RESUMO
Myopia most often develops during school age, with the highest incidence in countries with intensive education systems. Interactions between genetic variants and educational exposure are hypothesized to confer susceptibility to myopia, but few such interactions have been identified. Here, we aimed to identify genetic variants that interact with education level to confer susceptibility to myopia. Two groups of unrelated participants of European ancestry from UK Biobank were studied. A 'Stage-I' sample of 88,334 participants whose refractive error (avMSE) was measured by autorefraction and a 'Stage-II' sample of 252,838 participants who self-reported their age-of-onset of spectacle wear (AOSW) but who did not undergo autorefraction. Genetic variants were prioritized via a 2-step screening process in the Stage-I sample: Step 1 was a genome-wide association study for avMSE; Step 2 was a variance heterogeneity analysis for avMSE. Genotype-by-education interaction tests were performed in the Stage-II sample, with University education coded as a binary exposure. On average, participants were 58 years-old and left full-time education when they were 18 years-old; 35% reported University level education. The 2-step screening strategy in the Stage-I sample prioritized 25 genetic variants (GWAS P < 1e-04; variance heterogeneity P < 5e-05). In the Stage-II sample, 19 of the 25 (76%) genetic variants demonstrated evidence of variance heterogeneity, suggesting the majority were true positives. Five genetic variants located near GJD2, RBFOX1, LAMA2, KCNQ5 and LRRC4C had evidence of a genotype-by-education interaction in the Stage-II sample (P < 0.002) and consistent evidence of a genotype-by-education interaction in the Stage-I sample. For all 5 variants, University-level education was associated with an increased effect of the risk allele. In this cohort, additional years of education were associated with an enhanced effect of genetic variants that have roles including axon guidance and the development of neuronal synapses and neural circuits.
Assuntos
Miopia , Erros de Refração , Humanos , Pessoa de Meia-Idade , Adolescente , Estudo de Associação Genômica Ampla , Miopia/genética , Escolaridade , Erros de Refração/genética , Alelos , Fatores de Processamento de RNA/genéticaRESUMO
Refractive errors are associated with a range of pathological conditions, such as myopic maculopathy and glaucoma, and are highly heritable. Studies of missense and putative loss of function (pLOF) variants identified via whole exome sequencing (WES) offer the prospect of directly implicating potentially causative disease genes. We performed a genome-wide association study for refractive error in 51 624 unrelated adults, of European ancestry, aged 40-69 years from the UK and genotyped using WES. After testing 29 179 pLOF and 495 263 missense variants, 1 pLOF and 18 missense variants in 14 distinct genomic regions were taken forward for fine-mapping analysis. This yielded 19 putative causal variants of which 18 had a posterior inclusion probability >0.5. Of the 19 putative causal variants, 12 were novel discoveries. Specific variants were associated with a more myopic refractive error, while others were associated with a more hyperopic refractive error. Association with age of onset of spectacle wear (AOSW) was examined in an independent validation sample (38 100 early AOSW cases and 74 243 controls). Of 11 novel variants that could be tested, 8 (73%) showed evidence of association with AOSW status. This work identified COL4A4 and ATM as novel candidate genes associated with refractive error. In addition, novel putative causal variants were identified in the genes RASGEF1, ARMS2, BMP4, SIX6, GSDMA, GNGT2, ZNF652 and CRX. Despite these successes, the study also highlighted the limitations of community-based WES studies compared with high myopia case-control WES studies.
