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1.
DEN Open ; 4(1): e317, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38226397

RESUMO

Introduction: Our simulation-based mastery learning (SBML) curriculum, delivered in person, has been shown to successfully train novices in structured esophagogastroduodenoscopy (EGD). SBML with virtual coaching (VC) has the potential to improve the effectiveness and efficiency of endoscopy training and expand access to trainees from around the world. We share our observations conducting an EGD training course using SBML with VC. Methods: We conducted a 1-week virtual SBML course for novice trainees across seven academic centers in the USA and Asia. The cognitive component was delivered using an online learning platform. For technical skills, a virtual coach supervised hands-on training and local coaches provided assistance when needed. At the end of training, an independent rater assessed simulation-based performance using a validated assessment tool. We assessed the clinical performance of 30 EGDs using the ASGE Assessment of Competency in Endoscopy tool. We compared the trainees' scores to our cohort trained using in-person SBML training using non-inferiority t-tests. Results: We enrolled 21 novice trainees (mean age: 30.8 ± 3.6 years; female: 52%). For tip deflection, the trainees reached the minimum passing standard after 31 ± 29 runs and mastery after 52 ± 37 runs. For structured EGD, the average score for the overall exam was 4.6 ± 0.6, similar to the in-person cohort (4.7 ± 0.5, p = 0.49). The knowledge-based assessment was also comparable (virtual coaching: 81.9 ± 0.1; direct coaching: 78.3 ± 0.1; p = 0.385). Over time, our novice trainees reached clinical competence at a similar rate to our historical in-person control. Conclusions: VC appears feasible and effective for training novice gastroenterology trainees. VC allowed us to scale our SBML course, expand access to experts, and administer SBML simultaneously across different sites at the highest standards.

2.
Eur J Investig Health Psychol Educ ; 13(9): 1738-1750, 2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37754465

RESUMO

BACKGROUND: The World Health Organization (WHO) warns that vaccine hesitancy is an ongoing major global health threat. While vaccination against severe acute respiratory syndrome coronavirus (SARS-CoV-2) proves to be an effective strategy in protecting against the disease, vaccine hesitancy represents a major barrier to stopping the spread of the virus. Willingness for vaccination can be influenced by several factors, including education level and health literacy. Although several studies demonstrate the value of video educational programs in improving coronavirus disease 2019 (COVID-19) vaccine knowledge and acceptance, no studies to date have evaluated if race, gender, and other demographic factors impact the influence of an educational video on COVID-19 vaccine knowledge and hesitancy among university students in the United States (U.S.). AIMS: This study was conducted to determine the impact of an educational video on U.S. university undergraduate students' COVID-19 vaccine perception and acceptance. It also aims to evaluate whether demographic factors affect the influence of the video. METHODS: An online survey was used to measure perceived understanding and acceptance of COVID-19 vaccines before and after viewing a video regarding the effectiveness and safety of COVID-19 vaccinations. The impact of demographic factors on the Video Influence Score was analyzed. KEY RESULTS: After viewing the video, respondents' (n = 285) perceived awareness and acceptance of COVID-19 vaccines significantly increased (p < 0.05). In addition, gender, political party affiliation, age, study major, and influenza vaccination history did not significantly impact the Video Influence Score (p > 0.05). However, African American/Black respondents (3.81 ± 4.24) were significantly more influenced by the video compared to respondents of other races (p < 0.05), such as White/Caucasian (1.91 ± 3.75), Hispanic/Latino (0.17 ± 3.67), Asian (0.29 ± 1.53), and Indigenous American (0.64 ± 2.52). CONCLUSIONS: This study suggests the potential impact of an educational video on COVID-19 vaccine perception and acceptance among university students. Despite limitations such as a modest survey response rate, this study provides valuable insight concerning the influential factors affecting vaccine acceptance in diverse student populations. Future studies are warranted to explore how student response to vaccine educational videos may vary depending on students' racial and cultural backgrounds. IMPLICATIONS: A targeted educational video to promote vaccine acceptance is a valuable tool for public health campaigns to combat vaccine hesitancy. The study also highlights the importance of tailoring interventions to specific demographic groups such as considering racial factors to maximize the impact of educational interventions on vaccine attitudes.

