Abstract
Background
Life extension by medical interventions and health-related quality of life (HRQOL) are sometimes conflicting aspects of medical care. Long-term ventilation in children with ...neuromuscular disease is a well-established life-extending procedure and often at the center of this conflict. HRQOL and the mental health of affected children and their families become even more important in respect to emerging therapies in neuromuscular diseases with longer life-expectancy of treated patients and considerable costs of medical treatment.
Methods
We performed a questionnaire survey in a total of forty-three families of children with neuromuscular disease treated in the University Medical Center Hamburg-Eppendorf and the Children’s Hospital Altona. We evaluated self- and proxy-reported HRQOL and mental health outcomes of affected children and their parents using validated and age-appropriate instruments.
Results
Compared to normative data, children with neuromuscular diseases and their families experienced a lower HRQOL and mental health. However, there was no additional negative influence on the overall HRQOL by ventilator use.
Conclusions
As ventilator use was not responsible for the reduction of HRQOL and mental health our data contributes an important aspect to the discussion about life-prolonging procedures, in particular mechanical ventilation, in severly disabled patients.
Background Advances in genetic and pharmaceutical technology and pediatric care have enabled treatment options for an increasing number of rare diseases in affected children. However, as current ...treatment options are primarily of palliative nature, the Health-Related Quality of Life (HRQoL) and mental health of this impaired population and their siblings are of increasing importance. Among children and adolescents with rare diseases, those who are technology-dependent carry a high disease burden and are selected as the target population in our study. In a cross-sectional observational design, the children's HRQoL was assessed with the DISABKIDS (DCGM-37) as well as KIDSCREEN-27, while mental health was assessed with the Strengths and Difficulties Questionnaire (SDQ) by both the affected children, their parents, and siblings. Results Results of the study sample were compared to normative data. Affected children scored significantly lower than the norm on almost all HRQoL subscales as reported by parent and child. From the parental perspective, more mental health subscales were significantly impaired compared to the child's perspective. Siblings showed no impairment in HRQoL as well as significantly fewer behavioral problems and higher prosocial behavior regarding their mental health compared to the norm. Conclusion Children and adolescents with rare diseases seem particularly impaired in social and emotional aspects of HRQoL and mental health. Interventions may focus primarily on promoting social skills, fostering prosocial behavior and peer relationships. Keywords: Health-Related Quality of Life, Mental health, Technologically dependent, Siblings
The Need for Psychosocial Support in Parents of Chronically Ill Children Chronic illness in childhood and adolescence is associated with special requirements and demands on affected families. In ...particular, severe chronic diseases and rare diseases with a high level of health care needs or with progressive medical diagnoses permanently challenge the families' resources. The aim of this study was to assess the need for psychological, nursing, legal and organisational support from a parent's perspective. Using qualitative content analysis according to Mayring, data from 96 parents of 68 chronically ill children were evaluated. The findings suggest an increased need for psychosocial support, but, the ideas, needs, and goals of parents are very versatile. However, family-based psychosocial support programs, which are adapted to the specific family situations, are unanimously judged to be useful. Interventions should be flexible as well as tailored to the affected families' individual needs.
Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral ...haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.
We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18–80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0–2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.
We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0–2 (adjusted absolute risk difference 0·6% 90% upper confidence bound 6·8%). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.
Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0–2) at day 90 would be futile.
US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.
Hematoma volume (HV) is a powerful determinant of outcome after intracerebral hemorrhage. We examined whether the effect of the iron chelator, deferoxamine, on functional outcome varied depending on ...HV in the i-DEF trial (Intracerebral Hemorrhage Deferoxamine).
A post hoc analysis of the i-DEF trial; participants were classified according to baseline HV (small <10 mL, moderate 10-30 mL, and large >30 mL). Favorable outcome was defined as a modified Rankin Scale score of 0-2 at day-180; secondarily at day-90. Logistic regression was used to evaluate the differential treatment effect according to HV.
Two hundred ninety-one subjects were included in the as-treated analysis; 121 with small, 114 moderate, and 56 large HV. Day-180 modified Rankin Scale scores were available for 270/291 subjects (111 with small, 105 moderate, and 54 large HV). There was a differential effect of treatment according to HV on day-180 outcomes (
-for-interaction =0.0077); 50% (27/54) of deferoxamine-treated patients with moderate HV had favorable outcome compared with 25.5% (13/51) of placebo-treated subjects (adjusted odds ratio, 2.7 95% CI, 1.13-6.27;
=0.0258). Treatment effect was not significant for small (adjusted odds ratio, 1.37 95% CI, 0.62-3.02) or large (adjusted odds ratio, 0.12 95% CI, 0.01-1.05) HV. Results for day-90 outcomes were comparable (
-for-interaction =0.0617). Sensitivity analyses yielded similar results.