Assuntos
Miopia , Erros de Refração , Adulto , Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Miopia/genética , Proteínas de Neoplasias/genética , Proteínas Citotóxicas Formadoras de Poros , Erros de Refração/genética , Sequenciamento do ExomaRESUMO
AIM: We examined children 10 to 11 years after grade 3 or 4 intraventricular haemorrhage and ventricular dilation (IVHVD) and investigated whether the grade of IVHVD affected their visual outcome. We explored associations between visual outcomes with cognitive outcomes and extra support at school. METHOD: The visual examinations were part of a 10-year follow-up study for children in a randomized trial. Testers followed a protocol and were masked to whether the child had experienced grade 3 or grade 4 IVHVD and all other data. RESULTS: Thirty-two children were tested: 24 were male and mean (standard deviation) age was 10 years 5 months (1 year 2 months); range 8 years 9 months to 12 years 9 months. All had at least one visual impairment. The median (interquartile range) number of impairments per child was six (six to nine) for children who experienced a grade 4 IVHVD compared with three (two to four) for children who experienced a grade 3 IVHVD (p = 0.003). Each extra vision impairment per child was associated with increased educational support at school, after adjustment for developmental age equivalence (odds ratio = 1.7 [95% confidence interval 1.1-2.6], p = 0.015). INTERPRETATION: Children who experience grade 3 or 4 IVHVD have a high level of visual morbidity at age 10 to 11 years. These children may have unmet visual needs and their outcomes might improve if these needs could be addressed. WHAT THIS PAPER ADDS: Parent-reported questionnaire responses underestimated directly assessed visual morbidity. Grade 4 intraventricular haemorrhage and ventricular dilatation (IVHVD) was followed by more vision impairments than grade 3 IVHVD. Simple tests of visual perceptual skills correlated with the neuropsychology tests. Children with supranuclear eye movement disorders were more likely to be receiving extra help at school. Each additional visual impairment increased the likelihood of extra educational support.
Assuntos
Hemorragia Cerebral , Transtornos da Visão , Criança , Feminino , Humanos , Masculino , Dilatação , Seguimentos , Estudos Prospectivos , Transtornos da Visão/etiologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. CONCLUSIONS: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN49407852.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Humanos , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Oligopeptídeos/uso terapêutico , Análise de Sobrevida , Reino UnidoRESUMO
Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunomodulação , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Quimioterapia de Consolidação , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Indução de Remissão , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Transplante de Células-Tronco , Transplante AutólogoRESUMO
AIM: To estimate how many children in mainstream primary schools have cerebral visual impairment (CVI)-related vision problems and to investigate whether some indicators might be useful as red flags, if they were associated with increased risk for these problems. METHOD: We conducted a survey of primary school children aged 5 to 11 years, using whether they were getting extra educational help and/or teacher- and parent-reported behaviour questionnaires to identify children at risk for CVI. These and a random 5% sample were assessed for CVI-related vision problems. We compared the usefulness of potential red flags using likelihood ratios. RESULTS: We received questionnaires on 2298 mainstream-educated children and examined 248 children (152 [61%] males, 96 females [39%]; mean age 8y 1mo, SD 20mo, range 5y 6mo-11y 8mo). We identified 78 out of 248 children (31.5% of those examined, 3.4% of the total sample), who had at least one CVI-related vision problem. The majority (88%) were identified by one or more red flag but none were strongly predictive. Fewer than one in five children with any CVI-related vision problem had reduced visual acuity. INTERPRETATION: Children with CVI-related vision problems were more prevalent than has been appreciated. Assessment of at-risk children may be useful so that opportunities to improve outcomes for children with CVI-related vision problems are not missed.
Assuntos
Transtornos da Visão/diagnóstico , Visão Ocular/fisiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Instituições Acadêmicas , Inquéritos e Questionários , Transtornos da Visão/fisiopatologia , Testes VisuaisRESUMO
Genome-wide association studies (GWAS) have revealed that the genetic contribution to certain complex diseases is well-described by Fisher's infinitesimal model in which a vast number of polymorphisms each confer a small effect. Under Fisher's model, variants have additive effects both across loci and within loci. However, the latter assumption is at odds with the common observation of dominant or recessive rare alleles responsible for monogenic disorders. Here, we searched for evidence of non-additive (dominant or recessive) effects for GWAS variants known to confer susceptibility to the highly heritable quantitative trait, refractive error. Of 146 GWAS variants examined in a discovery sample of 228,423 individuals whose refractive error phenotype was inferred from their age-of-onset of spectacle wear, only 8 had even nominal evidence (p < 0.05) of non-additive effects. In a replication sample of 73,577 individuals who underwent direct assessment of refractive error, 1 of these 8 variants had robust independent evidence of non-additive effects (rs7829127 within ZMAT4, p = 4.76E-05) while a further 2 had suggestive evidence (rs35337422 in RD3L, p = 7.21E-03 and rs12193446 in LAMA2, p = 2.57E-02). Accounting for non-additive effects had minimal impact on the accuracy of a polygenic risk score for refractive error (R2 = 6.04% vs. 6.01%). Our findings demonstrate that very few GWAS variants for refractive error show evidence of a departure from an additive mode of action and that accounting for non-additive risk variants offers little scope to improve the accuracy of polygenic risk scores for myopia.