3.
Am J Gastroenterol ; 118(10): 1880-1887, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37307537

RESUMO

INTRODUCTION: Cold snare polypectomy (CSP) is strongly recommended as the optimal technique for the complete removal of small polyps. Though significant variability in polypectomy technique and quality has been established, the learning curve and impact of targeted training on CSP are unknown. Video feedback has shown promise as an effective pedagogy to improve performance among surgical trainees. We aimed to compare CSP performance between trainees who received video-based feedback and those who received conventional apprentice-based concurrent feedback. We hypothesized that video-based feedback would accelerate competence. METHODS: We conducted a single-blinded, randomized controlled trial on competence for CSP of polyps <1 cm, comparing video-based feedback with conventional feedback. We randomly assigned deidentified consecutively recorded CSP videos to blinded raters to assess using the CSP Assessment Tool. We shared cumulative sum learning curves every 25 CSP with each trainee. The video feedback trainees also received biweekly individualized terminal feedback. Control trainees received conventional feedback during colonoscopy. The primary outcome was CSP competence. We also assessed competence across domains and change over polypectomy volume. RESULTS: We enrolled and randomized 22 trainees, 12 to video-based feedback and 10 to conventional feedback, and evaluated 2,339 CSP. The learning curve was long; 2 trainees (16.7%) in the video feedback achieved competence, after a mean of 135 polyps, and no one in the control ( P = 0.481) achieved competence. Overall and in all steps of CSP, a higher percentage of the video feedback group met competence, increasing 3% every 20 CSP ( P = 0.0004). DISCUSSION: Video feedback aided trainees to competence in CSP. However, the learning curve was long. Our findings strongly suggest that current training methods are not sufficient to support trainees to competency by the completion of their fellowship programs. The impact of new training methods, such as simulation-based mastery learning, should be assessed to determine whether such methods can result in achievement of competence at a faster rate; ClinicalTrials.gov : NCT03115008.


Assuntos
Pólipos do Colo , Colonoscopia , Humanos , Colonoscopia/métodos , Pólipos do Colo/cirurgia , Microcirurgia
4.
J Neurophysiol ; 129(6): 1468-1481, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37198134

RESUMO

Calyx terminals make afferent synapses with type I hair cells in vestibular epithelia and express diverse ionic conductances that influence action potential generation and discharge regularity in vestibular afferent neurons. Here we investigated the expression of hyperpolarization-activated current (Ih) in calyx terminals in central and peripheral zones of mature gerbil crista slices, using whole cell patch-clamp recordings. Slowly activating Ih was present in >80% calyces tested in both zones. Peak Ih and half-activation voltages were not significantly different; however, Ih activated with a faster time course in peripheral compared with central zone calyces. Calyx Ih in both zones was blocked by 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD7288; 100 µM), and the resting membrane potential became more hyperpolarized. In the presence of dibutyryl-cAMP (dB-cAMP), peak Ih was increased, activation kinetics became faster, and the voltage of half-activation was more depolarized compared with control calyces. In current clamp, calyces from both zones showed three different categories of firing: spontaneous firing, phasic firing where a single action potential was evoked after a hyperpolarizing pulse, or a single evoked action potential followed by membrane potential oscillations. In the absence of Ih, the latency to peak of the action potential increased; Ih produces a small depolarizing current that facilitates firing by driving the membrane potential closer to threshold. Immunostaining showed the expression of HCN2 subunits in calyx terminals. We conclude that Ih is found in calyx terminals across the crista and could influence conventional and novel forms of synaptic transmission at the type I hair cell-calyx synapse.NEW & NOTEWORTHY Calyx afferent terminals make synapses with vestibular hair cells and express diverse conductances that impact action potential firing in vestibular primary afferents. Conventional and nonconventional synaptic transmission modes are influenced by hyperpolarization-activated current (Ih), but regional differences were previously unexplored. We show that Ih is present in both central and peripheral calyces of the mammalian crista. Ih produces a small depolarizing resting current that facilitates firing by driving the membrane potential closer to threshold.


