Blood counts in children with Down syndrome.

BACKGROUND: Children with Down syndrome (DS) are more likely to have hematologic and immunologic abnormalities compared to their typically developing peers, but normal ranges have not been defined. The goal of this study was to create references for complete blood counts (CBCs) in patients with DS. METHODS: A retrospective investigation of 355 (male = 196, 55.2%; mean age = 6.49 years, SD = 5.07) healthy pediatric patients with DS who received a CBC between 2011 and 2017 as part of their medical care at a single, large, pediatric teaching hospital. Control data on 770 healthy patients without DS were included. Descriptive statistics were performed on demographic and clinical characteristics. Kruskal-Wallis H tests, nested analysis-of-variance tests, and t-tests were run to determine the significant associations. RESULTS: Age-related normative curves for healthy children with DS outlining 2.5th, 25th, 50th, 75th, and 97.5th percentiles are provided for total white blood count, hemoglobin concentration, hematocrit, mean corpuscular volume, and platelet, absolute neutrophil, absolute lymphocyte, eosinophil, monocyte, and basophil counts. Statistical differences were found between children with and without DS receiving care at the same hospital based on matched age/sex groups. CONCLUSIONS: This study demonstrates that patients with DS have different reference ranges for multiple blood counts compared to those without DS, creating a new resource for pediatricians to refer to when evaluating CBCs in this population.

Incorporating genetic counseling into the evaluation of pediatric bone marrow failure.

The timely identification of germline genetic causes of pediatric bone marrow failure (BMF) impacts medical screening practices, family counseling, therapeutic decision-making, and risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). At diagnosis, treatment decisions need to be made quickly to mitigate risks associated with profound cytopenias. As genetic testing options are rapidly evolving, an efficient multi-disciplinary approach and algorithm, including early involvement of a genetics team, is needed to expedite diagnosis and therapeutic decision-making. This process aids in the identification of appropriate candidates for molecular genetic testing. We present our single center experience reviewing the implementation of genetic counseling and a diagnostic and therapeutic algorithm used to guide genetic evaluation of pediatric BMF. Disease-specific next-generation sequencing (NGS) panels were most often pursued in patients who presented with a clinical phenotype consistent with a known inherited BMF syndrome and when trying to reduce incidental or uninformative results. Broader BMF NGS panels were most often utilized when unable to narrow the suspected etiology to a single disorder. Whole exome sequencing helped with optimizing treatment decision-making in higher risk children with BMF who required expedited hematopoietic stem cell transplantation. The experience has led to improvements to our process for evaluating patients with BMF.

Autoimmune cytopenias following allogeneic hematopoietic stem cell transplant in pediatric patients: Response to therapy and late effects.

BACKGROUND: Autoimmune cytopenias (AICs) are rare, but serious complications of allogeneic hematopoietic cell transplantation (allo-HSCT). PROCEDURE: We performed a case-control study using 20 pediatric AIC cases and 40 controls, matched by stem cell source and primary indication comparing clinical and transplant characteristics, treatment, outcomes, and late effects. RESULTS: Cases were more likely to be human leukocyte antigen mismatched (P = 0.04). There was no difference in conditioning regimen, serotherapy use, graft-versus-host disease (GVHD) prophylaxis, incidence of acute or chronic GVHD, ABO compatibility, infections, and donor engraftment. The median time to AIC onset was 219 days (range, 97-1205 days) and AIC resolution was 365 days (range, 10 days to 2737.5 days). First-line therapies for AIC patients most commonly included corticosteroids (75%) and rituximab (55%). Only 25% of patients responded to first-line treatment. At a median of 611.5 days from last rituximab dose, 82.5% patients were still receiving intravenous immune globulin for hypogammaglobulinemia compared with 2.5% of controls (P < 0.0001). Iron overload was higher in AIC patients (P = 0.0004), as was avascular necrosis (P = 0.04). There was no difference in overall survival at one year after HSCT (85% vs 82.5%). Two patients with refractory autoimmune hemolytic anemia responded to daratumumab and had resolution of B-cell aplasia. CONCLUSIONS: In this study, we find poor initial responses to AIC-directed therapies and significant late effects.