Assuntos
Estudo de Associação Genômica Ampla , Miopia/genética , Característica Quantitativa Herdável , Erros de Refração/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Feminino , Genes Dominantes/genética , Predisposição Genética para Doença , Variação Genética/genética , Humanos , Laminina/genética , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Miopia/patologia , Polimorfismo de Nucleotídeo Único/genética , Erros de Refração/patologiaRESUMO
BACKGROUND: Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. INTERPRETATION: Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. FUNDING: Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK.
Assuntos
Lenalidomida/uso terapêutico , Quimioterapia de Manutenção , Mieloma Múltiplo/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Análise de Intenção de Tratamento , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Mieloma Múltiplo/cirurgia , Intervalo Livre de Progressão , Transplante Autólogo , Resultado do TratamentoRESUMO
Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Mutação , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Estrabismo/genética , Estrabismo/patologia , Tetraspaninas/genética , Adulto , Idoso , Animais , Estudos de Casos e Controles , Criança , Estudos de Coortes , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Família Multigênica , Proteínas Nucleares/metabolismo , Retina/metabolismo , Fatores de Risco , Estrabismo/metabolismo , Tetraspaninas/metabolismo , Acuidade VisualRESUMO
The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group.
Assuntos
Mieloma Múltiplo/genética , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/ultraestrutura , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 4/ultraestrutura , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Terapia Combinada , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Terapia de Salvação , Deleção de Sequência , Translocação Genética , Transplante AutólogoRESUMO
BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).
Assuntos
Deficiências do Desenvolvimento/epidemiologia , Mortalidade Infantil , Lactente Extremamente Prematuro/sangue , Oxigenoterapia/métodos , Oxigênio/sangue , Austrália , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Oximetria , Oxigenoterapia/efeitos adversos , Risco , Reino UnidoRESUMO
Lemurs are highly endangered mammals inhabiting the forests of Madagascar. In this study, we performed virus discovery on serum samples collected from 84 wild lemurs and identified viral sequence fragments from 4 novel viruses within the family Flaviviridae, including members of the genera Hepacivirus and Pegivirus. The sifaka hepacivirus (SifHV, two genotypes) and pegivirus (SifPgV, two genotypes) were discovered in the diademed sifaka (Propithecus diadema), while other pegiviral fragments were detected in samples from the indri (Indri indri, IndPgV) and the weasel sportive lemur (Lepilemur mustelinus, LepPgV). Although data are preliminary, each viral species appeared host species-specific and frequent infection was detected (18 of 84 individuals were positive for at least one virus). The complete coding sequence and partial 5' and 3' untranslated regions (UTRs) were obtained for SifHV and its genomic organization was consistent with that of other hepaciviruses, with one unique polyprotein and highly structured UTRs. Phylogenetic analyses showed the SifHV belonged to a clade that includes several viral species identified in rodents from Asia and North America, while SifPgV and IndPgV were more closely related to pegiviral species A and C, that include viruses found in humans as well as New- and Old-World monkeys. Our results support the current proposed model of virus-host co-divergence with frequent occurrence of cross-species transmission for these genera and highlight how the discovery of more members of the Flaviviridae can help clarify the ecology and evolutionary history of these viruses. Furthermore, this knowledge is important for conservation and captive management of lemurs.
Assuntos
Infecções por Flaviviridae/veterinária , Flaviviridae/isolamento & purificação , Lemur/virologia , Doenças dos Primatas/virologia , Animais , Flaviviridae/classificação , Flaviviridae/genética , Flaviviridae/fisiologia , Infecções por Flaviviridae/virologia , Variação Genética , Madagáscar , FilogeniaRESUMO
Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.
