The Bias of Medicine in Sickle Cell Disease.

Sickle cell disease (SCD) is the most common monogenetic condition in the United States (US) and one that has been subjected to a history of negative bias. Since SCD was first described approximately 120 years ago, the medical establishment has, directly and indirectly, harmed patients by reinforcing biases and assumptions about the disease. Furthermore, negative biases and stigmas have been levied upon patients with SCD by healthcare providers and society, researchers, and legislators. This article will explore the historical context of SCD in the US; discuss specific issues in care that lead to biases, social and self-stigma, inequities in access to care, and research funding; and highlight interventions over recent years that address racial biases and stigma.

D-dimer and risk for thrombosis in adults with newly diagnosed acute lymphoblastic leukemia.

Patients with acute lymphoblastic leukemia (ALL) are at increased risk of thrombotic and/or bleeding events during early chemotherapy, especially when receiving asparaginase. D-dimer is a marker of fibrinolysis that has been associated with thrombotic risk in solid cancers and acute myeloid leukemia; however, to date, no ALL-based study has assessed D-dimer level and risk for thrombosis. We sought to examine D-dimer as a biomarker for risk of thrombosis or bleeding during ALL treatment in a retrospective cohort study at The University of Chicago. We identified 61 consecutive adult patients with ALL, gathering demographic characteristics, treatment regimens, initial biomarkers including D-dimer, and assessing occurrence of venous or arterial thrombosis and bleeding in the first 100 days after diagnosis (index). The 100-day cumulative incidence (95% confidence interval [CI]) of venous or arterial thrombosis in patients with high D-dimer (≥4 µg/mL) was 52.9% (95% CI, 26.4-73.8) compared with 13.8% (95% CI, 5.5-25.7) in patients with low to moderate D-dimer (<4 µg/mL), corresponding with a hazard ratio of 5.04 (95% CI, 1.79-14.22). When testing for potential confounders in a series of bivariate logistic regression models, the association between D-dimer and thrombosis remained after adjusting for body mass index, age, sex, asparaginase treatment, disseminated intravascular coagulation score, initial platelet level, and ALL phenotype. In conclusion, D-dimer levels at ALL diagnosis are associated with venous or arterial thrombosis at 100 days. Future studies should include D-dimer collated with other known risk factors to build a risk assessment model for thrombosis in patients with newly diagnosed ALL.

Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia: An Urgent Plea for New Treatments Is Being Answered!

The treatment of acute lymphoblastic leukemia (ALL) has dramatically changed over the past three decades. However, relapsed and/or refractory ALL still remains with a very low survival and high morbidity associated with its treatment. Here, we will review the outstanding progress that has been made in the treatment of relapsed and/or refractory ALL and discuss future directions and challenges that require further investigation.

Implementation and Assessment of a Proning Protocol for Nonintubated Patients With COVID-19.

INTRODUCTION: The COVID-19 pandemic has caused over 1,250,000 deaths worldwide. With limited therapeutic options, proning nonintubated patients emerged as a safe and affordable intervention to manage hypoxemia. METHODS: A proning protocol to identify and prone eligible patients was implemented. Patients were encouraged to self-prone for 2-3 hours, 3 times daily. Investigators created educational materials for nurses and patients and developed a COVID-19-specific proning order within the electronic health record (EHR). Investigators completed an 800-person retrospective chart review to study the implementation of this protocol. RESULTS: From March 22, 2020, to June 5, 2020, 586 patients were admitted to the COVID-19 floor. Of these patients, 42.8% were eligible for proning. Common contraindications were lack of hypoxia, altered mental status, and fall risk. The proning protocol led to a significant improvement in provider awareness of patients appropriate for proning, increasing from 12% to 83%, as measured by placement of a proning order into the EHR. There was a significant improvement in all appropriate patients documented as proned, increasing from 18% to 45% of eligible patients. CONCLUSIONS: The creation of an effective hospital-wide proning protocol to address the exigencies of the COVID-19 pandemic is possible and may be accomplished in a short period of time.

Implementing Prone Positioning for COVID-19 Patients Outside the Intensive Care Unit.

BACKGROUND: Proning intubated intensive care unit patients for the management of acute respiratory distress syndrome is an accepted standard of practice. We examined the nursing climate in 4 units and its impact on implementing a novel self-proning protocol to treat COVID-19 patients outside the intensive care unit. LOCAL PROBLEM: Nursing units previously designated for medical/surgical populations had to adjust quickly to provide evidence-based care for COVID-19 patients attempting self-proning. METHODS: Nurses from 4 nursing units were surveyed about the implementation process on the self-proning protocol. Their perception of unit implementation was assessed via the Implementation Climate Scale. INTERVENTIONS: A new self-proning nursing protocol was implemented outside the intensive care unit. RESULTS: Consistent education on the protocol, belief in the effectiveness of the intervention, and a strong unit-based climate of evidence-based practice contributed to greater implementation of the protocol. CONCLUSIONS: Implementation of a new nursing protocol is possible with strong unit-based support, even during a pandemic.