Among patients with moderate HV, a greater proportion of deferoxamine- than placebo-treated patients achieved modified Rankin Scale score 0-2. The treatment effect was not significant for small or large HVs. These findings have important trial design and therapeutic implications.
URL: https://www.
gov; Unique identifier: NCT02175225.
The cell cycle is a temporal program that regulates DNA synthesis and cell division. When we compared the codon usage of cell cycle‐regulated genes with that of other genes, we discovered that there ...is a significant preference for non‐optimal codons. Moreover, genes encoding proteins that cycle at the protein level exhibit non‐optimal codon preferences. Remarkably, cell cycle‐regulated genes expressed in different phases display different codon preferences. Here, we show empirically that transfer RNA (tRNA) expression is indeed highest in the G2 phase of the cell cycle, consistent with the non‐optimal codon usage of genes expressed at this time, and lowest toward the end of G1, reflecting the optimal codon usage of G1 genes. Accordingly, protein levels of human glycyl‐, threonyl‐, and glutamyl‐prolyl tRNA synthetases were found to oscillate, peaking in G2/M phase. In light of our findings, we propose that non‐optimal (wobbly) matching codons influence protein synthesis during the cell cycle. We describe a new mathematical model that shows how codon usage can give rise to cell‐cycle regulation. In summary, our data indicate that cells exploit wobbling to generate cell cycle‐dependent dynamics of proteins.
Most cell cycle‐regulated genes adopt non‐optimal codon usage, namely, their translation involves wobbly matching codons. Here, the authors show that tRNA expression is cyclic and that codon usage, therefore, can give rise to cell‐cycle regulation of proteins.
Synopsis
Most cell cycle‐regulated genes adopt non‐optimal codon usage, namely, their translation involves wobbly matching codons. Here, the authors show that tRNA expression is cyclic and that codon usage, therefore, can give rise to cell‐cycle regulation of proteins.
Most cell cycle‐regulated genes adopt non‐optimal codon usage.
Non‐optimal codon usage can give rise to cell‐cycle dynamics at the protein level.
The high expression of transfer RNAs (tRNAs) observed in G2 phase enables cell cycle‐regulated genes to adopt non‐optimal codon usage, and conversely the lower expression of tRNAs at the end of G1 phase is associated with optimal codon usage.
The protein levels of aminoacyl‐tRNA synthetases oscillate, peaking in G2/M phase, consistent with the observed cyclic expression of tRNAs.
Lakes in permafrost regions are dynamic landscape
components and play an important role for climate change feedbacks. Lake
processes such as mineralization and flocculation of dissolved organic
...carbon (DOC), one of the main carbon fractions in lakes, contribute to the
greenhouse effect and are part of the global carbon cycle. These processes
are in the focus of climate research, but studies so far are limited to specific
study regions. In our synthesis, we analyzed 2167 water samples from 1833
lakes across the Arctic in permafrost regions of Alaska, Canada, Greenland,
and Siberia to provide first pan-Arctic insights for linkages between DOC
concentrations and the environment. Using published data and unpublished
datasets from the author team, we report regional DOC differences linked to
latitude, permafrost zones, ecoregions, geology, near-surface soil organic
carbon contents, and ground ice classification of each lake region. The lake
DOC concentrations in our dataset range from 0 to
1130 mg L−1 (10.8 mg L−1 median DOC concentration). Regarding the
permafrost regions of our synthesis, we found median lake DOC concentrations
of 12.4 mg L−1 (Siberia), 12.3 mg L−1 (Alaska),
10.3 mg L−1 (Greenland), and 4.5 mg L−1 (Canada). Our synthesis
shows a significant relationship between lake DOC concentration and lake
ecoregion. We found higher lake DOC concentrations at boreal permafrost
sites compared to tundra sites. We found significantly higher DOC
concentrations in lakes in regions with ice-rich syngenetic permafrost
deposits (yedoma) compared to non-yedoma lakes and a weak but significant
relationship between soil organic carbon content and lake DOC concentration
as well as between ground ice content and lake DOC. Our pan-Arctic dataset
shows that the DOC concentration of a lake depends on its environmental
properties, especially on permafrost extent and ecoregion, as well as
vegetation, which is the most important driver of lake DOC in this study.