Red cell exchange transfusion halts progressive proliferative sickle cell retinopathy in a teenaged patient with hemoglobin SC disease.

A male with sickle SC disease presented at age 8 years with proliferative sickle cell retinopathy (PSCR) and bilateral vitreous hemorrhage which spontaneously resolved, then recurred at 13 years of age. Despite conventional therapy with repeated pan-retinal photocoagulation and pars plana vitrectomy, he developed progressive PSCR and recurrent vitreous hemorrhage over the next 30 months. We describe the successful use of chronic red cell exchange transfusion (RCE) to preserve his vision and stabilize the retinopathy.

Therapy Selection for Hodgkin Lymphoma in Sickle Cell Disease: balancing risks and benefits.

Advances in treatment have reduced mortality from Hodgkin lymphoma; therefore, greater attention should be focused on minimizing the late effects. A variety of risk-adapted treatment regimens exist that prioritize disease presentation but not patient-specific comorbidities. Herein, we describe a patient with sickle cell disease diagnosed with Hodgkin lymphoma and the considerations made in treatment planning to minimize therapy-related acute toxicity and late effects that overlap with the patient's preexisting sickle cell disease complications.

Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.

Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.

A Quality Initiative to Decrease Time to Antibiotics in Children with Sickle Cell Disease and Fever.

Children with sickle cell disease (SCD) are at increased risk for sepsis secondary to functional asplenia. Timely administration of antibiotics, within 60 minutes of triage, is a national indicator of quality SCD care in the United States. However, there are no reports demonstrating the feasibility of doing so in the outpatient hematology-oncology clinic setting. LOCAL PROBLEM: At baseline, in our pediatric hematology-oncology outpatient center, just 10% of children with SCD and fever received timely antibiotics. METHODS: We implemented a process improvement initiative for children with SCD and fever with the aim of ≥90% receiving timely antibiotics. We enacted interventions focused on general clinic processes from check-in to antibiotics and population-specific interventions, including an intravenous access protocol, notification/communication among staff members, and design of an electronic order set. RESULTS: The percentage of children receiving timely antibiotics improved from 10% to 77% with successful maintenance following the interventions. Residual delays are due to nonexpeditious order placement and difficult intravenous access. CONCLUSION: Improving the timely administration of antibiotics in the outpatient hematology-oncology clinic setting for children with SCD and fever is possible. Achieving at least 90% timely antibiotics for children with SCD and fever in the outpatient clinic setting will require ongoing efforts at expeditious order placement and intravenous access.

Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects.

Severe congenital neutropenia type 4 (SCN-4) is an autosomal recessive condition in which mutations in the G6PC3 gene encoding for the catalytic 3 subunit of glucose-6-phosphatase-ß result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by compound heterozygous mutations in G6PC3, a previously identified missense mutation in exon 6 (c.758G>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony-stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient's neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope-labeled tracers (U-13C-glucose, 13C,15N-glutamine, and U-13C-fructose) demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool, which could explain the dramatic cell dysfunction displayed by the patient's neutrophils. Preliminary experiments with fructose supplementation to bypass the enzyme block demonstrated that the metabolic profile could be reversed, but was not sustained long enough for functional improvement. In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.

Large cell neuroendocrine tumor of the cervix and human papillomavirus 16: a case report.

BACKGROUND: Large cell neuroendocrine cancer of the cervix is a rare entity. Most cervical cancers are high-risk human papillomavirus (HPV)-related neoplasms. CASE: A 31-year-old woman presented with pelvic pain and daily vaginal bleeding for 6 months. Uterine curettage revealed an undifferentiated malignancy. A total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic, common iliac, and periaortic lymphadenectomy and peritoneal cytology were performed. The pathological findings revealed a poorly differentiated large cell neuroendocrine carcinoma of the cervix with metastasis to 1 right obturator lymph node. Nonisotopic in situ hybridization stains were positive for high-risk HPV in the cervical tumor and in the lymph node metastasis in virtually every tumor cell indicative of viral integration into the host genome. Specific HPV typing by polymerase chain reaction was positive for HPV-16. CONCLUSIONS: Integration of high-risk HPV, in particular type 16, is associated with this uncommon variant of cervical carcinoma.