Assuntos
Fosfatase Ácida/genética , Astigmatismo/genética , Claudinas/genética , Doenças da Córnea/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Povo Asiático , Astigmatismo/diagnóstico , Astigmatismo/etnologia , Astigmatismo/patologia , Estudos de Coortes , Córnea/metabolismo , Córnea/patologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/etnologia , Doenças da Córnea/patologia , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Software , População BrancaRESUMO
PURPOSE: To investigate whether a genetic risk score (GRS) improved performance of predicting refractive error compared to knowing a child's number of myopic parents (NMP) alone. METHODS: This was a retrospective analysis of data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. Refractive error was assessed longitudinally between age 7-15 using non-cycloplegic autorefraction. Genetic variants (n = 149) associated with refractive error from a Consortium for Refractive Error And Myopia (CREAM) genome-wide association study were used to calculate a GRS for each child. Using refractive error at ages 7 and 15 years as the outcome variable, coefficient of determination (R2 ) values were calculated via linear regression models for the predictors: NMP, GRS and a combined model. RESULTS: Number of myopic parents was weakly predictive of refractive error in children aged 7 years, R2 = 3.0% (95% CI 1.8-4.1%, p < 0.0001) and aged 15 years, R2 = 4.8% (3.1-6.5%, p < 0.0001). The GRS was also weakly predictive; age 7 years, R2 = 1.1% (0.4-1.9%, p < 0.0001) and 15 years R2 = 2.6% (1.3-3.9%, p < 0.0001). Combining the 2 variables gave larger R2 values at age 7, R2 = 3.7% (2.5-5.0%, p < 0.0001) and 15, R2 = 7.0% (5.0-9.0%, p < 0.0001). The combined model improved performance at both ages (both p < 0.0001). CONCLUSION: A GRS improved the ability to detect children at risk of myopia independently of knowing the NMP. We speculate this may be because NMP captures information concerning environmental risk factors for myopia. Nevertheless, further gains are required to make such predictive tests worthwhile in the clinical environment.
Assuntos
Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Miopia/genética , Refração Ocular/fisiologia , Adolescente , Criança , Feminino , Seguimentos , Humanos , Incidência , Masculino , Miopia/diagnóstico , Miopia/epidemiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained ("missing heritability"). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10-4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10-3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10-3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10-4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10-4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10-4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10-4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10-4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the "missing" myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Hiperopia/genética , Miopia/genética , Proteínas do Tecido Nervoso/genética , Acuidade Visual/genética , Adolescente , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Criança , Chlorocebus aethiops , Interação Gene-Ambiente , Predisposição Genética para Doença , Variação Genética/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças dos Macacos/genética , Proteínas do Tecido Nervoso/metabolismo , Retina/fisiologia , Acuidade Visual/fisiologiaRESUMO
Coquerel's sifakas ( Propithecus coquereli) are diurnal, folivorous lemurs native to Madagascar and one of only two members of the genus Propithecus currently housed in human care settings outside of Madagascar. This species has a lifespan of approximately 30 yr but minimal information exists regarding morbidity and mortality in human care settings. In this retrospective study, medical records, postmortem exam, and autopsy reports from 56 animals housed at the Duke Lemur Center from 1990 to 2015 were evaluated. Mortality assessments included age, sex, time of year, histopathological findings, major organ system impacted, and etiological factors. Mortality was most prevalent among adults greater than 2 yr of age (42.9%) and neonates less than 7 days of age (30.4%). The top four morphological diagnoses accounted for 51.7% of all deaths and included stillbirths (19.6%), enteritis-colitis (12.5%), failure to thrive (10.7%), and systemic protozoal infections (8.9%). The two most commonly affected organ systems in animals over 7 days of age were multisystem disease (30.8%) and the gastrointestinal system (28.2%). Infections were the most common etiology with bacterial being the most prevalent followed by protozoal infections. The results provide insight into common causes of mortality of this species and can be used to guide management of this endangered primate and improve longevity in human care settings.
Assuntos
Animais de Zoológico , Mortalidade , Strepsirhini , Fatores Etários , Animais , Espécies em Perigo de Extinção , North Carolina/epidemiologia , Estudos RetrospectivosRESUMO
Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged <10 years; 5,000 aged 10-25 years; and 16,274 aged >25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) were associated with AL/CR. In the age group 10-25 years, four loci (BMP2, KCNQ5, A2BP1, CACNA1D) were associated; and in adults 20 loci were associated. Association with GRS increased with age; ß = 0.0016 per risk allele (P = 2 × 10-8 ) in <10 years, 0.0033 (P = 5 × 10-15 ) in 10- to 25-year-olds, and 0.0048 (P = 1 × 10-72 ) in adults. Genes with strongest effects (LAMA2, GJD2) had an early effect that increased with age. Our results provide insights on the age span during which myopia genes exert their effect. These insights form the basis for understanding the mechanisms underlying high and pathological myopia.