This new dataset will be fundamental to quantify a pan-Arctic lake DOC pool
for estimations of the impact of lake DOC on the global carbon cycle and
climate change.
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Eosinophils are elusive cells involved in allergic inflammation. Single-cell RNA-sequencing (scRNA-seq) is an emerging approach to deeply characterize cellular properties, ...heterogeneity, and functionality.
We sought to comprehensively characterize the transcriptome and biological functions of human eosinophils at a site of severe allergic inflammation in the esophagus (ie, eosinophilic esophagitis EoE).
We employed a gravity-based scRNA-seq methodology to sequence blood eosinophils from patients with EoE and control individuals compared to a reanalyzed public scRNA-seq dataset of human esophageal eosinophils of EoE patients. We used flow cytometry, immunostaining, and a stimulation assay to verify mRNA findings.
In total, scRNA-seq was obtained from 586 eosinophils (188 from blood n = 6 individuals and 398 from esophagus n = 6 individuals). The esophageal eosinophils were composed of a population of activated eosinophils (enriched in 659 genes compared with peripheral blood–associated eosinophils) and a small population of eosinophils resembling peripheral blood eosinophils (enriched in 62 genes compared with esophageal eosinophils). Esophageal eosinophils expressed genes involved in sensing and responding to diverse stimuli, most notably IFN-γ, IL-10, histamine and leukotrienes, and succinate. Esophageal eosinophils were most distinguished from other esophageal populations by gene expression of the receptors CCR3, HRH4, SUCNR1, and VSTM1; transcription factors CEBPE, OLIG1, and OLIG2; protease PRSS33; and the hallmark eosinophil gene CLC. A web of bidirectional eosinophil interactions with other esophageal populations was derived. Comparing esophageal eosinophils and mast cells revealed that esophageal eosinophils expressed genes involved in DNAX-activation protein-12 (also known as TYROBP) interactions, IgG receptor-triggered events, immunoregulation, and IL-10 signaling.
In EoE, esophageal eosinophils exist as 2 populations, a minority population resembling blood eosinophils and the other population characterized by high de novo transcription of diverse sensing receptors and inflammatory mediators readying them to potentially intersect with diverse cell types.
The Arctic is rich in aquatic systems and experiences rapid warming due to climate change. The accelerated warming causes permafrost thaw and the mobilization of organic carbon. When dissolved ...organic carbon is mobilized, this DOC can be transported to aquatic systems and degraded in the water bodies and further downstream. Here, we analyze the influence of different landscape components on DOC concentrations and export in a small (6.45 km
2
) stream catchment in the Lena River Delta. The catchment includes lakes and ponds, with the flow path from Pleistocene yedoma deposits across Holocene non-yedoma deposits to the river outlet. In addition to DOC concentrations, we use radiocarbon dating of DOC as well as stable oxygen and hydrogen isotopes (δ
18
O and δD) to assess the origin of DOC. We find significantly higher DOC concentrations in the Pleistocene yedoma area of the catchment compared to the Holocene non-yedoma area with medians of 5 and 4.5 mg L
−1
(
p
< 0.05), respectively. When yedoma thaw streams with high DOC concentration reach a large yedoma thermokarst lake, we observe an abrupt decrease in DOC concentration, which we attribute to dilution and lake processes such as mineralization. The DOC ages in the large thermokarst lake (between 3,428 and 3,637
14
C y BP) can be attributed to a mixing of mobilized old yedoma and Holocene carbon. Further downstream after the large thermokarst lake, we find progressively younger DOC ages in the stream water to its mouth, paired with decreasing DOC concentrations. This process could result from dilution with leaching water from Holocene deposits and/or emission of ancient yedoma carbon to the atmosphere. Our study shows that thermokarst lakes and ponds may act as DOC filters, predominantly by diluting incoming waters of higher DOC concentrations or by re-mineralizing DOC to CO
2
and CH
4
. Nevertheless, our results also confirm that the small catchment still contributes DOC on the order of 1.2 kg km
−2
per day from a permafrost landscape with ice-rich yedoma deposits to the Lena River.
Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and ...specific pathways, and the functional consequences.
Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro.
TSPAN12 was the gene most correlated with fibrostenosis (r = −0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = −0.41, P < .001), and genes enriched in cell cycle–related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti–IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell–fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling.
Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
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We deciphered the role of TSPAN12 in fibrostenotic eosinophilic esophagitis by transcriptomic analysis across a multisite cohort, its association with clinical parameters and specific pathways, and the functional consequences in vitro.
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