Shared brain areas but not functional connections controlling movement timing and order.

Virtually every aspect of the enormous repertoire of human behaviors is embedded in a sequential context, but brain mechanisms underlying the adjustment of two fundamental dimensions defining a motor sequence (order of a series of movements and intervals separating them) as a function of a given goal are poorly understood. Using functional magnetic resonance imaging, we demonstrate that, at the neuronal level, these tasks can only be distinguished by differences in functional interactions between associative areas of common activation, which included bilateral subcortico-parieto-frontal regions, and two subcortical structures. Activity in these shared associative areas was preferentially coupled with that in right putamen during manipulation of timing and with that in right posterior cerebellum during manipulation of serial order. This finding is important because it provides evidence for an efficient organization of the brain during cognitive control of motor sequences and supports a recently proposed principle according to which the role of brain regions involved in different behavioral tasks without differential alterations in their measured activity depends on changes in their interactions with other connected areas as a function of the tasks.

Frontal cortex functional connectivity changes during sound categorization.

Using functional connectivity analysis of functional magnetic resonance imaging data, we investigated the role of the inferior frontal gyrus in categorization of simple sounds. We found stronger functional connectivity between left inferior frontal gyrus and auditory processing areas in the temporal cortex during categorization of speech (vowels, syllables) and nonspeech (tones, combinations of tones and sweeps) sounds relative to an auditory discrimination task; the hemispheric lateralization varied depending on the speech-like properties of the sounds. Our results attest to the importance of interactions between temporal cortex and left inferior frontal gyrus in sound categorization. Further, we found different functional connectivity patterns between left inferior frontal gyrus and other brain regions implicated in categorization of syllables compared with other stimuli, reflecting the greater facility for categorization of syllables.

Recovery outcomes of schizophrenia patients treated with paliperidone palmitate in a community setting: patient and provider perspectives on recovery.

OBJECTIVES: This study evaluated the effect of paliperidone palmitate long-acting injectable (LAI) antipsychotic on recovery-oriented mental health outcomes from the perspective of healthcare providers and patients during the treatment of patients with schizophrenia or schizoaffective disorders. METHODS: Archival data for patients with a primary diagnosis of schizophrenia or schizoaffective disorder receiving ≥6 months of paliperidone palmitate LAI were retrieved from the electronic medical records system at the Mental Health Center of Denver. Mental health recovery was assessed from both a provider's (Recovery Markers Inventory [RMI]) and patient's (Consumer Recovery Measure [CRM]) perspective. A three-level hierarchical linear model (HLM) was utilized to determine changes in CRM and RMI scores by including independent variables in the models: intercept, months from treatment (slope), treatment time period (pretreatment and treatment), age, gender, primary diagnosis, substance abuse diagnosis, concurrent medications, and adherence to paliperidone palmitate LAI. RESULTS: A total of 219 patients were identified and included in the study. Results of the final three-level HLMs indicated an overall increase in CRM scores (p < 0.05), an overall increase (p < 0.01), and an increased rate of change (p < 0.05) in RMI scores during the paliperidone palmitate LAI treatment period vs the pre-treatment period. LIMITATIONS: This study contained a retrospective, non-comparative design, and did not adjust for multiplicity Conclusions: The current study demonstrates that changes in recovery-oriented mental health outcomes can be detected following the administration of a specific antipsychotic treatment in persons with schizophrenia or schizoaffective disorders. Furthermore, patients receiving paliperidone palmitate LAI can effectively improve recovery-oriented outcomes, thereby supporting the drug's use as schizophrenia treatment from a recovery-oriented perspective.

Measuring Mental Health Recovery: An Application of Rasch Modeling to the Consumer Recovery Measure.