Prevalence and Outcomes of Congenital Heart Disease in Very Low Birth Weight Preterm Infants: An Observational Study From the Brazilian Neonatal Network Database.

OBJECTIVES: To evaluate the prevalence of congenital heart disease and their outcomes in a Brazilian cohort of very low birth weight preterm infants. DESIGN: Post hoc analysis of data from the Brazilian Neonatal Network database, complemented by retrospective data from medical charts and a cross-sectional survey. SETTING: Twenty public tertiary-care university hospitals. PATIENTS: A total of 13,955 newborns weighing from 401 to 1,499 g and between 22 and 36 weeks of gestational age, born from 2010 to 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The prevalence of congenital heart disease was 2.45% (95% CI, 2.20-2.72%). In a multivariate regression analysis, risk factors associated with congenital heart disease were maternal diabetes (relative risk, 1.55; 95% CI, 1.11-2.20) and maternal age above 35 years (relative risk, 2.09; 95% CI, 1.73-2.51), whereas the protection factors were maternal hypertension (relative risk, 0.54; 95% CI, 0.43-0.69), congenital infection (relative risk, 0.45; 95% CI, 0.21-0.94), and multiple gestation (relative risk, 0.73; 95% CI, 0.55-0.97). The pooled standardized mortality ratio in patients with congenital heart disease was 2.48 (95% CI, 2.22-2.80), which was significantly higher than in patients without congenital heart disease (2.08; 95% CI, 2.03-2.13). However, in multiple log-binomial regression analyses, only the presence of major congenital anomaly, gestational age (< 29 wk; relative risk, 2.32; 95% CI, 2.13-2.52), and Score for Neonatal Acute Physiology and Perinatal Extension II (> 20; relative risk, 3.76; 95% CI, 3.41-4.14) were independently associated with death, whereas the effect of congenital heart disease was spotted only when a conditional inference tree approach was used. CONCLUSIONS: The overall prevalence of congenital heart disease in this cohort of very low birth weight infants was higher and with higher mortality than in the general population of live births. The occurrence of a major congenital anomaly, gestational age (< 29 wk), and Score for Neonatal Acute Physiology and Perinatal Extension II (> 20) were significantly and independently associated with death, whereas the association of congenital heart disease and death was only evident when a major congenital anomaly was present.

Clinical and biochemical outcomes of patients with medium-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency is a fatty acid oxidation disorder that can have variable clinical severity. There is still limited information on its clinical presentation and longitudinal history by genotype, and effectiveness of newborn screening (NBS). METHODS: Retrospective data were collected from 90 patients (44 female, 46 male) to compare biochemical data with clinical outcomes. The frequency of adverse events (number of hypoglycemia-related ER visits and admissions) was assessed by genotype (homozygosity or not for the common pathogenic variant, p.Lys329Glu, in the ACADM gene), and method of diagnosis (NBS vs. clinical). RESULTS: MCAD deficiency in Utah was more frequent compared to the United States average (1: 9266 versus 1:17,759 newborns). With age, C8-carnitine did not change significantly whereas C2-carnitine decreased (p < .001), possibly reflecting reduced carnitine supplementation typically seen with age. Children with MCAD deficiency had normal growth. p.Lys329Glu homozygotes had higher NBS C8-carnitine (23.4 ± 19.6 vs. 6.6 ± 3.0 µmol/L) and lifetime plasma C8-carnitine levels (6.2 ± 5 vs. 3.6 ± 1.9 µmol/L) compared to patients with at least one other pathogenic variant (p < .001 for both) and higher transaminases compared to compound heterozygotes (ALT 41.9 ± 6.2 vs. 31.5 ± 3.7 U/L, AST 63.9 ± 5.8 vs. 45.7 ± 1.8 U/L, p < .05 for both). On average, p.Lys329Glu homozygotes had more hypoglycemic events than compound heterozygotes (1.44 versus 0.49 events/patient) as did patients diagnosed clinically compared to those diagnosed by NBS (2.15 versus 0.62 events/patient), though these differences were not statistically significant. Neonatal death was observed before results of newborn screening were available in one patient homozygous for the common p.Lys329Glu pathogenic variant, but severe neonatal complications (hypoglycemia, cardiac arrhythmia) were also seen in patients with other mutations. No irreversible complications were observed after diagnosis in any patient with MCAD deficiency. DISCUSSION: Homozygosity for the common ACADM p.Lys329Glu pathogenic variant was associated with increased levels of C8-carnitine and transaminases. Newborn screening provides the opportunity to reduce morbidity and post-neonatal mortality in all patients with MCAD deficiency, regardless of genotype.