Assuntos
Conexinas/genética , Estudo de Associação Genômica Ampla , Laminina/genética , Miopia/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Alelos , Biometria , Criança , Feminino , Loci Gênicos , Genótipo , Humanos , Masculino , Fatores de Risco , Adulto Jovem , Proteína delta-2 de Junções ComunicantesRESUMO
PURPOSE: This study presents a two-degree customized animated stimulus developed to evaluate smooth pursuit in children and investigates the effect of its predetermined characteristics (stimulus type and size) in an adult population. Then, the animated stimulus is used to evaluate the impact of different pursuit motion paradigms in children. METHODS: To study the effect of animating a stimulus, eye movement recordings were obtained from 20 young adults while the customized animated stimulus and a standard dot stimulus were presented moving horizontally at a constant velocity. To study the effect of using a larger stimulus size, eye movement recordings were obtained from 10 young adults while presenting a standard dot stimulus of different size (1° and 2°) moving horizontally at a constant velocity. Finally, eye movement recordings were obtained from 12 children while the 2° customized animated stimulus was presented after three different smooth pursuit motion paradigms. Performance parameters, including gains and number of saccades, were calculated for each stimulus condition. RESULTS: The animated stimulus produced in young adults significantly higher velocity gain (mean: 0.93; 95% CI: 0.90-0.96; P = .014), position gain (0.93; 0.85-1; P = .025), proportion of smooth pursuit (0.94; 0.91-0.96, P = .002), and fewer saccades (5.30; 3.64-6.96, P = .008) than a standard dot (velocity gain: 0.87; 0.82-0.92; position gain: 0.82; 0.72-0.92; proportion smooth pursuit: 0.87; 0.83-0.90; number of saccades: 7.75; 5.30-10.46). In contrast, changing the size of a standard dot stimulus from 1° to 2° did not have an effect on smooth pursuit in young adults (P > .05). Finally, smooth pursuit performance did not significantly differ in children for the different motion paradigms when using the animated stimulus (P > .05). CONCLUSIONS: Attention-grabbing and more dynamic stimuli, such as the developed animated stimulus, might potentially be useful for eye movement research. Finally, with such stimuli, children perform equally well irrespective of the motion paradigm used.
Assuntos
Movimentos Oculares/fisiologia , Percepção de Movimento/fisiologia , Acompanhamento Ocular Uniforme/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Generalização do Estímulo , Humanos , Masculino , Movimentos Sacádicos , Adulto JovemRESUMO
PURPOSE: Previous studies have reported that eye movements differ between good/average and poor readers. However, these studies have been limited to investigating eye movements during reading related tasks, and thus, the differences found could arise from deficits in higher cognitive processes involved in reading rather than oculomotor performance. The purpose of the study is to determine the extent to which eye movements in children with delayed reading skills are different to those obtained from children with good/average reading skills in non-reading related tasks. METHODS: After a screening optometric assessment, eye movement recordings were obtained from 120 children without delayed reading skills and 43 children with delayed reading skills (4 to 11 years) using a Tobii TX300 eye tracker. Cartoon characters were presented horizontally from -20° to +20° in steps of 5° to study saccades. An animated stimulus in the centre of the screen was presented for 8 seconds to study fixation stability. Saccadic main sequences, and the number and amplitude of the saccades during fixation were obtained for each participant. Children with delayed reading skills (n = 43) were unmasked after data collection was completed. Medians and quartiles were calculated for each eye movement parameter for children without (n = 120) and with (n = 43) delayed reading skills. RESULTS: Independent t-tests with Bonferroni correction showed no significant differences in any of the saccadic main sequence parameters (Slope, Intercept, A, n and Q ratio) between children without and with delayed reading (p > 0.01). Similarly, no significant differences were found in the number of saccades and their amplitude during the fixation task between the two groups (p > 0.05). Further, none of the gross optometric parameters assessed (visual acuity, refractive error, ocular alignment, convergence, stereopsis and accommodation accuracy) were found to be associated with delayed reading skills (p > 0.05). CONCLUSIONS: Eye movements in children with delayed reading skills are quantitatively similar to those found in children without delayed reading skills. These findings suggest that, in these children, delayed reading skills are not associated with eye movements and further question interventions targeted at improving eye movement control.