Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared ...etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are
,
,
,
,
,
,
,
,
,
, and long non-coding RNAs:
and
. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
A variety of surgical procedures exist for repair of both traumatic and degenerative osseous and soft-tissue pathologic conditions involving the foot and ankle. It is necessary for the radiologist to ...be familiar with these surgical procedures, so as to assess structural integrity, evaluate for complicating features, and avoid diagnostic pitfalls. Adequate interpretation of postoperative changes often requires access to surgical documentation to evaluate not only the surgery itself but the expected timeline for resolution of normal postoperative changes versus progressive disease. Appropriate use of surgical language in radiology reports is another important skill set to hone and is instrumental in providing a high-quality report to the referring surgeons. The pathophysiology of a myriad of surgical complaints, beginning from the Achilles tendon and concluding at the plantar plate, are presented, as are their common appearances at computed tomography and magnetic resonance imaging. Commonly encountered entities include Achilles tendon tear, spastic equinus, nonspastic equinus, talar dome osteochondral defect, tarsal tunnel syndrome, plantar fasciitis, pes planovalgus, pes cavovarus, peroneal tendinosis, lateral ligament complex pathology, Morton neuroma, plantar plate tear, and metatarsophalangeal joint instability. Computer-generated three-dimensional models are included with many of the procedures to provide a more global view of the surgical anatomy. Correlation with intraoperative photographs is made when available. When appropriate, discussion of postoperative complications, including entities such as infection and failure of graft integration, is presented, although a comprehensive review of postoperative complications is beyond the scope of this article. Notably absent from the current review are some common foot and ankle procedures including hallux valgus and hammertoe corrections, as these are more often evaluated radiographically than with cross-sectional imaging.
RSNA, 2016.
Abstract
Background
Reduction in detection of asymptomatic carriage of Haemophilus influenzae type b (Hib) can be used to assess vaccine impact. In Nepal, routine vaccination against Hib in children ...at 6, 10, and 14 weeks of age was introduced in 2009. Before vaccine introduction, Hib carriage was estimated at 5.0% among children aged <13 years in Nepal, with higher rates among children under 5. Large-scale evaluation of Hib carriage in children has not been investigated since the introduction of the pentavalent diphtheria-tetanus-pertussis/Hib/hepatitis B (DTP-Hib-HepB) vaccine in Nepal.
Methods
A total of 666 oropharyngeal swabs were collected between August and December 2018 from healthy children between 6 months and 5 years of age attending the vaccination clinic at Patan Hospital, Kathmandu, Nepal. Of these 666 swabs, 528 (79.3%) were tested for Hib by culture. Demographic and vaccination data were collected.
Results
Among 528 swabs tested for Hib, 100% came from fully vaccinated children. No swabs were positive for Hib (95% confidence interval, .0–.7). The absence of Hib in 2018 suggests vaccine-induced protection against Hib carriage 9 years after vaccine introduction.
Conclusions
Following 3 doses of pentavalent DTP-Hib-HepB vaccine, Hib carriage in children under the age of 5 years in Nepal is no longer common. Ongoing high coverage with Hib vaccine in early childhood is expected to maintain protection against Hib disease in Nepal.
Informed Decision Making Holmes-Rovner, Margaret; Montgomery, Jeffrey S.; Rovner, David R. ...
Medical decision making,
11/2015, Letnik:
35, Številka:
8
Journal Article
Recenzirano
Introduction. Little is known about how physicians present diagnosis and treatment planning in routine practice in preference-sensitive treatment decisions. We evaluated completeness and quality of ...informed decision making in localized prostate cancer post biopsy encounters. Methods. We analyzed audio-recorded office visits of 252 men with presumed localized prostate cancer (Gleason 6 and Gleason 7 scores) who were seeing 45 physicians at 4 Veterans Affairs Medical Centers. Data were collected between September 2008 and May 2012 in a trial of 2 decision aids (DAs). Braddock’s previously validated Informed Decision Making (IDM) system was used to measure quality. Latent variable models for ordinal data examined the relationship of IDM score to treatment received. Results. Mean IDM score showed modest quality (7.61±2.45 out of 18) and high variability. Treatment choice and risks and benefits were discussed in approximately 95% of encounters. However, in more than one-third of encounters, physicians provided a partial set of treatment options and omitted surveillance as a choice. Informing quality was greater in patients treated with surveillance (β = 1.1, p = .04). Gleason score (7 vs 6) and lower age were often cited as reasons to exclude surveillance. Patient preferences were elicited in the majority of cases, but not used to guide treatment planning. Encounter time was modestly correlated with IDM score (r = 0.237, p = .01). DA type was not associated with IDM score. Discussion. Physicians informed patients of options and risks and benefits, but infrequently engaged patients in core shared decision-making processes. Despite patients having received DAs, physicians rarely provided an opportunity for preference-driven decision making. More attention to the underused patient decision-making and engagement elements could result in improved shared decision making.
