Canadian perspectives in multiple myeloma on the use of steroids in clinical practice based on patient and healthcare provider interviews

Corticosteroid (steroid) medications are associated with challenging adverse effects that can negatively impact patient quality of life. However, owing to a long legacy of effective use in treatment protocols, they remain a cornerstone of multiple myeloma (MM) care. We conducted a roundtable with Canadian healthcare providers (HCPs) with diverse healthcare backgrounds and involvement in MM care as well as with patients with MM. Our goal was to develop clear guidance for steroid management aimed at improving patient quality of life, taking into account patient perspective and experiences with managing the disease. Our recommendations, which are based on the insights acquired from this discussion, can be categorized to the following areas: steroid prescribing, dosing, and modifications; managing adverse effects; and patient-HCP communication. These recommendations can be used by the entire multi-disciplinary hematology team to improve patient quality of life while being treated with steroid medication for multiple myeloma

Identifying children who are struggling in school

Abstract : Introduction : School-age children with motor coordination challenges typically require formal referral for occupational therapy services and often experience lengthy wait times for one-to-one intervention. In a new service delivery model called Partnering for Change, therapists work collaboratively with educators in classrooms to observe, identify, and support children. This study describes children identified through a traditional referral process and compares them with children identified by occupational therapists through classroom observation and dynamic performance analysis. Methods : Participants included 246 children enrolled in a 2-year evaluative study of the Partnering for Change service delivery. Parents completed a demographic questionnaire, the Developmental Coordination Disorder Questionnaire, and the Strengths and Difficulties Questionnaire. Children’s educators completed the Strengths and Difficulties Questionnaire and the School Function Assessment. Children completed the Movement Assessment Battery for Children. Results : Children identified were significantly younger and more likely to be girls than those referred under the traditional model. Using observation and dynamic performance analysis, occupational therapists identified children who had equally marked difficulties as those who came from the waitlist. In the Partnering for Change model, waitlists for service were eliminated for all children. Conclusions : Occupational therapists can identify children who are experiencing significant challenges participating at school without the need for standardized assessment, formal referrals, and waitlists

The on-orbit performance of the Orbiting Carbon Observatory-2 (OCO-2) instrument and its radiometrically calibrated products

The Orbiting Carbon Observatory-2 (OCO-2) carries and points a three-channel imaging grating spectrometer designed to collect high-resolution, co-boresighted spectra of reflected sunlight within the molecular oxygen (O_2) A-band at 0.765 microns and the carbon dioxide (CO_2) bands at 1.61 and 2.06 microns. These measurements are calibrated and then combined into soundings that are analyzed to retrieve spatially resolved estimates of the column-averaged CO_2 dry-air mole fraction, XCO_2. Variations of XCO_2 in space and time are then analyzed in the context of the atmospheric transport to quantify surface sources and sinks of CO_2. This is a particularly challenging remote-sensing observation because all but the largest emission sources and natural absorbers produce only small (< 0.25 %) changes in the background XCO_2 field. High measurement precision is therefore essential to resolve these small variations, and high accuracy is needed because small biases in the retrieved XCO_2 distribution could be misinterpreted as evidence for CO_2 fluxes. To meet its demanding measurement requirements, each OCO-2 spectrometer channel collects 24 spectra s^(−1) across a narrow ( 17 000), dynamic range (∼ 10^4), and sensitivity (continuum signal-to-noise ratio > 400). The OCO-2 instrument performance was extensively characterized and calibrated prior to launch. In general, the instrument has performed as expected during its first 18 months in orbit. However, ongoing calibration and science analysis activities have revealed a number of subtle radiometric and spectroscopic challenges that affect the yield and quality of the OCO-2 data products. These issues include increased numbers of bad pixels, transient artifacts introduced by cosmic rays, radiance discontinuities for spatially non-uniform scenes, a misunderstanding of the instrument polarization orientation, and time-dependent changes in the throughput of the oxygen A-band channel. Here, we describe the OCO-2 instrument, its data products, and its on-orbit performance. We then summarize calibration challenges encountered during its first 18 months in orbit and the methods used to mitigate their impact on the calibrated radiance spectra distributed to the science community

The on-orbit performance of the Orbiting Carbon Observatory-2 (OCO-2) instrument and its radiometrically calibrated products

The Orbiting Carbon Observatory-2 (OCO-2) carries and points a three-channel imaging grating spectrometer designed to collect high-resolution, co-boresighted spectra of reflected sunlight within the molecular oxygen (O_2) A-band at 0.765 microns and the carbon dioxide (CO_2) bands at 1.61 and 2.06 microns. These measurements are calibrated and then combined into soundings that are analyzed to retrieve spatially resolved estimates of the column-averaged CO_2 dry-air mole fraction, XCO_2. Variations of XCO_2 in space and time are then analyzed in the context of the atmospheric transport to quantify surface sources and sinks of CO_2. This is a particularly challenging remote-sensing observation because all but the largest emission sources and natural absorbers produce only small (< 0.25 %) changes in the background XCO_2 field. High measurement precision is therefore essential to resolve these small variations, and high accuracy is needed because small biases in the retrieved XCO_2 distribution could be misinterpreted as evidence for CO_2 fluxes. To meet its demanding measurement requirements, each OCO-2 spectrometer channel collects 24 spectra s^(−1) across a narrow ( 17 000), dynamic range (∼ 10^4), and sensitivity (continuum signal-to-noise ratio > 400). The OCO-2 instrument performance was extensively characterized and calibrated prior to launch. In general, the instrument has performed as expected during its first 18 months in orbit. However, ongoing calibration and science analysis activities have revealed a number of subtle radiometric and spectroscopic challenges that affect the yield and quality of the OCO-2 data products. These issues include increased numbers of bad pixels, transient artifacts introduced by cosmic rays, radiance discontinuities for spatially non-uniform scenes, a misunderstanding of the instrument polarization orientation, and time-dependent changes in the throughput of the oxygen A-band channel. Here, we describe the OCO-2 instrument, its data products, and its on-orbit performance. We then summarize calibration challenges encountered during its first 18 months in orbit and the methods used to mitigate their impact on the calibrated radiance spectra distributed to the science community

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype