here, neonatal leukaemias are rare. In two-thirds of patients the disease manifests as an acute myeloid leukaemia, frequently with monocytic/monoblastic characteristics. Most other cases are acute lymphoblastic leukaemia, particularly B lineage, but some are mixed phenotype or blastic plasmacytoid dendritic cell neoplasms. The most frequently observed cytogenetic/molecular abnormality is t(4;11)(q21.3;q23.3)/KMT2A-AFF1 followed by t(1;22)(p13.3;q13.1)/RBM15-MKL1 and t(8;16)(p11.2;p13.3)/KAT6A-CREBBP. Common clinical features include prominent hepatosplenomegaly and a high incidence of skin involvement, sometimes in the absence of bone marrow disease. A distinctive feature is the occurrence of spontaneous remission in some cases, particularly in association with t(8;16). In this review, we summarise current knowledge of the clinical, cytogenetic and molecular features of neonatal leukaemia and discuss clinical management of these cases.