Description of a national, multi-center registry of patients with sickle cell disease and SARS-CoV-2 infection: Data from the Pediatric COVID-19 United States Registry.

Children with sickle cell disease (SCD) are at risk of complications from viral infections, including SARS-CoV-2. We present the clinical characteristics and outcomes of pediatric patients with SCD from the Pediatric COVID-19 United States Registry who developed acute COVID-19 due to SARS-CoV-2 infection (n = 259) or multisystem inflammatory syndrome in children (MIS-C; n = 4). Nearly half of hospitalized children with SCD and SARS-CoV-2 infection required supplemental oxygen, though children with SCD had fewer intensive care (ICU) admissions compared to the general pediatric and immunocompromised populations. All registry patients with both SCD and MIS-C required ICU admission. Children with SCD are at risk of severe disease with SARS-CoV-2 infection, highlighting the importance of vaccination in this vulnerable population.

Thrombotic events in critically ill children with coronavirus disease 2019 or multisystem inflammatory syndrome in children.

PURPOSE OF REVIEW: To provide an update regarding what is known about thrombotic events and thromboprophylaxis in critically ill children with SARS-CoV-2 infection. RECENT FINDINGS: Pediatric patients with SARS-CoV-2 generally have mild illness; however, intensive care is required in about 20-30% of hospitalized children with COVID-19 and an even higher proportion in those with MIS-C. Increased rates of thrombosis have been observed in adults hospitalized with COVID-19, and clinical trials have attempted to optimize thromboprophylaxis. There is significant variability in the estimated incidence of thrombosis in pediatric patients (0-27%) because of variation in patient populations and study design. Multiple studies demonstrate an increased rate of thrombosis compared with baseline in hospitalized pediatric patients. Few studies have evaluated risk factors for thrombosis, but critical illness, older age, and other known thrombosis risk factors appear to increase the risk. Thromboprophylaxis strategies are inconsistent, with little evidence of efficacy but few reports of major bleeding. SUMMARY: Critically ill children with SARS-CoV-2-related illnesses are at increased risk of thrombosis. Thromboprophylaxis should be considered in select patients with COVID-19 or MIS-C, though the optimal strategy is not yet known. More data is required to guide practice to prevent thrombosis in this population.

A novel TP53 tandem duplication in a child with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in TP53 are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels.

Constitutively active Akt inhibits trafficking of amyloid precursor protein and amyloid precursor protein metabolites through feedback inhibition of phosphoinositide 3-kinase.

Amyloid-beta (Abeta) peptides, generated through sequential proteolytic cleavage of amyloid precursor protein (APP), aggregate to form amyloid plaques in Alzheimer's disease (AD). Understanding the regulation of Abeta generation and cellular secretion is critical to our understanding of AD pathophysiology. In the present study, we examined the role of the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway in regulating APP trafficking and Abeta secretion. Previous studies have demonstrated that insulin or IGF-1 stimulation can increase Abeta and APP secretion in a phosphoinositide 3-kinase (PI3K) dependent manner. To expand upon these studies and better understand the molecular targets responsible for alterations in APP secretion, we constitutively activated Akt, a downstream component of the insulin/IGF-1 signaling pathway. Counterintuitively, constitutively active Akt (myr-Akt) overexpression produced an opposite effect to insulin/IGF-1 stimulation and inhibited secretion of APP and APP metabolites in multiple cell lines. Myr-Akt overexpression also resulted in increased APP protein stability. Since the insulin/IGF-1 signaling pathway is tightly regulated by feedback inhibition pathways, we hypothesized that myr-Akt overexpression may be inducing feedback inhibition of PI3K, resulting in impaired APP trafficking. In support of this hypothesis, myr-Akt acted at a known node of PI3K inhibition and decreased insulin receptor substrate 1 (IRS1) protein levels. Our studies provide further support for PI3K as a modulator of APP trafficking and demonstrate that overactivation of the insulin/IGF-1 signaling pathway may result in feedback inhibition of PI3K through IRS1 and reduce APP trafficking and Abeta secretion.

Patterns of Individual Variation in Visual Pathway Structure and Function in the Sighted and Blind.

Many structural and functional brain alterations accompany blindness, with substantial individual variation in these effects. In normally sighted people, there is correlated individual variation in some visual pathway structures. Here we examined if the changes in brain anatomy produced by blindness alter the patterns of anatomical variation found in the sighted. We derived eight measures of central visual pathway anatomy from a structural image of the brain from 59 sighted and 53 blind people. These measures showed highly significant differences in mean size between the sighted and blind cohorts. When we examined the measurements across individuals within each group we found three clusters of correlated variation, with V1 surface area and pericalcarine volume linked, and independent of the thickness of V1 cortex. These two clusters were in turn relatively independent of the volumes of the optic chiasm and lateral geniculate nucleus. This same pattern of variation in visual pathway anatomy was found in the sighted and the blind. Anatomical changes within these clusters were graded by the timing of onset of blindness, with those subjects with a post-natal onset of blindness having alterations in brain anatomy that were intermediate to those seen in the sighted and congenitally blind. Many of the blind and sighted subjects also contributed functional MRI measures of cross-modal responses within visual cortex, and a diffusion tensor imaging measure of fractional anisotropy within the optic radiations and the splenium of the corpus callosum. We again found group differences between the blind and sighted in these measures. The previously identified clusters of anatomical variation were also found to be differentially related to these additional measures: across subjects, V1 cortical thickness was related to cross-modal activation, and the volume of the optic chiasm and lateral geniculate was related to fractional anisotropy in the visual pathway. Our findings show that several of the structural and functional effects of blindness may be reduced to a smaller set of dimensions. It also seems that the changes in the brain that accompany blindness are on a continuum with normal variation found in the sighted.

Massage, Music, and Art Therapy in Hospice: Results of a National Survey.

CONTEXT: Complementary and alternative medicine (CAM) provides clinical benefits to hospice patients, including decreased pain and improved quality of life. Yet little is known about the extent to which U.S. hospices employ CAM therapists. OBJECTIVES: To report the most recent national data regarding the inclusion of art, massage, and music therapists on hospice interdisciplinary teams and how CAM therapist staffing varies by hospice characteristics. METHODS: A national cross-sectional survey of a random sample of hospices (n = 591; 84% response rate) from September 2008 to November 2009. RESULTS: Twenty-nine percent of hospices (169 of 591) reported employing an art, massage, or music therapist. Of those hospices, 74% employed a massage therapist, 53% a music therapist, and 22% an art therapist, and 42% expected the therapist to attend interdisciplinary staff meetings, indicating a significant role for these therapists on the patient's care team. In adjusted analyses, larger hospices compared with smaller hospices had significantly higher odds of employing a CAM therapist (adjusted odds ratio 6.38; 95% CI 3.40, 11.99) and for-profit hospices had lower odds of employing a CAM therapist compared with nonprofit hospices (adjusted odds ratio 0.52; 95% CI 0.32, 0.85). Forty-four percent of hospices in the Mountain/Pacific region reported employing a CAM therapist vs. 17% in the South Central region. CONCLUSION: Less than one-third of U.S. hospices employ art, massage, or music therapists despite the benefits these services may provide to patients and families. A higher proportion of large hospices, nonprofit hospices, and hospices in the Mountain/Pacific region employ CAM therapists, indicating differential access to these important services.