Assuntos
Células Ciliadas Vestibulares , Vestíbulo do Labirinto , Animais , Células Ciliadas Vestibulares/fisiologia , Neurônios Aferentes , Potenciais de Ação/fisiologia , Potenciais da Membrana , Mamíferos
5.
Gastrointest Endosc ; 97(5): 934-940, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36649745

RESUMO

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) are at risk of developing dysplasia. According to the Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations, "After complete removal of endoscopically resectable nonpolypoid dysplastic lesions, surveillance colonoscopy is suggested rather than colectomy." We sought to add data to the literature and hypothesized that the endoscopic resection of nonpolypoid colorectal dysplasia (NP-CRD) is safe and effective. METHODS: We conducted a retrospective study of a large cohort of patients with IBD at 2 medical centers who underwent colonoscopy between 2007 and 2018. Patients with at least 1 nonpolypoid lesion ≥10 mm were identified. We measured the feasibility of endoscopic resection, incidence of local recurrence, incidence of cancer, need for surgery, and frequency of adverse events. RESULTS: We studied 326 patients who underwent a mean ± standard deviation of 3.6 ± 3.0 (range, 1-16) colonoscopies during a total follow-up of 1208 patient-years. In 36 patients, 161 lesions ≥10 mm were identified, 63 of which were nonpolypoid (mean size, 17.8 ± 8.9 mm; range, 10-45 mm) (prevalence, 7.7%). The majority of nonpolypoid lesions (96.8% [61 of 63]) were managed endoscopically. Four lesions (mean index lesion size, 32.5 ±11.0 mm) had small local recurrences that were successfully retreated with endoscopy. There were no severe adverse events related to IBD or colorectal cancer observed in the follow-up period. CONCLUSIONS: In this IBD cohort, surveillance colonoscopy rather than colectomy was found to be safe and effective in patients with NP-CRD after undergoing endoscopic resection. After complete removal of endoscopically resectable NP-CRD, surveillance colonoscopy should be considered a safe and effective first-line strategy rather than colectomy.


Assuntos
Carcinoma in Situ , Neoplasias Colorretais , Doenças Inflamatórias Intestinais , Humanos , Estudos Retrospectivos , Colonoscopia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Colectomia , Hiperplasia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/cirurgia , Doenças Inflamatórias Intestinais/patologia , Carcinoma in Situ/cirurgia
6.
Community Dent Oral Epidemiol ; 51(3): 399-407, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-35607884

RESUMO

OBJECTIVES: This study evaluated which predisposing and enabling factors prospectively predicted dental utilization over 6 months among people with serious mental illness. METHODS: A sample of individuals with serious mental illness (86.3% African American; 97.4% with public health insurance) was recruited from community mental health centres in Detroit, Michigan, and responded to questionnaires at baseline and at least one follow-up visit at 3 or 6 months (N = 190). Baseline assessments included demographic and clinical information, established measures of health literacy, health insurance literacy, stigma related to mental illness, experiences of racial discrimination and medical mistrust. Insurance coverage for dental care and the availability of dental services at the participants' mental health centres was recorded. At follow-up visits, participants reported healthcare utilization, including dental and primary care, since baseline. RESULTS: Three factors emerged as meaningful predictors of having a dental visit in bivariate and multivariate analyses: more medical comorbidities and dental care co-located with mental health care predicted increased likelihood of a dental visit, whereas having experienced racial discrimination in a medical setting predicted lower odds of having a dental visit in the follow-up period. Co-location of dental care with mental health care was the strongest predictor of having a dental visit. CONCLUSIONS: Co-locating dental care with mental health care may increase dental utilization among people with serious mental illness, possibly by mitigating known barriers to dental care for this population. Among African Americans, the co-location of dental care with mental health care may also attenuate the negative effect of prior racial discrimination in a medical setting on dental utilization.


Assuntos
Transtornos Mentais , Confiança , Humanos , Michigan/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde , Transtornos Mentais/complicações , Transtornos Mentais/epidemiologia , Causalidade
7.
Clin Gastroenterol Hepatol ; 19(9): 1883-1889.e1, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33618027