Curcuma longa L. ameliorates asthma control in children and adolescents: A randomized, double-blind, controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Roots of Curcuma longa L. are used as medicine for millennia. They possess several pharmacological properties, including anti-inflammatory action, and can be suitable for asthma treatment. AIM OF THE STUDY: We aimed to test the hypothesis that, in children and adolescents with persistent asthma, the administration of powdered roots of C. longa for 6 months, in addition to standard treatment, compared to placebo, will result in better disease control. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled, phase II clinical trial. Patients were randomly assigned to receive 30 mg/kg/day of C. longa for 6 months, or placebo. Data were collected prospectively. All patients were categorized for asthma severity and control according to GINA-2016 and underwent pulmonary function tests. RESULTS: Overall, both groups experienced amelioration of their frequency of symptoms and interference with normal activity, but no differences were found between the two treatment groups. However, patients receiving C. longa experienced less frequent nighttime awakenings, less frequent use of short-acting ß-adrenergic agonists, and better disease control after 3 and 6 months. CONCLUSION: The powdered roots of C. longa led to less frequent nighttime awakenings, less frequent use of short-acting ß-adrenergic agonists, and better disease control after 3 and 6 months, when compared to placebo.

Transplantation of Zebrafish Pediatric Brain Tumors into Immune-competent Hosts for Long-term Study of Tumor Cell Behavior and Drug Response.

Tumor cell transplantation is an important technique to define the mechanisms controlling cancer cell growth, migration, and host response, as well as to assess potential patient response to therapy. Current methods largely depend on using syngeneic or immune-compromised animals to avoid rejection of the tumor graft. Such methods require the use of specific genetic strains that often prevent the analysis of immune-tumor cell interactions and/or are limited to specific genetic backgrounds. An alternative method in zebrafish takes advantage of an incompletely developed immune system in the embryonic brain before 3 days, where tumor cells are transplanted for use in short-term assays (i.e., 3 to 10 days). However, these methods cause host lethality, which prevents the long-term study of tumor cell behavior and drug response. This protocol describes a simple and efficient method for the long-term orthotopic transplantation of zebrafish brain tumor tissue into the fourth ventricle of a 2-day-old immune-competent zebrafish. This method allows: 1) long-term study of tumor cell behaviors, such as invasion and dissemination; 2) durable tumor response to drugs; and 3) re-transplantation of tumors for the study of tumor evolution and/or the impact of different host genetic backgrounds. In summary, this technique allows cancer researchers to assess engraftment, invasion, and growth at distant sites, as well as to perform chemical screens and cell competition assays over many months. This protocol can be extended to studies of other tumor types and can be used to elucidate mechanisms of chemoresistance and metastasis.

Energy and Protein Delivery in Overweight and Obese Children in the Pediatric Intensive Care Unit.

BACKGROUND: Early and optimal energy and protein delivery have been associated with improved clinical outcomes in the pediatric intensive care unit (PICU). Overweight and obese children in the PICU may be at risk for suboptimal macronutrient delivery; we aimed to describe macronutrient delivery in this cohort. METHODS: We performed a retrospective study of PICU patients ages 2-21 years, with body mass index (BMI) ≥85th percentile and >48 hours stay. Nutrition variables were extracted regarding nutrition screening and assessment, energy and protein prescription, and delivery. RESULTS: Data from 83 patient encounters for 52 eligible patients (52% male; median age 9.6 [5-15] years) were included. The study cohort had a longer median PICU length of stay (8 vs 5 days, P < .0001) and increased mortality rate (6/83 vs 182/5572, P = .045) than concurrent PICU patient encounters. Detailed nutrition assessment was documented for 60% (50/83) of patient encounters. Energy expenditure was estimated primarily by predictive equations. Stress factor >1.0 was applied in 44% (22/50). Median energy delivered as a percentage of estimated requirements by the Schofield equation was 34.6% on day 3. Median protein delivered as a percentage of recommended intake was 22.1% on day 3. CONCLUSIONS: The study cohort had suboptimal nutrition assessments and macronutrient delivery during their PICU course. Mortality and duration of PICU stay were greater when compared with the general PICU population. Nutrition assessment, indirect calorimetry-guided energy prescriptions, and optimizing the delivery of energy and protein must be emphasized in this cohort. The impact of these practices on clinical outcomes must be investigated.

MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells.

Malignant brain tumors are the leading cause of cancer-related deaths in children. Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are particularly aggressive embryonal tumors of unknown cellular origin. Recent genomic studies have classified CNS-PNETs into molecularly distinct subgroups that promise to improve diagnosis and treatment; however, the lack of cell- or animal-based models for these subgroups prevents testing of rationally designed therapies. Here, we show that a subset of CNS-PNETs co-express oligoneural precursor cell (OPC) markers OLIG2 and SOX10 with coincident activation of the RAS/MAPK (mitogen-activated protein kinase) pathway. Modeling NRAS activation in embryonic OPCs generated malignant brain tumors in zebrafish that closely mimic the human oligoneural/NB-FOXR2 CNS-PNET subgroup by histology and comparative oncogenomics. The zebrafish CNS-PNET model was used to show that MEK inhibitors selectively eliminate Olig2+/Sox10+ CNS-PNET tumors in vivo without impacting normal brain development. Thus, MEK inhibitors represent a promising rationally designed therapy for children afflicted with oligoneural/NB-FOXR2 CNS-PNETs.