To characterize the socioeconomic and racial and/or ethnic disparities impacting the diagnosis and outcomes of multisystem inflammatory syndrome in children (MIS-C).
This multicenter retrospective ...case-control study was conducted at 3 academic centers from January 1 to September 1, 2020. Children with MIS-C were compared with 5 control groups: children with coronavirus disease 2019, children evaluated for MIS-C who did not meet case patient criteria, children hospitalized with febrile illness, children with Kawasaki disease, and children in Massachusetts based on US census data. Neighborhood socioeconomic status (SES) and social vulnerability index (SVI) were measured via a census-based scoring system. Multivariable logistic regression was used to examine associations between SES, SVI, race and ethnicity, and MIS-C diagnosis and clinical severity as outcomes.
Among 43 patients with MIS-C, 19 (44%) were Hispanic, 11 (26%) were Black, and 12 (28%) were white; 22 (51%) were in the lowest quartile SES, and 23 (53%) were in the highest quartile SVI. SES and SVI were similar between patients with MIS-C and coronavirus disease 2019. In multivariable analysis, lowest SES quartile (odds ratio 2.2 95% confidence interval 1.1-4.4), highest SVI quartile (odds ratio 2.8 95% confidence interval 1.5-5.1), and racial and/or ethnic minority background were associated with MIS-C diagnosis. Neither SES, SVI, race, nor ethnicity were associated with disease severity.
Lower SES or higher SVI, Hispanic ethnicity, and Black race independently increased risk for MIS-C. Additional studies are required to target interventions to improve health equity for children.
Purpose
This retrospective cohort study compares the natural history of patients with extralobar sequestrations (ELS) who do not undergo intervention with those who undergo resection to assess the ...safety of non-operative management.
Methods
126 patients with pulmonary sequestrations or congenital pulmonary airway malformations born between 1999 and 2016 were identified. 49 patients had ELS on postnatal imaging, but two were excluded for associated congenital diaphragmatic hernia. Demographic and clinical data were retrospectively reviewed, with phone follow-up for non-operative patients with no records for > 1 year. Statistical analysis was by Fisher’s exact test or Wilcoxon signed-rank test (two-tailed
p
< 0.05).
Results
40% (19/47) were managed non-operatively and 60% (28/47) underwent resection. Non-operative patients were less likely to have an intrathoracic ELS: 47% (9/19) vs. 75% (21/28),
p
= 0.07. No symptoms were attributable directly to the ELS. Non-operative patients had median follow-up 3.2 years, during which time 88% (15/17) of ELS decreased in size on serial imaging. For patients who underwent resection, there was 100% concordance between imaging and intraoperative findings. There was no evidence of inflammation, infection or malignancy on final pathology, though 57% (16/28) of resected lesions had foci of non-aerated cysts.
Conclusions
Although further longitudinal study is required, this study supports the safety of non-operative ELS management.
The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, ...whether these distinct pruritogens activate the same or different afferent fibers. Using a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker, we found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1(+) or TRPA1(+) neurons allowed allyl isothiocyanate or capsaicin, respectively, to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus.
To examine associations between measurements of neurodevelopment and psychosocial health status at age 8 and 16 years in patients with repaired dextro-transposition of the great arteries.
In the ...16-year follow-up of the Boston Circulatory Arrest Study, 137 parents completed the Child Health Questionnaire—Parent Form-50, of whom 135 had completed the Child Health Questionnaire—Parent Form-50 when their child was age 8 years. Psychosocial and physical summary scores were used to assess change in health status from age 8 to 16 years. A comprehensive battery of neurodevelopmental testing was performed at ages 8 and 16 years to examine associations with adolescent health status.
Lower psychosocial summary scores of 16 year old subjects with dextro-transposition of the great arteries were highly associated with numerous concurrent domains of neurodevelopmental function, most notably with higher (worse) scores on the Conners' Attention Deficit Hyperactivity Disorder/Diagnostic and Statistical Manual-4th Edition Scales (parent: r = −0.62, P < .001; adolescent: r = −0.43, P < .001) and the Behavior Rating Inventory of Executive Function Global Executive Composite (parent: r = −0.66, P < .001; adolescent: r = −0.39, P < .001). Psychosocial and physical summary scores tracked from ages 8 to 16 years (r = 0.44 and 0.47, respectively, P < .001 for each). Higher (worse) scores of multiple attention measures at age 8 years predicted worse psychosocial summary scores at age 16 years.
Attention deficits at age 8 years were highly predictive of worse psychosocial health status in adolescence. Further studies are needed to assess whether treatment of childhood attention deficit hyperactivity disorder could improve adolescent well-being.