The use and utility of targeted gene panels for diagnosing the type of Charcot‐Marie‐Tooth have grown rapidly because commercial gene panels that contain most of the relevant genes are available and ...affordable for many patients. We used a targeted gene panel to analyze 175 patients who had an unexplained axonal polyneuropathy affecting large myelinated axons, 86 of whom reported a family history of neuropathy, and 89 of whom did not. In patients reporting a family history, the panel identified a pathogenic variant causing the neuropathy in six cases (7%); in patients not reporting a family history, the gene panel identified pathogenic variants causing neuropathy in two patients (2%). Interpretation in a tertiary referral setting, current gene panels identify the genetic cause of neuropathy in a small minority of patients who have an unexplained axonal neuropathy, even in those reporting a family history.
We have developed a 4D computer-assisted reconstruction and motion analysis system, J3D-DIAS 4.1, and applied it to the reconstruction and motion analysis of tumorigenic cells in a 3D matrix. The ...system is unique in that it is fast, high-resolution, acquires optical sections using DIC microscopy (hence there is no associated photoxicity), and is capable of long-term 4D reconstruction. Specifically, a z-series at 5 μm increments can be acquired in less than a minute on tissue samples embedded in a 1.5 mm thick 3D Matrigel matrix. Reconstruction can be repeated at intervals as short as every minute and continued for 30 days or longer. Images are converted to mathematical representations from which quantitative parameters can be derived. Application of this system to cancer cells from established lines and fresh tumor tissue has revealed unique behaviors and cell types not present in non-tumorigenic lines. We report here that cells from tumorigenic lines and tumors undergo rapid coalescence in 3D, mediated by specific cell types that we have named "facilitators" and "probes." A third cell type, the "dervish", is capable of rapid movement through the gel and does not adhere to it. These cell types have never before been described. Our data suggest that tumorigenesis in vitro is a developmental process involving coalescence facilitated by specialized cells that culminates in large hollow spheres with complex architecture. The unique effects of select monoclonal antibodies on these processes demonstrate the usefulness of the model for analyzing the mechanisms of anti-cancer drugs.
ABSTRACT
We report de novo occurrence of the 7p11.2 folate‐sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG‐repeat expansion mutation (∼450 repeats) in a ...5′ intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband‐derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG‐repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.
Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally ...exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.
We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD.
We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal
= 1.85 × 10
; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (
), synapse formation (
and
), and postsynaptic scaffolding (
and
), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified
as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in
.
Our findings suggest that rare CNVs may contribute to the etiology of OCD.
The resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B ...amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies.
HCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan-Meier analysis.
Faldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (<1%) at baseline. Virologic response to faldaprevir/deleobuvir/ribavirin was not compromised by common baseline NS3 polymorphisms (e.g. Q80K in 17.5% of GT-1a) or by NS5B A421V, present in 20% of GT-1a. In GT-1b, alanine at NS5B codon 499 (present in 15% of baseline sequences) was associated with reduced response. Treatment-emergent RAVs consolidated previous findings: NS3 R155 and D168 were key faldaprevir RAVs; NS5B A421 and P495 were key deleobuvir RAVs. Among on-treatment virologic breakthroughs, RAVs emerged in both NS3 and NS5B (>90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months).
Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen.
A 4D high-resolution computer-assisted reconstruction and motion analysis system has been developed and applied to the long-term (14-30 days) analysis of cancer cells migrating and aggregating within ...a 3D matrix. 4D tumorigenesis models more closely approximate the tumor microenvironment than 2D substrates and, therefore, are improved tools for elucidating the interactions within the tumor microenvironment that promote growth and metastasis. The model we describe here can be used to analyze the growth of tumor cells, aggregate coalescence, directed cell motility and chemotaxis, matrix degradation, the effects of anticancer drugs, and the behavior of immune and endothelial cells mixed with cancer cells. The information given in this chapter is also intended to acquaint the reader with computer-assisted methods and algorithms that can be used for high-resolution 3D reconstruction and quantitative motion analysis.
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