RESUMO

BACKGROUND & AIMS: Adenoma detection rate (ADR) is a key measure of colonoscopy quality. However, efficient measurement of ADR can be challenging because many colonoscopies are performed for non-screening purposes. Measuring ADR without being restricted to screening indication may likely facilitate more widespread implementation of quality monitoring. We hypothesized that the ADR for all colonoscopies, irrespective of the indication, would be equivalent to the ADR for screening colonoscopies. METHODS: We reviewed consecutive colonoscopies at two Veterans Affairs centers performed by 21 endoscopists over 6 months in 2015. We calculated the ADR for screening exams, non-screening (surveillance and diagnostic) exams, and all exams (irrespective of indication), correcting for within-endoscopist correlation. We then performed simulation modeling to calculate the ADRs under 16 hypothetical scenarios of various indication distributions. We simulated 100,000 trials with 3,000 participants, randomly assigned indication (screening, surveillance, diagnostic, and FIT+) from a multinomial distribution, randomly drew adenoma using the observed ADRs per indication, and calculated 95% confidence intervals of the mean differences in ADR of screening and non-screening indications. RESULTS: Among 2628 colonoscopies performed by 21 gastroenterologists, the indication was screening in 28.9%, surveillance in 48.2% and diagnostic in 22.9%. There was no significant difference in the ADR, 50% (95%CI: 45-56%) for all colonoscopies vs 49% (95%CI: 43-56%) for screening exams (p=.55). ADRs were 56% for surveillance and 38% for diagnostic exams. In our simulation modeling, only one out of 16 scenarios (screening 10%, surveillance 70%, diagnostic 10% and FIT+ 10%) resulted in a significant difference between the calculated ADRs for screening and non-screening indications. CONCLUSIONS: In our study, the overall ADR computed from all colonoscopies was not significantly different than the conventional ADR based on screening colonoscopies. Assessing ADR for colonoscopy irrespective of indication may be adequate for quality monitoring, and could facilitate the implementation of quality measurement and reporting. Future prospective studies should evaluate the validity of using overall ADR for quality reporting in other jurisdictions before adopting this method in clinical practice.


Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Humanos , Programas de Rastreamento , Estudos Prospectivos
8.
Endoscopy ; 52(12): 1122-1126, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32650345

RESUMO

BACKGROUND: Although validated colonoscopy assessment tools exist, they do not measure efficiency. This study aimed to assess content validity of polypectomy efficiency (PE) and neoplastic polypectomy efficiency (NPE) as colonoscopy efficiency indices. METHODS: Data from a randomized controlled trial evaluating polypectomy among gastroenterology trainees were utilized. PE and NPE were defined as number of polyps (or neoplastic polyps) removed/withdrawal time × 100. Content validity was assessed by determining the association between efficiency indices and polypectomy times. RESULTS: 20 trainees performed 601 colonoscopies. There was a strong association between PE/NPE and actual polypectomy times: as polypectomy time increased by 1 minute, the PE decreased by 0.48 (P = 0.001) and NPE decreased by 0.24 (P = 0.03). CONCLUSIONS: The study proposed and provided content validity for PE and NPE as colonoscopy efficiency indices.


Assuntos
Competência Clínica , Pólipos do Colo , Gastroenterologia , Benchmarking , Pólipos do Colo/cirurgia , Colonoscopia , Humanos
11.
Gastrointest Endosc Clin N Am ; 30(1): 99-106, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739970

RESUMO

Training practicing physicians to adopt new technology may be difficult because most endoscopy training is given during fellowship training. As such, the adoption of new technology in gastroenterology is typically slow. We designed our course to train our cohort of practicing physicians using flipped learning, a pedagogical approach in which instructional cognitive content is delivered to the individual instead of the group, usually through online platforms and outside of the classroom. We describe our methods and results of the training courses on the techniques of clipping over the scope for gastrointestinal bleeding and endoscopic balloon dilation.


Assuntos
Educação Médica Continuada/métodos , Endoscopia Gastrointestinal/educação , Gastroenterologia/educação , Instrumentos Cirúrgicos , Ensino , Endoscopia Gastrointestinal/instrumentação , Desenho de Equipamento , Humanos
12.
Gastrointest Endosc Clin N Am ; 29(4): 613-628, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445686

RESUMO

Current endoscopy training methodology does not meet the learning traits, skills, and needs of the newer generation of gastroenterologists. This article provides information on assessment of the malignant potential of colorectal neoplasms. It takes a modern approach on the topic and integrates relevant information that aligns with the thinking process. The theory of thinking fast (reflex) and slow (rational) is used. By doing so, it is hoped that the learning process can be expedited and practiced immediately. The focus is on preresection assessment of nonpolypoid colorectal neoplasms. Assessment of polypoid, sessile-serrated adenoma/polyp, or inflammatory bowel disease dysplasia is briefly discussed.