Hyperactivation of the mechanistic target of rapamycin (mTOR) kinase, as a result of loss-of-function mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis ...dysregulation, increased cell size, and aberrant neuronal connectivity. Dysregulated synthesis of synaptic proteins has been implicated in the pathophysiology of autism spectrum disorder (ASD) associated with TSC and fragile X syndrome. However, cell type-specific translational profiles in these disease models remain to be investigated. Here, we used high-fidelity and unbiased Translating Ribosome Affinity Purification (TRAP) methodology to purify ribosome-associated mRNAs and identified translational alterations in a rat neuronal culture model of TSC. We find that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed. Importantly, transcripts for the activating transcription factor-3 (Atf3) and mitochondrial uncoupling protein-2 (Ucp2) are highly induced in Tsc2-deficient neurons, as well as in a neuron-specific Tsc1 conditional knock-out mouse model, and show differential responses to the mTOR inhibitor rapamycin. Gelsolin, a known target of Atf3 transcriptional activity, is also upregulated. shRNA-mediated block of Atf3 induction suppresses expression of gelsolin, an actin-severing protein, and rescues spine deficits found in Tsc2-deficient neurons. Together, our data demonstrate that a cell-autonomous program consisting of a stress-induced Atf3-gelsolin cascade affects the change in dendritic spine morphology following mTOR hyperactivation. This previously unidentified molecular cascade could be a therapeutic target for treating mTORopathies.
Tuberous sclerosis complex (TSC) is a genetic disease associated with epilepsy and autism. Dysregulated protein synthesis has been implicated as a cause of this disease. However, cell type-specific translational profiles that are aberrant in this disease are unknown. Here we show that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed in neurons missing the Tsc2 gene expression. Identification of genes whose translation is abnormal in TSC may provide insights to previously unidentified therapeutic targets.
BACKGROUND: The first generation of South African (SA) children perinatally infected with HIV is entering adulthood, and there is now a pressing need for systematised transfer of these patients from ...paediatric to adult care. OBJECTIVES: Previous research has investigated the HIV healthcare transition in North America and Europe, yet none has been conducted in SA. Our study is the first to describe the perspectives of healthcare providers overseeing the transition in resource-limited settings. METHODS. We approached healthcare providers working in government paediatric HIV clinics and hospitals in the Western Cape Province, SA. Seven physicians and counsellors in adolescent/paediatric care, representing five clinics, were interviewed, and 43 completed a written survey. Interviews addressed the current state of the transition, barriers and facilitators, and model components. Interviews were assessed for major themes using framework analysis, while logistic regression was applied to survey responses to identify associations with measured covariates. RESULTS: Analysis of interview transcripts revealed several overarching perspectives that were corroborated by survey responses. One barrier identified was the healthcare providers' difficulty in letting go of their relationships with the adolescent patients. Since healthcare providers regarded their patients as particularly vulnerable, they felt a strong and protective attachment towards them. A second barrier identified was a lack of structure and effective communication between adult and paediatric providers; accordingly, healthcare providers feared that they were transferring their adolescents unprepared, to a judgemental, depersonalised and overburdened environment. All interviewees and a majority of survey respondents (>80%) agreed that the formation of adolescent support groups in adult care clinics as well as a later transition age would improve the transition process. CONCLUSION: This study highlights the need for a systematic healthcare transition for HIV-positive adolescents cared for in the Western Cape, while acknowledging the limitations of the current healthcare infrastructure. Several feasible recommendations have been identified, including forming support groups and greater involvement of adolescent healthcare providers to facilitate the transition.
Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant
, which has now been reported in ...94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b2
. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.
Many pollinator species visit multiple crops in multiple regions, yet we know little about their pollination service provisioning at local and regional scales. We investigated the floral visitors (n ...= 13,200), their effectiveness (n = 1718 single visits) and response to landscape composition across three crops avocado, mango and macadamia within a single growing region (1 year), a single crop (3 years) and across different growing regions in multiple years. In total, eight wild visitor groups were shared across all three crops. The network was dominated by three pollinators, two bees (Apis mellifera and Tetragonula spp.) and a fly, Stomorhina discolor. The visitation network for the three crops was relatively generalised but with the addition of pollen deposition data, specialisation increased. Sixteen managed and wild taxa were consistently present across three years in avocado, yet their contribution to annual network structure varied. Node specialisation (d') analyses indicated many individual orchard sites across each of the networks were significantly more specialised compared to that predicted by null models, suggesting the presence of site-specific factors driving these patterns. Identifying the taxa shared across multiple crops, regions and years will facilitate the development of specific pollinator management strategies to optimize crop pollination services in horticultural systems.
Haemochromatosis (HH) is a clinically and genetically heterogeneous disease caused by inappropriate iron absorption. Most HH patients are homozygous for the C282Y mutation in the HFE gene. However, ...penetrance of the C282Y mutation is incomplete, and other genetic factors may well affect the HH phenotype. Ferroportin and TFR2 mutations also cause HH, and two HAMP mutations have recently been reported that causes juvenile haemochromatosis (JH) in the homozygous state. Here, we report evidence for digenic inheritance of HH. We have detected two new HAMP mutations in two different families, in which there is concordance between severity of iron overload and heterozygosity for HAMP mutations when present with the HFE C282Y mutation. In family A, the proband has a JH phenotype and is heterozygous for C282Y and a novel HAMP mutation Met50del IVS2+1(-G). This is a four nucleotide ATGG deletion which causes a frameshift. The proband's unaffected mother is also heterozygous for Met50del IVS2+1(-G), but lacks the C282Y mutation and is heterozygous for the HFE H63D mutation. Met50del IVS2+1(-G) was absent from 642 control chromosomes. In family B, a second novel, less severe HAMP mutation, G71D, was identified. This was detected in the general population at an allele frequency of 0.3%. We propose that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation.
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