7 research outputs found
Global Retinoblastoma Presentation and Analysis by National Income Level
Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved
The effect of microgrooved culture substrates on calcium cycling of cardiac myocytes derived from human induced pluripotent stem cells
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have been widely proposed as in vitro models of myocardial physiology and disease. A significant obstacle, however, is their immature phenotype. We hypothesised that Ca2+ cycling of iPSC-CM is influenced by culture conditions and can be manipulated to obtain a more mature cellular behaviour. To test this hypothesis we seeded iPSC-CM onto fibronectin coated microgrooved polydimethylsiloxane (PDMS) scaffolds fabricated using photolithography, or onto unstructured PDMS membrane. After two weeks in culture, the structure and function of iPSC-CM were studied. PDMS microgrooved culture substrates brought about cellular alignment (p < 0.0001) and more organised sarcomere. The Ca2+ cycling properties of iPSC-CM cultured on these substrates were significantly altered with a shorter time to peak amplitude (p = 0.0002 at 1 Hz), and more organised sarcoplasmic reticulum (SR) Ca2+ release in response to caffeine (p < 0.0001), suggesting improved SR Ca2+ cycling. These changes were not associated with modifications in gene expression. Whilst structured tissue culture may make iPSC-CM more representative of adult myocardium, further construct development and characterisation is required to optimise iPSC-CM as a model of adult myocardium
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Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations
Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study—and most other large-scale human genetics studies—was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10−6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations. © 2023, The Author(s).Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Global Retinoblastoma Presentation and Analysis by National Income Level
This cross-sectional analysis reports the retinoblastoma stage at
diagnosis across the world during a single year, investigates
associations between clinical variables and national income level, and
investigates risk factors for advanced disease at diagnosis.
Key PointsQuestionIs the income level of a country of residence
associated with the clinical stage of presentation of patients with
retinoblastoma? FindingsIn this cross-sectional analysis that included
4351 patients with newly diagnosed retinoblastoma, approximately half of
all new retinoblastoma cases worldwide in 2017, 49.1\% of patients from
low-income countries had extraocular tumor at time of diagnosis compared
with 1.5\% of patients from high-income countries. MeaningThe clinical
stage of presentation of retinoblastoma, which has a major influence on
survival, significantly differs among patients from low-income and
high-income countries, which may warrant intervention on national and
international levels.
ImportanceEarly diagnosis of retinoblastoma, the most common intraocular
cancer, can save both a child's life and vision. However, anecdotal
evidence suggests that many children across the world are diagnosed
late. To our knowledge, the clinical presentation of retinoblastoma has
never been assessed on a global scale. ObjectivesTo report the
retinoblastoma stage at diagnosis in patients across the world during a
single year, to investigate associations between clinical variables and
national income level, and to investigate risk factors for advanced
disease at diagnosis. Design, Setting, and ParticipantsA total of 278
retinoblastoma treatment centers were recruited from June 2017 through
December 2018 to participate in a cross-sectional analysis of
treatment-naive patients with retinoblastoma who were diagnosed in 2017.
Main Outcomes and MeasuresAge at presentation, proportion of familial
history of retinoblastoma, and tumor stage and metastasis. ResultsThe
cohort included 4351 new patients from 153 countries; the median age at
diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976
patients (45.4\%) were female. Most patients (n=3685 {[}84.7\%]) were
from low- and middle-income countries (LMICs). Globally, the most common
indication for referral was leukocoria (n=2638 {[}62.8\%]), followed by
strabismus (n=429 {[}10.2\%]) and proptosis (n=309 {[}7.4\%]). Patients
from high-income countries (HICs) were diagnosed at a median age of 14.1
months, with 656 of 666 (98.5\%) patients having intraocular
retinoblastoma and 2 (0.3\%) having metastasis. Patients from low-income
countries were diagnosed at a median age of 30.5 months, with 256 of 521
(49.1\%) having extraocular retinoblastoma and 94 of 498 (18.9\%) having
metastasis. Lower national income level was associated with older
presentation age, higher proportion of locally advanced disease and
distant metastasis, and smaller proportion of familial history of
retinoblastoma. Advanced disease at diagnosis was more common in LMICs
even after adjusting for age (odds ratio for low-income countries vs
upper-middle-income countries and HICs, 17.92 {[}95\% CI, 12.94-24.80],
and for lower-middle-income countries vs upper-middle-income countries
and HICs, 5.74 {[}95\% CI, 4.30-7.68]). Conclusions and RelevanceThis
study is estimated to have included more than half of all new
retinoblastoma cases worldwide in 2017. Children from LMICs, where the
main global retinoblastoma burden lies, presented at an older age with
more advanced disease and demonstrated a smaller proportion of familial
history of retinoblastoma, likely because many do not reach a
childbearing age. Given that retinoblastoma is curable, these data are
concerning and mandate intervention at national and international
levels. Further studies are needed to investigate factors, other than
age at presentation, that may be associated with advanced disease in
LMICs