A widening world : a discussion of the social attitudes and social problems of young people in Soviet literature, 1957-1963

During the period of Khrushchev's power there was a considerable amount of writing and discussion about young people, their attitudes and problems. This interest in the situation and attitudes of the young spread over several dominant themes, and since, in most cases, the prose dealing with this subject contained a great deal of critical comment, often of matters that had hitherto been excluded from discussion, it drew upon itself the fire of orthodox literary critics and officialdom. There was a tendency to see the writing which fell into this category as an illustration of the 'conflict of generations', and' certainly, in at least two of the principal themes, that of de-Stalinisation and that of meshchanstvo, it did appear as if there was a division along generation lines among the characters portrayed

Adaptive Mobile Health Intervention for Adolescents with Asthma: Iterative User-Centered Development

Background: Adolescents diagnosed with persistent asthma commonly take less than 50% of their prescribed inhaled corticosteroids (ICS), placing them at risk for asthma-related morbidity. Adolescents’ difficulties with adherence occur in the context of normative developmental changes (eg, increased responsibility for disease management) and rely upon still developing self-regulation and problem-solving skills that are integral for asthma self-management. We developed an adaptive mobile health system, Responsive Asthma Care for Teens (ReACT), that facilitates self-regulation and problem-solving skills during times when adolescents’ objectively measured ICS adherence data indicate suboptimal rates of medication use. Objective: The current paper describes our user-centered and evidence-based design process in developing ReACT. We explain how we leveraged a combination of individual interviews, national crowdsourced feedback, and an advisory board comprised of target users to develop the intervention content. Methods: We developed ReACT over a 15-month period using one-on-one interviews with target ReACT users (n=20), national crowdsourcing (n=257), and an advisory board (n=4) to refine content. Participants included 13-17–year-olds with asthma and their caregivers. A total of 280 adolescents and their caregivers participated in at least one stage of ReACT development. Results: Consistent with self-regulation theory, adolescents identified a variety of salient intrapersonal (eg, forgetfulness, mood) and external (eg, changes in routine) barriers to ICS use during individual interviews. Adolescents viewed the majority of ReACT intervention content (514/555 messages, 93%) favorably during the crowdsourcing phase, and the advisory board helped to refine the content that did not receive favorable feedback during crowdsourcing. Additionally, the advisory board provided suggestions for improving additional components of ReACT (eg, videos, message flow). Conclusions: ReACT involved stakeholders via qualitative approaches and crowdsourcing throughout the creation and refinement of intervention content. The feedback we received from participants largely supported ReACT’s emphasis on providing adaptive and personalized intervention content to facilitate self-regulation and problem-solving skills, and the research team successfully completed the recommended refinements to the intervention content during the iterative development process

Responsive Asthma Care for Teens (ReACT): Development protocol for an adaptive mobile health intervention for adolescents with asthma

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Introduction Asthma is a leading cause of youth morbidity in the USA, affecting >8% of youth. Adherence to inhaled corticosteroids (ICS) can prevent asthma-related morbidity; however, the typical adolescent with asthma takes fewer than 50% of their prescribed doses. Adolescents are uniquely vulnerable to suboptimal asthma self-management due to still-developing executive functioning capabilities that may impede consistent self-regulation and weaken attempts to use problem solving to overcome barriers to ICS adherence. Methods and analysis The aims of this project are to improve adherence to ICS as an important step towards better self-management among adolescents aged 13–17 years diagnosed with asthma by merging the efficacious behaviour change strategies found in behavioural health interventions with scalable, adaptive mobile health (mHealth) technologies to create the Responsive Asthma Care for Teens programme (ReACT). ReACT intervention content will be developed through an iterative user-centred design process that includes conducting (1) one-on-one interviews with 20 teens with asthma; (2) crowdsourced feedback from a nationally representative panel of 100 adolescents with asthma and (3) an advisory board of youth with asthma, a paediatric pulmonologist and a behavioural health expert. In tandem, we will work with an existing technology vendor to programme ReACT algorithms to allow for tailored intervention delivery. We will conduct usability testing of an alpha version of ReACT with a sample of 20 target users to assess acceptability and usability of our mHealth intervention. Participants will complete a 4-week run-in period to monitor their adherence with all ReACT features turned off. Subsequently, participants will complete a 4-week intervention period with all ReACT features activated. The study started in October 2018 and is scheduled to conclude in late 2019. Ethics and dissemination Institutional review board approval was obtained at the University of Kansas and the University of Florida. We will submit study findings for presentation at national research conferences that are well attended by a mix of psychologists, allied health professionals and physicians. We will publish study findings in peer-reviewed journals read by members of the psychology, nursing and pulmonary communities

Australia\u27s health 1992 : the third biennial report of the Australian Institute of Health and Welfare

Australia\u27s Health is the most comprehensive and authoritative source of national information on health in Australia. Australia\u27s Health is published mid-year in even-numbered years and provides national statistics and related information that form a record of health status, service provision and expenditure in Australia

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

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

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

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 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

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

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