Assuntos
Adenocarcinoma/patologia , Competência Clínica , Colonoscopia/métodos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Mucosa Intestinal/patologia , Adenocarcinoma/cirurgia , Pólipos do Colo/patologia , Neoplasias Colorretais/diagnóstico , Feminino , Gastroenterologia/educação , Humanos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Segurança do Paciente
15.
Regeneration (Oxf) ; 2(4): 182-201, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27499874

RESUMO

Urodele amphibians are unique among adult vertebrates in their ability to regenerate complex body structures after traumatic injury. In salamander regeneration, the cells maintain a memory of their original position and use this positional information to recreate the missing pattern. We used an in vivo gain-of-function assay to determine whether components of the extracellular matrix (ECM) have positional information required to induce formation of new limb pattern during regeneration. We discovered that salamander limb ECM has a position-specific ability to either inhibit regeneration or induce de novo limb structure, and that this difference is dependent on heparan sulfates that are associated with differential expression of heparan sulfate sulfotransferases. We also discovered that an artificial ECM containing only heparan sulfate was sufficient to induce de novo limb pattern in salamander limb regeneration. Finally, ECM from mouse limbs is capable of inducing limb pattern in axolotl blastemas in a position-specific, developmental-stage-specific, and heparan sulfate-dependent manner. This study demonstrates a mechanism for positional information in regeneration and establishes a crucial functional link between salamander regeneration and mammals.

16.
Case Rep Neurol Med ; 2014: 257373, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24716017

RESUMO

This report describes a case of bilateral greater occipital neuralgia treated with cooled radiofrequency ablation. The case is considered in relation to a review of greater occipital neuralgia, continuous thermal and pulsed radiofrequency ablation, and current medical literature on cooled radiofrequency ablation. In this case, a 35-year-old female with a 2.5-year history of chronic suboccipital bilateral headaches, described as constant, burning, and pulsating pain that started at the suboccipital region and radiated into her vertex. She was diagnosed with bilateral greater occipital neuralgia. She underwent cooled radiofrequency ablation of bilateral greater occipital nerves with minimal side effects and 75% pain reduction. Cooled radiofrequency ablation of the greater occipital nerve in challenging cases is an alternative to pulsed and continuous RFA to alleviate pain with less side effects and potential for long-term efficacy.

17.
Am J Hum Genet ; 92(2): 221-37, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23375656

RESUMO

Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Duplicações Segmentares Genômicas/genética , Estudos de Casos e Controles , Criança , Deleção Cromossômica , Duplicação Cromossômica/genética , Éxons/genética , Rearranjo Gênico/genética , Genoma Humano/genética , Humanos , Fenótipo
18.
Am J Med Genet A ; 158A(6): 1279-84, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22529060

RESUMO

Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.


Assuntos
Variações do Número de Cópias de DNA , Defeitos dos Septos Cardíacos/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 20 , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 3 , Síndrome de Down/genética , Humanos , Masculino
19.
PLoS Genet ; 7(11): e1002334, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22102821

RESUMO

While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58 × 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 × 10(-18), odds ratio = 14.45), or controls (p = 2.75 × 10(-17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 × 10(-6), odds ratio = 6) or ID (16%, p = 3.55 × 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).


Assuntos
Transtorno Autístico/genética , Variações do Número de Cópias de DNA/genética , Dislexia/genética , Deficiência Intelectual/genética , Neurogênese/imunologia , Adolescente , Transtorno Autístico/diagnóstico , Transtorno Autístico/patologia , Criança , Hibridização Genômica Comparativa/métodos , Proteínas do Citoesqueleto , Dislexia/diagnóstico , Dislexia/patologia , Endopeptidases/genética , Feminino , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Neurogênese/genética , Fenótipo , Proteínas/genética , Proteínas Repressoras/genética , Deleção de Sequência/genética , Fatores de Transcrição
20.
Nat Genet ; 43(9): 838-46, 2011 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-21841781

RESUMO

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.


Assuntos
Mapeamento Cromossômico , Anormalidades Congênitas/genética , Deficiências do Desenvolvimento/genética , Dosagem de Genes , Variação Genética , Adulto , Pré-Escolar , Humanos
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