As the need for recovery-oriented outcomes increases, it is critical to understand how numeric recovery scores are developed. In the current article, the modern Rasch modeling techniques were applied to establish numeric scores of consumers' perceptions of recovery. A sample of 1,973 adult consumers at a community-based mental health center (57.5% male; average age of 47 years old) completed the 15-item Consumer Recovery Measure. A confirmatory factor analysis revealed the unidimensional nature of the Consumer Recovery Measure and provided construct validity evidence. The Rasch analysis displayed that the items produced acceptable model fit, reliability, and identified the difficulty of the items. The conclusion emphasizes the value of Rasch modeling regarding the measurement of recovery and its relevance to consumer-derived assessments in the clinical decision-making process.

DNA translocation through a nanopore in a single-layered doped semiconductor membrane.

Recently, we developed a computational model that allowed us to study the influence a semiconductor membrane has on a DNA molecule translocating through a nanopore in this membrane. Our model incorporated both the self-consistent Poisson-Nernst-Planck simulations for the electric potential of a solid state membrane immersed in an electrolyte solution together with the Brownian dynamics of the biomolecule. In this paper, we study how the applied electrolyte bias, the semiconductor membrane bias, and the semiconductor material type (n-Si or p-Si) affect the translocation dynamics of a single-stranded DNA moving through a nanopore in a single-layered semiconductor membrane. We show that the type of semiconductor material used for the membrane has a prominent effect on the biomolecule's translocation time, with DNA exhibiting much longer translocation times through the p-type membrane than through the n type at the same electrolyte and membrane potentials, while the extension of the biomolecule remains practically unchanged. In addition, we find the optimal combination for the membrane-electrolyte system's parameters to achieve the longest translocation time and largest DNA extension. With our single-layered electrically tunable membranes, the DNA translocation time can be manipulated to have an order of magnitude increase.

Validation of SOBI components from high-density EEG.

Second-order blind identification (SOBI) is a blind source separation (BSS) algorithm that can be used to decompose mixtures of signals into a set of components or putative recovered sources. Previously, SOBI, as well as other BSS algorithms, has been applied to magnetoencephalography (MEG) and electroencephalography (EEG) data. These BSS algorithms have been shown to recover components that appear to be physiologically and neuroanatomically interpretable. While some proponents of these algorithms suggest that fundamental discoveries about the human brain might be made through the application of these techniques, validation of BSS components has not yet received sufficient attention. Here we present two experiments for validating SOBI-recovered components. The first takes advantage of the fact that noise sources associated with individual sensors can be objectively validated independently from the SOBI process. The second utilizes the fact that the time course and location of primary somatosensory (SI) cortex activation by median nerve stimulation have been extensively characterized using converging imaging methods. In this paper, using both known noise sources and highly constrained and well-characterized neuronal sources, we provide validation for SOBI decomposition of high-density EEG data. We show that SOBI is able to (1) recover known noise sources that were either spontaneously occurring or artificially induced; (2) recover neuronal sources activated by median nerve stimulation that were spatially and temporally consistent with estimates obtained from previous EEG, MEG, and fMRI studies; (3) improve the signal-to-noise ratio (SNR) of somatosensory-evoked potentials (SEPs); and (4) reduce the level of subjectivity involved in the source localization process.

Developmental aspects of language processing: fMRI of verbal fluency in children and adults.

We examined developmental differences, in location and extent of fMRI language activation maps, between adults and children while performing a semantic fluency task. We studied 29 adults and 16 children with echo planar imaging BOLD fMRI at 1.5 T using covert semantic verbal fluency (generation of words to categories compared to rest) using a block design. Post task testing was administered to assess performance. Individual data were analyzed with an a priori region of interest approach from t maps (t = 4) and asymmetry indices (AI). Group studies were analyzed using SPM 99 (Wellcome, UK; fixed effect, corrected P < 0.0001). We found no significant differences in location or laterality of activation between adults and children for a semantic verbal fluency task. Adults activated more pixels than children in left inferior frontal gyrus and left middle frontal gyrus, but AIs were the similar across ages (r(2) < 0.09). Extent or laterality of activation was not affected by performance (r(2) < 0.15). The brain areas that process semantic verbal fluency are similar in children and adults. The laterality of activation does not change appreciably with age and appears to be strongly lateralized by age 7 years.